AMSA-Indonesia International Competition Archive 2019/2020 by AMSA-Indonesia

AMINO | AMSA INTERNATIONAL COMPETITION 19/20

FOREWORD

Christina Wunardi Secretary of Academic AMSA-Indonesia 2019/2020

AMSA International Competition Archive is an archive of all academic works submitted by AMSA-Indonesia to AMSA International’s competitions. In this edition, this archive will consist of World AIDS Day Competition 2019 and World Immunization Week Competition 2020. This archive aims to provide thorough overview of AMSA International’s competitions to all member of AMSA-Indonesia. All qualified works that was submitted to AMSA International’s competition 2019/2020 have been compiled and are expected to draw forth inspiration and motivation in creating academic works in field of Scientific Paper, Public Poser, and Online Social Campaign. I would like to thank and express my sincere appreciation to all the participants of World AIDS Day Competition 2019 and World Immunization Week Competition 2020, the Academic Team, Executive Boards of AMSA-Indonesia 2019/2020, and other parties that have contributed to the creation of this archive. Hopefully, the release of AMSA International Competition Archive can enhance and intensify the academic enthusiasm and interest of all members of AMSA-Indonesia. “Enhancing Collaboration, Influencing Community” Viva AMSA!

AMINO | AMSA INTERNATIONAL COMPETITION 19/20

AMINO | AMSA INTERNATIONAL COMPETITION 19/20 TABLE OF CONTENTS WORLD AIDS DAY COMPETITION SCIENTIFIC PAPER...............................................................................................1 1st Winner The Potential of Antibody-Like Entry Inhibitor, eCD4-Ig, Delivered by Adeno-Associated Virus (AAV) Vector as a Novel Vaccine for HIV/AIDS Infection: A Systematic Review and Meta-Analysis............................................................5 2nd Winner Efficacy, Safety, Tolerability, and Pharmacokinetics of Long-Acting Pre-Exposure Prophylaxis for the Prevention of Human Immunodeficiency Virus Infections: A Systematic Review of Randomized Controlled Trials.................................19 3rd Winner Assessment of Factors Associated with Suboptimal Adherence of HIV Antiretroviral Therapy in Asia: A Systematic Review.................................................................................44 PUBLIC POSTER...................................................................................................69 1st Winner Accepting People with HIV through CHILL......................................................71 2nd Winner It’s Now or Never: Stop the Stigma!..................................................................75 3rd Winner Leave the Stigma and Welcome to the New Era............................................80 Preventing HIV/AIDS Transmission from Mother to Child with PLASENTA.......................................................................85 Let’s PARTY Against HIV!...................................................................................89 HIV? Let’s CLEAR it away!..................................................................................92 Don’t Let the Stigma of HIV AIDS Scare You! Let’s break the Stigma ! People on the move..................................................95 DIRECT: A Management and Prevention for HIV/AIDS...................................98 Treat For Life, Prevent To Live........................................................................101 ONLINE SOCIAL CAMPAIGN .......................................................................105 Winner Cut the HIV Stigma and Give Them Courage Through #StandUpRIGHT...107

AMINO | AMSA INTERNATIONAL COMPETITION 19/20 WORLD IMMUNIZATION WEEK COMPETITION SCIENTIFIC PAPER...........................................................................................119 Winner COMPREHENSIVE ASSESSMENT OF FACTORS ASSOCIATED WITH COMPLIANCE TOWARDS VACCINATION IN SOUTHEAST ASIA: A SYSTEMATIC REVIEW...................121 2nd Runner Up Immunogenicity and Safety Profile of Various Microneedle Array Patches as a Potential Novel Vaccine Delivery System to Enhance Vaccine Efficacy: A Systematic Review........................................................................................150 Breaking the Myth of Vaccine (DTP & MMR) and Its Preservative Substances Induced Neurodevelopmental Disorder : a Systematic Review, Meta-Analysis, and Epidemiological Review...........................................................................180 Women Empowering Peer Group: A Literature Review to Determine an Effective Way to Fight the Antivaccine Movement for Mother in Developing Countries.................210 COMBATING MYTHS: NO EVIDENCE BETWEEN AUTISM AND MMR VACCINE........................................................221 Skepticism In Fulfilling Immunization Against Immunization Coverage In Indonesia: A Literature Review...................................................................228 Involvement and Impact of Religious Leader to Eradicate Halal/Haram Myth of MR Vaccine and Promote Immunization in Indonesia..............................................................242

PUBLIC POSTER.................................................................................................251 Winner Immunization For Your SPECIAL One............................................................253 1st Runner Up The Adventure of Captain Vaccine: Banishing Vaccine Hesitancy.............259 2nd Runner Up Combatting Vaccine Myths by 5 CENTS.........................................................265 2nd Runner Up THE USE OF ABORTED FETAL TISSUE IN VACCINES FACT OR MYTH?.....269 MMR Vaccs Myth Busters.................................................................................273

AMINO | AMSA INTERNATIONAL COMPETITION 19/20 ONLINE SOCIAL CAMPAIGN........................................................................277 Winner INJECT TO PROTECT: ENDING VACCINE HESITANCY.................................279 1st Runner Up STRIVING TOWARDS 100% IMMUNIZATION COVERAGE AND ZERO VACCINATION MISCONCEPTION..............................................................................................303 2nd Runner Up Get Children Vaccinated, Let the Immunity Encouraged to Keep Them Protected #ImmunizationMatters.........................................325 Hepatitis B Vaccination for Health Workers..................................................347 VACCINE IS SHIELD..........................................................................................384

AMINO | AMSA INTERNATIONAL COMPETITION 19/20

THE POTENTIAL OF ANTIBODY-LIKE ENTRY INHIBITOR, eCD4-Ig, DELIVERED BY ADENO-ASSOCIATED VIRUS (AAV) VECTOR AS A NOVEL VACCINE FOR HIV/AIDS INFECTION: A SYSTEMATIC REVIEW AND META-ANALYSIS

ABSTRACT Introduction: HIV/AIDS has already become one of the world's major health issues taking its toll on millions of lives each year. Developing an HIV vaccine with excellent efficacy has become a global urgency that must be addressed immediately. Recently, researchers have successfully developed a more self-like molecule which is a fusion protein between human CD4 domains and immunoglobulin G (IgG) Fc with a CCR5-mimetic sulfopeptide in the carboxy terminus.[11,12,16,17] This molecule, eCD4-Ig, targets only the conserved regions of HIV Env and thus demonstrated the most remarkable potency and breadth so far. eCD4-Ig l

term expression in vivo can be achieved by using adeno-associated virus (AAV) vector. AAVeCD4-Ig is maintained stably at both protective and therapeutic levels for almost a year-long through a single injection. Objective: This study highlights the efficacy of eCD4-Ig, delivered with AAV vector, as a vaccine for HIV/AIDS infection. Key Findings: The current metaanalysis shows that eCD4-Ig delivered with AAV vector gives robust protection for rhesus macaques for almost a year long (Pooled OR = 0.01; 95% CI: 0.00-0.16; p = 0.83; I2 = 0%). Heterogeneity among studies included are not observed. Conclusion: This study offers evidences that AAV-eCD4-Ig appears to have the potential to be an effective vaccine to prevent HIV infection. Keywords: AAV, AIDS, eCD4-Ig, HIV, vaccine

1 5

In the early years of the AIDS

INTRODUCTION

epidemic, immunotherapy against HIV-1

Human immunodeficiency virus (HIV) i

ha a ack

was

developed.

Human

monoclonal

immune system. This highly contagious

antibodies (mAb) appear to shed light on

virus specifically targets the CD4+ T cells

HIV/AIDS therapy. Treatment with mAb

and later destroys the entire cells colonies.

showed a slight improvement than the

If left untreated, the number of CD4+ T cells

previously used therapies. However, mAbs

will continue to decline rendering the

had limited breadth against multiple HIV-1

immune system incapable of fighting off

strains.[8,9]

infection

a condition known as acquired

Several years after the discovery of

immunodeficiency syndrome (AIDS).[1,2]

mAB, researchers have tried to transfer

HIV/AIDS has become a worldwide

antibodies from the sera of HIV-infected

major health issue. According to World

subjects to AIDS patients. Unfortunately,

Health Organization (WHO) and Joint

these antibodies were ineffective against the

United Nations Programme on HIV/AIDS

diverse

(UNAIDS), there were approximately 37.9

However, studies demonstrated that 20 50%

million people worldwide living with

of chronically HIV-infected individuals

HIV/AIDS in 2018.[2,3] Since the beginning

could produce antibodies that target shared

of the AIDS epidemic, HIV has claimed

epitopes across various clades of HIV

more than 32 million of lives globally.[2]

later

and

highly

known

adaptive

broadly

virus.[5]

neutralizing

antibodies (bNAbs).[4,5,9,10]

For the last few decades, the medicine used for treating HIV/AIDS is

Since

then,

multiple

called antiretroviral therapy (ART). It does

targeting

not cure HIV infection, but only suppress

glycoprotein (Env) had been identified. The

viral load temporarily.[4,5] In 2018, WHO

best ones ever found, N6 and 10E8, manage

reported that 23.3 million people (62%)

to neutralize 98% of HIV strains with 50%

living with

are currently

inhibitory concentration (IC50) up to 50

receiving ART.[2] However, only 30% of

g/ L.[5,6,8,9,11] Although seems promising,

them had successfully suppressed HIV to

however, developing a potent and broad

undetectable levels.[6,7] As a result, such

bNAb requires excessive mutation of

high rates of AIDS-related deaths continue

antibody genes.[7] Thus, the newly-formed

to occur globally. ART as the current HIV

bNAbs are frequently subjected to the

therapy is necessary, but not competent

enough to end the global AIDS epidemic.

formation of anti-drug antibodies (ADA)

HIV/AIDS

different

HIV

bNAbs

envelope

inducing the

2 6

that further decrease their efficacy even

both preventive and therapeutic vaccine for

more.[7,12-15]

HIV/AIDS infection.

In order to ensure neutralization of HIV, excellent potency and breadth is a

METHODS

necessity for developing an effective HIV

This study is reported following the

vaccine. At the same time, it must maintain

Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA)

low

immunogenicity profile

when

administered to humans. Considering this,

criteria.

researchers have begun to explore the possibility

molecules

Eligibility Criteria

resembling

antibodies that could recognize HIV

The

following

criteria

are

conserved epitopes. Recently, researchers

have successfully developed a fusion

studies, problem, intervention, comparison,

protein which functions like an antibody.

outcome (PICO).

ide ed f

die

eligibili : type of

This more self-like molecule is a fusion between

human

CD4

domains

and

Type of Studies

immunoglobulin G (IgG) Fc with a CCR5-

Randomised-controlled trials are

mimetic sulfopeptide in the carboxy

included for this study. Identified articles

terminus.[11,12,16,17] This molecule, eCD4-Ig,

included humans and non-huma

targets only the conserved regions of HIV

Cross-sectional, case control, cohort, case

Env and thus demonstrated the most

report, case series, conference abstracts,

remarkable potency and breadth so far.

expert opinion, and review papers are

Besides being potent and broad, eCD4-Ig

die .

excluded. Articles with unavailable full-

g-term expression in vivo

text, languages other than English, and

must be maintained at protective and

irrelevant topics are also omitted.

therapeutic levels. This response can be Population

achieved by using adeno-associated virus (AAV) vector. AAV-expressed eCD4-Ig is

All subjects (humans or non-

maintained stably for almost a year-long

humans) challenged with infectious doses

through a single injection.[11,12,16]

of HIV are included for this study.

Therefore, this systematic review Intervention

and meta-analysis highlight the efficacy of eCD4-Ig, delivered with AAV vector, as

Studies evaluating the efficacy of eCD4-Ig

neutralize

HIV-infected 3

subjects are included. In addition, included

discrepancies will be resolved by consensus

studies also evaluate AAV-eCD4-Ig to

among the review team.

protect subjects from HIV infection. Data Extraction The following data is extracted from

Comparison the

Included studies compared HIV-

included

studies:

first

author,

infected subjects inoculated with and

publication year, sample characteristics

without eCD4-Ig to evaluate the efficacy at

(age, gender, species, and weight), sample

both therapeutic and preventive level.

size, HIV model (panel of isolates and doses), intervention (delivery method, dose, and time), key findings (numbers of

Outcome

infected animals after intervention), and

The key findings of included studies

follow-up time.

are the number of subjects fully protected from HIV infection.

Quality Assessment Data Sources and Search

Each study are assessed for their

Literature search is carried out with

quality by using Cochrane Risk of Bias.

multiple electronic databases, such as

This tool consists of 6 key domains: (1) risk

PubMed, ScienceDirect, and ProQuest. No

of bias arising from the randomization

time and language restriction is applied.

process; (2) risk of bias due to deviations

The keywords used are described as follow:

from the intended interventions (effect of

eCD4-Ig

AND

HIV

human

assignment to intervention); (3) risk of bias

immunodeficiency virus OR AIDS OR

due to deviations from the intended

acquired immunodeficiency syndrome .

interventions

(effect

adhering

intervention); (4) risk of bias due to missing Study Selection

outcome

data;

(5)

risk

bias

Articles are identified using the

measurement of outcome; and (6) risk of

keywords described above. After removing

bias in selection of the reported result. Each

duplicates

program,

domain is evaluated whether a study has

retrieved articles are screened based on

low or some concerns or high risk of bias.

their titles and abstracts. Thereafter,

Any discrepancies will be resolved by

potentially eligible full-text articles are

discussion among the review team.

using

EndNote

thoroughly assessed using the eligibility criteria described above. Any emerging 4 8

chosen. FEM will be used if the included

Data Analysis All statistical tests for this meta-

studies are considered homogenous (same

analysis are done using Review Manager

design and methodology or low variability

(RevMan) v5.3.

die

e l

a ia i

d e

random error). Otherwise, if heterogeneity Data Synthesis

between included studies is combined,

Odds Ratio (OR) with a confidence

REM will be used. Pooled estimate will be

interval (CI) of 95% will be used to

presented in forest plot.

determine the efficacy of AAV-eCD4-Ig in protecting test subjects from HIV infection.

Heterogeneity Evaluation

If OR equal to 1 is included in the

Heterogeneity of included studies is

calculated CI, it means that there is no

assessed using Cochrane

Q Test (chi-

significant effect of AAV-eCD4-Ig in

squared) and Higgins I2 statistics. For the Q

preventing HIV infection. To determine the

statistics, if the calculated p-value from chi-

effect size, either fixed-effect model (FEM)

squared test is lower than 0.1, included

or random-effect model (REM) will be

studies will be assumed to have statistical 5 9

heterogeneity. For I2 statistics, calculated value

less

than

25%

means

strong

Characteristics of Included Studies

homogeneity, 25-75% is average, more

In 2 studies, eCD4-Ig efficacy in

than 75% indicates strong heterogeneity.

neutralizing and protecting test subjects

Subgroup analysis will be performed to find

from

any possible sources of heterogeneity.

Therapeutic and preventive effects were

HIV

infection

was

assessed.

evaluated by comparing the number of Publication Bias

infected subjects in control and intervention

Publication bias is assessed visually

groups. Included studies were using rhesus

using funnel plot. An asymmetrical shape

macaques as test subjects. Characteristics

indicates the presence of publication bias.

of included studies are presented in Table

Publication bias cannot be determined by

funnel plot assymetry if included studies

Figure 2 shows methodological

are less than 10.

quality assessment of included studies according to Cochrane Risk of Bias tool. All studies show low risks of perfomance,

RESULTS

detection, and reporting bias. One study Search Results

shows

some

concerns

allocation

database

concealment. On the other hand, all studies

yielded 323 studies. Screening through

show serious selection bias and some

titles and abstracts found 32 articles, 9 of

concerns on attrition bias.

electronic

which met the inclusion criteria. A total of Meta-analysis

2 studies were included in the metaamalysis at last. Search flowchart and

Two studies evaluated AAV-eCD4-

selection methods used in this study was

Ig efficacy in protecting test subjects from

summarized in Figure 1.

HIV infection. Pooled analysis revealed 6 10

that the presence of eCD4-Ig significanly

and

(p=0.001) protected rhesus macaques from

sulfopeptide attached in the carboxy

HIV infection (Pooled OR = 0.01; 95% CI:

terminus

0.00-0.16; p = 0.83; I2 = 0%). Finding of

cooperatively binds to the CD4- and

this section is presented in Figure 3. No

coreceptor-binding sites (Figure 4b) on all

heterogeneity was observed in this study.

HIV subtypes hence its markedly superior

Publication bias can not be determined as

potency and breadth.[12,16,17]

IgG

with

(Figure

CCR5-mimetic 4a).

eCD4-Ig

eCD4-Ig eliminates HIV-infected

the number of included studies are less than cells

10.

through

main

mechanisms:

neutralization and antibody-dependent cellmediated

DISCUSSION

cytotoxicity

(ADCC).[12,16,18]

HIV/AIDS

eCD4-Ig engages the Env and potently

treatment is only limited to the suppression

neutralizes the highly diverse HIV isolates.

of viral load temporarily by using ART.

According to an in vitro study by Gardner

The therapy developed for the last few

et al., eCD4-Ig neutralized 100% of HIV-1,

decades focuses on targeting HIV Env by

HIV-2, and SIV strains with IC50 and IC80

using bNAbs. Despite the promising

less than 1.5

potency and breadth, bNAbs still have a

respectively (Figure 4c).[16] This finding is

major

supported by another study done by Fetzer

this,

et al. which has shown the excellent

researchers have shifted their focus on

potency of eCD4-Ig and its variants in

using a more self-like molecule to target the

neutralizing diverse HIV-1 isolates.[17]

Current

trend

drawback

immunogenicity.

conserved

regions

regarding Considering

HIV

Env.[8,11]

g/ L and 10

addition

g/ L,

enhancing

Recently, researchers have successfully

neutralization,

engineered eCD4-Ig, a Fc-fusion protein

sulfopeptides ensure no viral escape and

between domains 1 and 2 of human CD4

HIV-infection occurring in CD4-negative

CCR5-mimetic

7 11

cells.[11,16,19,20] According to the study by

NOD/SCID/ c (NSG)

Fellinger et al., eCD4-Ig was capable of

5x104

altering HIV-1 Envs, hence making the

Complete protection was achieved at the

viruses less infectious and more sensitive to

concentration of 2 4 g/ L a d ai ai ed

antibodies present in the serum of HIV-

up to 5 weeks after inoculation.

infected people.[20] Other studies done by

Moreover, the more self-like structure of

Davis-Gardner et al. and Fetzer et al. also

eCD4-Ig makes it less likely subjected to

supported this finding. eCD4-Ig has the

endogenous antibodies that can impair the

ability to expose the V3-loop of HIV Env

efficacy. Even the additional CCR5-

hence its ability to enhance the potency of

mimetic

V3-loop antibodies, which are abundant but

significant

non-neutralizing

These findings strongly suggested eCD4-Ig

HIV-infected

individuals.[18,21]

infectious

ice i fec ed

units

sulfopeptides antibody

HIVNL4-3.

not

[16]

elicit

responses.[12,16,19]

as a promising candidate for HIV vaccine

The remarkable potency of eCD4-Ig

development.

also comes from its ability in mediating

Another

important

issue

vaccine

for

ADCC. An in vitro study by Davis-Gardner

developing

et al. revealed that eCD4-Ig mediated

HIV/AIDS is the use of an appropriate

killing of HIV-infected cells up to 10 times

packaging system to ensure eCD4-Ig

more efficiently by natural killer (NK)

expression at protective and therapeutic

cells.[18] This finding is supported by

levels. Previously, antibodies or antibody-

another study by Gardner et al. It is

like inhibitors were passively administered.

revealed that eCD4-Ig enhanced ADCC

However, this method prompted the need of

activity by 30-40 times higher when tested

repeated infusion which could lower

against diverse HIV tropisms (Figure

a ie

effective

lia ce.[22,23] This approach is

4d).[16] Moreover, eCD4-Ig could alter the

deemed inefficient and thus an alternative is

conformation of HIV Env so that pre-

needed to express biologically active

existing non-neutralizing antibodies in

molecules in a prolonged manner with a

a ie

e a c ld bi d

HIV E

a d

single inoculation. In this case, AAV vector

promote ADCC activity by 100-fold.[18] Besides

having

appears to be a major breakthrough of this problem.

remarkable

therapeutic effect, eCD4-Ig is also proven

Adeno-associated virus (AAV) is a

to be capable of preventing HIV infection.

small (20 nm), non-enveloped virus. It

An in vivo study by Gardner et al. revealed

belongs to genus Dependoparvovirus,

that eCD4-Ig fully protected humanized

which

turn

belonging

family 8

Parvoviridae.[22]

AAV

vector-mediated

AAV-eCD4-Ig

can

give

full

gene transfer has gained a lot of attention as

protection from HIV infection in non-

it is able to express desired-protein for the

human studies. According to a study by

lifetime of the cell as long as the product is

Gardner et al. in 2015, AAV-eCD4-Ig

considered as self by one's immune

completely protected four of four rhesus

system.[23] AAV particles also show high

macaque from six escalating doses of

resistance to high temperature and widely-

simian-human

immunodeficiency

range pH, as well as stability after being

(SHIV-AD8)

infection.

stored for a long time.[22,23] Therefore, I

administration of 2.5x1013 genomic copies

strongly propose the use of AAV to

(GCs) of AAV-eCD4-Ig was capable of

efficiently deliver eCD4-Ig (AAV-eCD4-Ig)

maintaining stable eCD4-Ig expression

both as a prevention and treatment for HIV

between 17 77

infection.

protection for inoculated macaques up to

virus single

g/ L and giving robust

9 13

40-week long (Figure 5a).[16] Another

Consistent with the previous studies, the

study by Gardner et al. in 2019 revealed that

current meta-analysis shows that eCD4-Ig

AAV-eCD4-Ig was capable of preventing

delivered with AAV vector gives robust

SIVmac239 infection in four of four

protection for rhesus macaques for almost a

inoculated

serum

year long (Pooled OR = 0.01; 95% CI: 0.00-

concentration as low as 3-18 g/ L by the

0.16; p = 0.83; I2 = 0%). There is no

end of week-50 (Figure 5b).[12] These

observed heterogeneity in studies included

studies highlight the potential of AAV to

for this systematic review and meta-

achieve a long-term and stable transgene

analysis. This study offers evidences that

deli e

AAV-eCD4-Ig is a candidate HIV vaccine

i h

macaques

with

b die , a ic la l i

HIV-infected individuals. The delivery of

for its worldwide use in humans.

eCD4-Ig is boosted to a point where its

However, the current study has

effectivity reaches beyond average.

several limitations. First, a larger sample

To the best of our knowledge, this is

size is required for the calculated OR from

the first comprehensive study conducted

this meta-analysis to be more reliable and

that evaluate the efficacy of AAV-eCD4-Ig

representative.

Second,

the

limited

in protecting subjects from HIV infection. 10 14

evidence availaible implies that this meta-

analysis must be interpreted with caution.

HIV/AIDS | CDC [Internet]. Cdc.gov. 2019

[cited

August

Available

2019]. from:

https://www.cdc.gov/hiv/

CONCLUSION 2.

The extensive genetic diversity in

HIV/AIDS [Internet]. Who.int. 2019

HIV has been a challenge to develop an

[cited 20 August 2019]. Available from:

effective HIV vaccine. Recently, eCD4-Ig

https://www.who.int/news-room/fact-

has been developed and proven to be the

sheets/detail/hiv-aids 3.

most potent and broad therapy at present.

AIDSinfo

UNAIDS

[Internet].

eCD4-Ig neutralizes 100% of HIV-1, HIV-

Aidsinfo.unaids.org. 2019 [cited 4

2, and SIV strains at a low concentration. It

August

also mediates efficient killing by NK cells.

https://aidsinfo.unaids.org/

In addition, the self-like eCD4-Ig is less

2019].

Available

from:

Gama L, Koup RA. New-generation

likely targeted by pre-existing antibodies.

high-potency and designer antibodies:

This present study revealed that one-time

role in HIV-1 treatment. Annu Rev Med.

administration

2018;69:14.1-14.11.

AAV-eCD4-Ig

fully

protected test subjects from HIV infection

Burton DR, Hangartner L. Broadly

for at least a year. Thus, AAV-eCD4-Ig

neutralizing antibodies to HIV and

appears to have the potential to be an

their role in vaccine design. Annu Rev

effective vaccine to prevent HIV infection.

Immunol. 2016;34:635 59. 6.

neutralizing

RECOMMENDATION Further

Stephenson KE, Barouch DH. Broadly

comprehensive

studies

antibodies

for

HIV

eradication. Springer. 2016;13:31 7.

should be done to assess the efficacy of

Sahay B, Nguyen CQ, Yamamoto JK.

AAV-eCD4-Ig in vitro and in vivo, as it

Conserved HIV Epitopes for an

would serve as a foundation for future

Effective HIV Vaccine. J Clin Cell

management

Immunol. 2017;8(4):518.

HIV/AIDS

infection.

Moreover, it is recommended that clinical

Padte NN, Yu J, Huang Y, Ho DD.

trials are iniated to investigate the ability of

Engineering multi-specific antibodies

AAV-eCD4-Ig in giving protection and

against

treatment for HIV-infected patients.

2018;15(1):60. Published 2018 Aug 29. 9.

HIV-1. Retrovirology.

Ferrari G, Haynes BF, Koenig S, Nordstorm JL, Margolis DM, Tomaras

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Jun 28;93(14).

SP,

PedreĂąo-LĂłpez S, Rakasz EG, Gao G, 12 16

21. Fetzer I, Davis-Gardner ME, Gardner MR, et al. A Coreceptor-Mimetic Peptide Enhances the Potency of V3Glycan

Antibodies. J

2019;93(5):e01653-18.

Virol. Published

2019 Feb 19. 22. Brady JM, Baltimore D, Balazs AB. Antibody gene transfer with adenoassociated viral vectors as a method for HIV prevention. John Wiley Sons Ltd. 2017;275:324 33. 23. Fuchs SP, Desrosiers RC. Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV

antibodies.

Mol

Ther

Methods Clin Dev. 2016;3:16068.

13 17

APPENDICES Table 1. Characteristics of Included Studies Author,

Age (year) / Gender / Species /

Sample

HIV Model /

Intervention / Delivery Method /

Findings

Follow-

Year

Weight (gram)

Size

Dose

Dose / Intervention Time (week)

(Infected/Total)

Gardner,

2 / Male / Indian-origin rhesus

2015

macaques / 5200-8200

Gardner,

2-5 / Female / Indian-origin

2019

rhesus macaques / 2500-6380

8 12

SHIV-AD8 /

AAV-rh-eCD4-Ig / IM / 2.5×1013

200-3200 pg

GC / 8

SIVmac239 /

AAV-rh-eCD4-Ig / IM / 2×1013

20 pg

GC / 22

Control

Intervention

(week)

4/4

0/4

8/8

0/4

Abbreviation: AAV, Adeno-associated virus; GC, genome copies; IM, intra-muscular

14 18

Efficacy, safety, tolerability, and pharmacokinetics of long-acting pre-exposure prophylaxis for the prevention of human immunodeficiency virus infections: a systematic review of randomized controlled trials Gilbert Lazarus, Christianto

ABSTRACT Introduction Human immunodeficiency virus (HIV) infections is associated with severe morbidity and mortality, mainly attributing to its high transmission rate and lack of prevention strategies. Long-acting pre-exposure prophylaxis (PrEP) arises as a promising solution to these problems, as well as overcoming previous adherence problems. This systematic review aims to evaluate the efficacy, safety, tolerability, and pharmacokinetics of long-acting PrEP for the prevention in HIV, which may aid alleviating health burdens caused by HIV. Methods Relevant studies from PubMed, Scopus, and CENTRAL databases from inception to were screened, searching for randomized controlled trials (RCTs) investigating the use of longacting PrEP from inception to 28th October 2019. Included trials were assessed using Cochrane risk-of-bias tool for randomized trials ver. 2.0. Results The search yielded 7 RCTs with a total of 5025 patients. Long-acting PrEP emerges in the form of injectable and vaginal ring (VR). Long-acting injectable (LAI) cabotegravir (CAB) showed positive pharmacokinetics properties with 200x2mg, 400x2mg, 600mg q8wk, and 800mg q12wk dosing regimens resulted in plasma concentrations >4x PA-IC90 (0.644 Âľg/ml), indicating that LAI CAB successfully provided adequate protection. Furthermore, its long-acting nature was confirmed with terminal half-life ranging from 25.4-53.9 days. Dapivirine (DPV)-VR also showed similar results by reducing risk of infection and HIV incidence by roughly 30%, as well as providing adequate protection for over 28 days. Conclusion Long-acting PrEP yielded promising efficacy and pharmacokinetics properties as well as minimal and/or tolerable AEs, thus may reduce the persistently high HIV incidence. Further trials with larger populations are needed to better confirm the potential of long-acting PrEP. Key words: long-acting, pre-exposure prophylaxis, human immunodeficiency virus prevention, systematic review INTRODUCTION Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) continues to be a global health burden by causing devastating health effects with over 39 million deaths related to HIV/AIDS and 36 million people living with HIV.1 The high burden of HIV infections is attributed to the high transmission rate aggravated by increasing risk of HIV transmission such as sexual exposure, parenteral exposure, and blood transfusion, with the last posing as the greatest risk.2 Antiretroviral therapy (ART) emerges as a functional cure to control viral load rather than complete cure of HIV.3 When used consistently by uninfected people as pre-exposure prophylaxis (PrEP), ART substantially reduces the risk of becoming

infected.4 Despite major breakthroughs of ART as PrEP, the high incidence of HIV still persists. This seemingly ineffectiveness of ART as PrEP may due to low adherence to PrEP, especially for the highly adherence-dependent oral PrEP.5 Adherence to PrEP regimens may affect the success of PrEP which depends highly on achieving sustained antiretroviral tissue concentrations.6 Currently, there are a few options of long-acting PrEP regimen such as injectable, intravaginal ring, implant, and antibody PrEP for HIV prevention. This long-acting PrEP may improve the compliance to PrEP regimen and prevent HIV transmission.7,8 However, systematic reviews of higher-level evidences regarding the clinical activities of long-acting PrEP for preventing HIV have yet to be conducted. Therefore, this systematic review aims to critically evaluate the efficacy, safety, tolerability, and pharmacokinetics of long-acting PrEP for the prevention of HIV, which in turn may decrease the disease burdens caused by HIV infections. METHODS Search strategy This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.9 PubMed, Scopus, and Cochrane Controlled Register of Trials (CENTRAL) databases were systematically searched, searching for studies implementing long acting PrEP to prevent HIV infections from inception to 28 October 2019 using these keywords: "long-acting OR sustain* AND "pre-exposure prophylaxis OR prep OR prevention" AND "cabotegravir OR CAB OR rilpivirine OR RPV OR LAI OR integrase inhibitor OR dapivirine OR DPV OR DAP OR DVR OR GSK1265744 OR GSK744 AND "HIV OR AIDS OR human immunodeficiency virus OR acquired immunodeficiency syndrome". The search was limited to human participants, and no language restrictions were applied. However, studies included in this review was limited to English and Bahasa Indonesia, which were the only languages understandable by the authors. Further details on the literature search strategy are shown on Figure 1. Inclusion and exclusion criteria Inclusion criteria to filter the results were set as following: (1) study design, randomized controlled trials (RCTs); (2) study population, HIV-uninfected and/or healthy patients; and (3) intervention, long-acting PrEP. Conversely, exclusion criteria were also applied: (1) different outcome of interest (no outcomes on efficacy, safety, tolerability, or pharmacokinetics); (2)

irretrievable full-text articles; and (3) incompatible language (language other than English or Bahasa Indonesia) Data extraction and risk of bias assessment The following relevant data from included studies were extracted: (1) author and year; (2) study design (phase) and setting (masking, location); (3) interventions and comparators; (4) subject characteristics, including sample size and mean/median age of participants; (5) followup periods; (6) outcomes related to efficacy (prevalence and hazard ratio (HR)), safety and tolerability (adverse events (AE) grade 2), and pharmacokinetic. Pharmacokinetic parameters include: maximum plasma concentration (Cmax), time needed to reach maximum plasma concentration (Tmax), drug concentration at the end of dosing interval or follow-up period (C ), area under the plasma drug concentration-time curve over the dosing interval or follow-up period (AUC0– ), apparent half-life (t1/2), and apparent clearance (CL/F, defined as drug s clearance without taking account of the unknown drug s bioavailability).10 Risk of bias assessment of included RCTs were performed using the Cochrane risk-ofbias tool for randomized trials ver. 2.0. (RoB2)–consisting of five bias domains: randomization, assignment and adhering to intervention, missing outcome data, measurement of the outcome, and selection of reported results. Risk of bias assessment results were judged to be low, unclear/some concerns, and high risk of bias.11 Data extraction and risk of bias assessment were conducted by two independent reviewers (GL and C), and any discrepancies were resolved by consensus between all authors. Appendix 1 provides further details on the risk of bias assessment. RESULTS Study selection and characteristics Details on the literature search process of this review are illustrated on Figure 1. The initial search yielded 313 results–83 of which were deduplicated and 196 were excluded following title and abstract screening. On full-text articles assessments, 26 studies were excluded due to: 1212,13,22,23,14–21 studies with different outcome of interests (no outcome on efficacy, safety and tolerability, or pharmacokinetic), 88,24–30 studies with irretrievable full-text articles (424–27 unavailable and 48,28–30 conference abstracts), 67,31–35 studies with inappropriate study design (57,31–34 not randomized and 135 not controlled). Finally, 736–42 RCTs with a total subject of 5025 patients were included in this systematic review.

Figure 1. PRISMA flow diagram9 The main characteristics of patients included in this review are shown in Table 1. Subject characteristics were matched for HIV-negative patients. The trials were published between 2009 and 2018, and 4 out of 7 studies36â&#x20AC;&#x201C;39 were multicentered, while the other 241,42 were conducted in Belgium and 140 in USA. All studies with exception of Spreen et al40 were conducted in double-blind manners. Four studies38,39,41,42 assessed the implementation of dapivirine vaginal rings (DPV-VR), while the other 336,37,40 evaluated injectable PrEP. In the DPV-VR group, 238,39 studies were Phase III RCTs, and the other 241,42 were Phase I. One study40 implementing injectable PrEP was Phase I RCT, while the other 236,37 were Phase IIa. With regards to risk of bias analysis, 5 studies36â&#x20AC;&#x201C;39,41 presented low risk of bias, 142 presented some concern, while another 140 presented high risk of bias.

Table 1. Study characteristics and outcomes Subject characteristics Author and Year Landovi tz RJ, 2018

Pha se

Maski ng

Location

IIa

Double -blind

Multicent er

Treatment

CAB-LA IM 800mg q12wk vs placebo (C1)

Sample Size 199 (151 C, 48 P)

Mean (SD)/median (range) age in years 31 (24-40)

Followup period (weeks)

RoB2 score

CAB-LA IM 600mg q8wk vs placebo (C2) Markow itz M, 2017 Nel A, 2016

IIa

Double -blind

Multicent er

III

Double -blind

Multicent er

DPV-VR 25mg vs placebo

Baeten JM, 2016 Spreen W, 2014

III

Double -blind

Multicent er

DPV-VR 25mg vs placebo

Open label

USA

CAB-LA IM 800mg q12wk + placebo

744-LAa IM 100, 200, 400, 800mg vs placebo (C1-4)

126 (105 C, 21 P)

31 (20-61)

1959 (1307 C, 652 P) 2629 (1313 C, 1316 P) 72 (58 C, 14 P)

104

26 (18-45)

83.43

35.1 (10.4)

C: 29.8 P: 28.3 (18-40) C1: 30, C2: 24, P: 24 (18-35)

4.71

744-LAa SC 100, 200, 400mg vs placebo (C5-7) 744-LAa IM 400mg (200 x 2; C8) and 400mg (400 x 1; C9) Nel A, 2014

Double -blind

Belgium

Nel A, 2009

Double -blind

Belgium

DAP 25mg IVR vs placebo DAP 25mg M-IVR (C1) vs 25mg R-IVR (C2) vs placebo

16 (8 C, 8 P) 24 (8 C1, 8 C2, 8 P)

GSK1265744, HIV integrase inhibitor, later patented as CAB-LA; USA, United States of America; CAB-LA, cabotegravir long-acting; IM; intramuscular; SC, subcutaneous; C, cohort; P, placebo; DPV-VR, dapivirine vaginal ring; M-IVR, matrix intravaginal ring; R-IVR, reservoir intravaginal ring.

Injectable PrEP Injectable PrEP as a method of HIV prevention arises in the form of long acting injectable (LAI) cabotegravir (CAB). Reported outcomes related to the use of LAI CAB include safety, tolerability, and pharmacokinetics profiles. None of the included studies evaluated the efficacy of injectable PrEP as all studies were still Phase IIa or before. Landovitz et al reported that geometric mean of C CAB concentrations was higher in female than male (p<0.001), and higher concentration was observed in 600 mg q8wk dosing regimen.36 C varies between studies and doses. Landovitz et al36 reported that both 800 mg q12wk and 600 mg q8wk dosing regimens resulted in C CAB concentrations of above 4x PA-IC90 (0.644 Âľg/ml), while Spreen et al40 revealed that only 200x2 mg IM and 400x2 mg IM dosing regimens yielded

similar results; hence, indicating its significant protection towards infections. Nonetheless, Markowitz et al37 reported that 800 mg q12wk dosing regimen yielded suboptimal preventive effect (C = 0.387 Âľg/ml). Other pharmacokinetics analysis showed that terminal half-life of LAI CAB varied from 25.4 days (400x2 mg IM) to 53.9 days (200 mg IM), while a stable apparent clearance varied from 0.1 L/h. However, maximum plasma concentration and AUC0â&#x20AC;&#x201C; showed dose-dependent manners for either IM injection or SC injection, indicating that higher dosing regimens were associated with longer activity. Furthermore, the onset of action of intramuscularly injected CAB was longer with subcutaneous injection, with Tmax ranging from 7.58 to 69.0 days (IM) and from 6.0 to 27.0 days (SC), respectively. Maximum plasma concentration between IM CAB and SC CAB injections did not differ significantly. Overall, SC injection showed longer half-life and faster onset of action when compared to IM injection, although its plasma concentration was remarkably lower than that of IM injection. Dosing regimen 200x2 mg and 400x2 mg IM showed optimal efficacy with C CAB concentrations of higher than 4x PA-IC90. Adverse events (AEs) in each study were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table).43 In the included studies, interventions given were generally well tolerated and safe.36,37,40 The most common AEs related to long-acting injectable PrEP treatment is injection site reactions (ISR) which is experienced by 38.1%36, 74.5%37, and 67.5%40 patients. AEs related to drug administrations are summarized in Table 2. Landovitz et al reported treatmentrelated serious AEs (3%) and AE-related withdrawal (24.5%).36 Grade 3 AEs were experienced by 1.49%36 and 19%37 patients administered with long-acting injectable PrEP. There is no grade 4 AEs reported in the included studies.36,37,40 Dapivirine vaginal rings (DPV-VR) DPV-VR contains uniformly dispersed 25 mg DPV and silicone elastomer as the vehicle. The placebo was made identically to prevent unblinding, but without the addition of active ingredients. Nel A et al modified the matrix (normal) DPV-VR by adding radio-opaque barium sulfate as a marker to create reservoir intravaginal ring (R-IVR).41 Out of 4 studies evaluating the use of DPV-VR, 238,39 studies reported outcomes related to efficacy, 241,42 studies reported pharmacokinetics measures, and all studies reported AEs38,39,41,42. In terms of efficacy, DPV-VR is proven to be effective in preventing HIV infection with a whooping reduction of incidence ranging from -37.00% to -30.67%38. Furthermore, it is also associated

with reduced risk of HIV infection of roughly 30%, as expressed with hazard ratios of 0.63 (p=0.01) and 0.69 (p=0.04). Pharmacokinetics analysis of DPV-VR revealed that the mean maximum plasma concentration (Cmax) and time to Cmax (Tmax) varies widely, ranging from 51.87 to 1194 pg/ml and 8 hours to 10.5 days, respectively. Matrix intravaginal rings (M-IVR) designed by Nel et al41 took effect faster than any other VR design, taking effect after only 8 hours. Furthermore, the terminal half-life of DPV-RV ranges from 64 to 83 hours; which, although remarkably lower than that of injectable PrEP, may still indicate its long acting behavior. Overall, M-IVR showed higher geometric mean of Cmax and AUC0- than R-IVR (p<0.001). R-IVR also needed longer time to reach maximum plasma concentration, although its terminal half-life was longer by 19 hours. Similar to the injectable PrEP, AEs in this group were also assessed by DAIDS AE Grading Table43. AEs were described as generally safe and well tolerated with no AE-related withdrawal reported in all included studies.38,39,41,42 The rate of any treatment-related AEs ranges from 50% to 87.5%.38,41,42 One study reported serious AEs and AEs of grade â&#x2030;Ľ 3 experienced by 2.9% and 4.8% patients respectively.38 Headache was experienced by 0.1%39, 50%,41 and 37.5%42 patients receiving DPV-VR. Vulvovaginal discomfort is experienced by 37.5%41

and 12,5%42 patients receiving DPV-VR. Overall, there was no significant difference between placebo IVR and DPV-VR groups regarding rate of AEs.38,39,41,42

Table 2. Reported outcomes related to pharmacokinetics and adverse events of injectable PrEP Pharmacokinetics Author and year

Cmax (µg/ml); n(%)

Landovitz RJ, 2018

C1: : 3.39, :3.01 (p=0.461)

Tmax (days) ; n(%) NR

C2: : 3.82, : 3.66 (p=0.800)

Cτ (µg/ml); n(%) C1: : 0.83, : 1.65 (p=<0.00 1) C2: : 1.68, : 2.03 (p=0.259 )

AUC0–τ (h× µg/ml); n(%) C1: : 4428.24, : 4996.56 (p=0.332)

Adverse events t1/2 (days); n(%)

CL/F (L/h); n(%)

AE (PrEP vs placebo) (%)

AE ≥ Grade 2: 91.0 vs 88.4

AE-related withdrawal (PrEP vs placebo) (%) 24.5 vs 25

↓CrCl: 47.0 vs 46.5

Serious AE (PrEP vs placebo) (%) 3.0 vs 4.7 (p=0.634) Grade 3 AE: 1.49 vs 0 No grade 4 AE

ISR: 38.1 vs 2.3 (p<0.001) Musculoskeletal discomfort: 25.4 vs 14.0 URTI: 23.1 vs 23.3 Headache: 16.4 vs 9.3

C2: : 3912.96, :4027.92 (p=0.849)

Hypoglycemia: 11.2 vs 7.0 Influenza: 10.4 vs 7.0 Nasopharyngitis: 10.4 vs 4.7 ↑Blood creatinine: 9.7 vs 7.0 Conjunctivitis: 8.2 vs 2.3 UTI: 8.2 vs 2.3 ↑Lipase: 7.5 vs 9.3 Gastroenteritis: 7.5 vs 4.7 Rash: 6.7 vs 2.3 Dermatitis: 6.0 vs 4.7 Genital candidiasis: 5.2 vs 2.3 Sinusitis: 5.2 vs 2.3 Weight loss: 4.5 vs 7.0 ↑Blood CPK: 4.5 vs 12.0 Depression: 0 vs 7.0 (p=0.014)

AE ≥ Grade 2: 80 v 48 (p=0.0049)

0 vs 5

4.91 (4.315.60); 85 (66.6)

0.387 (0.2960.505); 66 (150)

4047 (35784357); 85 (35.3)

40.0 (35.145.7); 51 (49.6)

0.197 (0.1810.214); 68 (36.4)

ISR: 74.5 vs 5 (p=0.0049)

Grade 3 AE: 19% v 0 No grade 4 AE

Pyrexia: 6 vs 0 URTI: 4 vs 10 Back pain: 4 vs 0 ↑Blood CPK: 3 vs 5

Markowitz M, 2017

Gastroenteritis: 4 vs 0 Headache: 3 vs 5 Chills: 3 vs 0 Myalgia: 3 vs 0 Nasopharyngitis: 3 vs 0 Pharyngitis streptococcal: 3 vs 0

Spreen W, 2014

C1: 0.2 C2: 0.3 C3&9: 0.7 C4: 3.3 C5: 0.2 C6: 0.5 C7: 0.9 C8: 1.4

C1: 9.0 C2: 44.5 C3&9 : 69.0 C4: 7.58 C5: 16.5 C6: 6.0 C7: 27.0 C8: 13.0

C1: 0.1 C2: 0.2 C3&9: 0.4 C4: 2.0 C5: 0.1 C6: 0.1 C7: 0.1 C8: 1.1

C1: 607 C2: 1068 C3&9: 1921 C4: 5651 C5: 433 C6: 1005 C7: 2402 C8: 2445

C1: 33.3 C2: 53.9 C3&9: 38.3 C4: 25.4 C5: 50.4 C6: 42.7 C7: 42.8 C8: 31.7

C1: 0.1 C2: 0.1 C3&9: 0.1 C4: 0.1 C5: 0.1 C6: 0.1 C7: 0.1 C8: 0.1

Any AE: IM: 70 vs 62.50, SC: 94.44 vs 83.33 Any ISR: IM: 67.50 vs 25, SC: 94.44 vs 50 Erythema: IM: 12.50 vs 0, SC: 61.11 vs 0 Nodule: IM: 15 vs 0, SC: 77.78 vs 0 Pain: IM: 67.50 vs 25, SC: 77.78 vs 33.33 Any non-ISR: IM: 62.50 vs 62.50, SC: 88.89 vs 66.67 Nausea IM:10 vs 0, SC: 16.67 vs 0 Vomiting IM:7.50 vs 12.50, SC: 16.67 vs 0 Non-ISR pain IM: 5 vs 12.50, SC: 0 vs 0 ↑Blood CPK IM: 5 vs 0, SC: 0 vs 0 Back pain IM: 10 vs 0, SC: 16.67 vs 0 Headache

No withdrawalrelated AE

No grade ≥2 AE

IM: 30 vs 37.5, SC: 44.44 vs 16.67 Cough IM: 7.50 vs 25, SC: 16.67 vs 33.33 Oropharyngeal pain IM: 5 vs 13.33, SC:0 vs 33.33 Rhinorrhea IM: 0 vs 0, SC: 33.33 vs 16.67 Sneezing IM: 2.50 vs 0, SC: 33.33 vs 16.67 Erythema IM: 2.50 vs 0, SC: 11.11 vs 0 AE, adverse events; PrEP, pre-exposure prophylaxis; C, cohort; NR, not reported; NA, not available; CrCl, creatinine clearance; ISR, injection site reaction; URTI, upper respiratory tract infection; UTI, urinary tract infection; CPK, creatine phosphokinase.

Table 3. Reported outcomes related to efficacy, pharmacokinetics and adverse events of dapivirine (DPV) vaginal rings Efficacy Autho r and year

Pharmacokinetics

DPV n(%)

PBO n(%)

HR [95% CI]

P value

% diff. [95% CI[

Cmax (pg/ml); n(%)

Tmax (hours); n(%)

Cτ (pg/ml); n(%)

Nel A, 2016

4.1

6.1

0.69 [0.490.99]

0.04

-30.67 [-51.50, -0.90]

Baeten JM, 2016

3.3

4.5

0.63 [0.440.88]

0.01

-37.00 [-56.00, -12.00]

Nel A, 2014

355 (87.96)

Adverse events t1/2 (hours); n(%)

AUC0–τ (h× pg/ml); n(%) NR

168.54 (120.30336.43)

217.5 (82.38)

3022 (389.1)

67.35 (21.29)

AE (PrEP vs placebo) (%)

Any AE: 87.4 vs 85.7 Serious AE: 2.9 vs 0.9 Grade 3 or 4 AE: 4.8 vs 2.9 Product-related AE: 0.4 vs 0.5 No AE-related withdrawal AE≥2 Grade 2: 0.5 vs 0.7 Application site pain: 0 vs 0.2 Cervicitis: 0.1 vs 0.1 Pelvic inflammatory disease: 0 vs 0.1 Urinary tract infection: 0.1 vs 0.1 Neutrophil count decreased: 0 vs 0.1 Abnormal loss of weight: 0 vs 0.1 Headache: 0.1 vs 0 Urinary incontinence: 0.1 vs 0 Cervix erythema: 0.1 vs 0 Cervix edema: 0.1 vs 0 Dysmenorrhea: 0 vs 0.1 Dyspareunia: 0.1 vs 0 Pelvic pain: 0.2 vs 0.1 Vulvovaginal pruritus: 0 vs 0.1 No AE-related withdrawal Any AE: 87.5 vs 100 Metrorrhagia: 50 vs 37.5 Uterine cervical laceration: 12.5 vs 0 Vaginal discharge: 0 vs 12.5 Vaginal hemorrhage: 12.5 vs 0 Vaginal lesion: 12.5 vs 0 Vulvovaginal discomfort: 37.5 vs 0

Vulvovaginal pruritus: 12.5 vs 12.5 Vaginitis bacterial: 0 vs 12.5 Gastrointestinal disorders: 12.5 vs 12.5 Diarrhea: 0 vs 25 Influenza-like illness: 0 vs 25 Pyrexia: 12.5 vs 12.5 Nasopharyngitis: 25 vs 12.5 Back pain: 0 vs 25 Headache: 50 vs 37.5 No AE-related withdrawal Nel A, NA NA NA NA NA M-IVR: M-IVR: M-IVR: M-IVR: M-IVR: M-IVR vs R-IVR vs placebo IVR 2009 1194 8h 160 352,800 64 Any AE: 50 vs 62.5 vs 62.5 R-IVR: R-IVR: R-IVR: R-IVR: R-IVR: Headache: 37.5 vs 37.5 vs 37.5 51.87 10.5 days 32 28,840 83 Abdominal pain: 0 vs 12.5 vs 25 (p<0.001) (p<0.001) Fatigue: 0 vs 12.5 vs 12.5 Nausea: 12.5 vs 12.5 vs 12.5 Genital discharge: 12.5 vs 12.5 vs 12.5 Bacterial vaginitis: 0 vs 12.5 vs 0 Candidiasis : 12.5 vs 0 vs 0 Vulvovaginal discomfort: 12.5 vs 0 vs 0 Vulvovaginal pruritus: 12.5 vs 0 vs 0 No AE-related withdrawal DPV, dapivirine; PBO, placebo; HR, hazard ratio; NR, not reported; NA, not available; AE, adverse events; PrEP, pre-exposure prophylaxis; M-IVR, matrix intravaginal ring; R-IVR, reservoir intravaginal ring.

DISCUSSION Long-acting PrEP has been deemed as one of the main solutions in overcoming adherence problems; hence, potentially increasing HIV treatment and prevention outcomes. This review provides critical overview on the clinical activities of potential long-acting PrEP in the form of injectable and IVR as they are the only drug preparations ongoing RCT phases. Several other PrEP preparations–including broadly neutralizing antibodies and implants–are currently ongoing preclinical and clinical phases. The mechanism by which long-acting PrEP prevents HIV infection varies. Dapivirine–an epitome of non-nucleoside reverse transcriptase inhibitors (NNRTI)–prevents HIV infection by binding non-competitively to reverse transcriptase enzyme of HIV-1 strand. On the other hand, cabotegravir, a second-generation integrase strand transfer inhibitors (INSTI), blocks the insertion of HIV DNA to CD4 T cell, thus inhibiting viral replication and transmission.44 Long-acting injectable cabotegravir The use of CAB as a potential long-acting PrEP has been extensively researched.36,37,45– 47

Our study confirmed the long activity of CAB, with terminal half-life ranging from 25.4 days

to 53.9 days. According to Spreen et al40, IM CAB 200 mg and SC CAB 100 mg yielded the longest terminal half-life with 53.9 days and 50.4 days, respectively; although these dosing regimens showed suboptimal preventive effect (lower than 4x PA-IC90). Ito S stated that four half-lives are needed for a drug to reach its negligible therapeutic effects.48 Therefore, the time needed for CAB to reach its steady state is roughly 3-6 months depending on the dose administered. These terminal half-lives were roughly 7.5-15-times fold than daily oral CAB.46 However, Spreen et al40 also reported that the drug distribution to tissues were limited due to high plasma protein binding and low volume of distribution. Nonetheless, the drug concentrations were found to be higher than 4x PA-IC90, indicating that LAI CAB is capable of providing adequate protection to HIV infection.40 The long-acting nature of LAI CAB was further confirmed by Trezza et al, stating that CAB is primarily eliminated in the feces as unchanged drug, which suggest that enterohepatic circulation may prolong its pharmacokinetic profiles. In addition, CAB does not induce nor inhibit several highly utilized cytochrome enzymes as well as hepatic, renal, or intestinal drug transporters, which suggests that its drug interaction is minimal.49 This review revealed that IM injection of LAI CAB with >200 mg dosing regimens resulted in plasma concentration >1x PA-IC90 (0.166 µg/ml). However, only dosing regimens of 200x2 mg, 400x2 mg, 600 mg q8wk, and 800 mg q12wk yielded plasma concentration higher than 4x PA-IC90. In a study evaluating the use of LAI CAB in macaque model, Andrews

et al stated that plasma concentration of >1x PA-IC90 provided ~97% protection and >3x PAIC90 (0.498 Âľg/ml) provided 100% protection from Simian-HIV.45 These data were expected to be comparable to HIV-1 exposures in human45, thus indicating that those dosing regimens would give adequate protection from HIV infection. Markowitz et al reported that 800 mg q12wk dosing regimen resulted in suboptimal preventive effects, with plasma concentrations lower than 4x PA-IC90.37 This finding was later confirmed by Landovitz et al, stating that 800 mg q12wk dosing regimen did not consistently meet prespecified PA-IC90 target (80% participants >4x PA-IC90 and 95% >1x PA-IC90). This resulted in second cohort enrollment with 600 mg q8wk dosing regimen, which showed better outcomes where all participants met the prespecified targets.36 Hence, indicating that 600 mg q8wk dosing regimen might be a better alternative than 800 mg q12wk in preventing HIV infection. Safety profiles of injectable long-acting CAB (LA-CAB) are generally acceptable. Spreen et al reported no grade â&#x2030;Ľ2 AE, while Landovitz et al and Markowitz et al reported that 1.49% and 19% patients receiving injectable LA-CAB experienced grade 3 AEs respectively with injection site reaction (ISR) as the main cause in both studies.36,37,40 Spreen et al40 reported that ISR experienced by patients were all mild (Grade 1) and self-limited in severity. The rates of ISR grade <3 were consistent in all studies which showed higher rate in the LA-CAB group compared to placebo group (38.1%36 vs 74.5%37 vs 67.5% IM and 94.44% SC40). Study of long-acting cabotegravir and rilpivirine IM in adults with HIV-1 also showed similar result with our results finding, in which ISR was the most common AEs (97%) experienced and by patients receiving the treatment.50 This result was also consistent with previous studies by Spreen et al.51 Despite the high incidence of ISR, there was no ISR-related withdrawal reported in all studies which indicates that ISR related to LA-CAB administration were mostly tolerable. This might be due to the decline of ISR severity with subsequent injection in all studies.36,37,40 Some common therapy-related AEs were headache (3-44.44%)36,37,40 , musculoskeletal discomfort (3-25.4%)36,37,40, nasopharyngitis (3-10.4%)36,37, and upper respiratory tract infection (4-23.1%)36,37. Recent study of long-acting cabotegravir and rilpivirine IM showed that headache was experienced by 6% patients receiving treatment.50 Spreen et al reported that the only non-ISR AEs that occurred in more than one subject was headache (n = 4).40 While there might be various incidence of AEs, all studies believed that other non-ISR AEs were of low frequency and not significant.36,37,40,50 Landovitz et al reported SAEs occurred in 3% patients receiving LA-CAB, including vertigo, transient weakness, laryngitis, and acute kidney

injury with the last two events were assessed and determined by investigators to be unrelated to study products. Landovitz et al also reported AE-related withdrawals experienced by 24.5% patients receiving LA-CAB which included clinical AEs (n=10) such as constipation, rash/urticaria, headaches, neuropathy, transient weakness, papilledema, and seizure event (patient had preexisting history of seizure disorder) as well as lab abnormality (n=7). However Landovitz et al deemed that SAEs and AE-related withdrawals were not significant statistically and were not safety concern.36 Markowitz et al37 and Spreen et al40 reported no AE-related withdrawal in patients receiving LA-CAB. No studies reported AEs of grade 4 or higher.36,37,40 In terms of cost-effectiveness, LAI CAB might be cost-effective especially for patients with poor adherence. A study evaluating the use of LAI rilpivirine (RPV)52â&#x20AC;&#x201C;an NNRTI approved in first-line HIV therapy for patients with viral load <100,000 copies/ml44â&#x20AC;&#x201C;stated that optimal PrEP prioritization showed significant cost reduction, albeit suboptimal regimens might potentially increase costs and minimize benefits.52 Ten-year behavioral risk prioritization scenario could prevent 4-8% infection, costing $298-1242 per infection prevented (IP); which is further confirmed as cost-saving over lifetime analysis. Furthermore, lifetime analysis of PrEP scale-up among 15% of uninfected 20- to 29-years old female populations might potentially prevent 4.1-7.9% infections while costing $4459-12,721 per IP, superimposing that of unprioritized prophylaxis of 15% of populations (2.3-4.3% IP, $13,85729,873/IP). Despite the fact that HIV preventions might be costly, benefits gained from prevented infections might superimpose the cost spent and thus reducing the disease burdens caused by HIV infections.52 The cost-effectiveness of LAI CAB is further strengthened by the fact that CAB has a higher genetic barrier than first-generation INSTIs, although lower than dolutegravir and bictegravir. It yielded potent clinical activities in HIV isolates resistant to firstgeneration INSTIs and several other mutations. This higher resistance barrier may reduce the hospitalization and higher doses costs, as well as reducing disease burdens caused by drug resistances.46 Although the data inferred in this review suggested that LAI CAB was safe, tolerable, and yielded great pharmacokinetics activities, LAI CAB have several drawbacks, especially its nature which needs resource-intensive settings with frequent patient clinic with a dosing frequency of every few months to ensure adequate protection. In addition, although CAB has a higher genetic resistance barrier and long-acting injections may increase patients adherence, non-adherences may still increase the risk of resistance and cause unwanted adverse effects, thereby suggesting adequate resources and follow-up to prevent patients lost to follow-up.53

Dapivirine vaginal ring (DPV-VR) DPV-VR is a promising candidate for vaginal HIV microbicide as it is associated with practical use, low frequency of administration, and sustained release, thus potentially increasing patients adherence. Furthermore, the clinical activity and safety profile of its oral preparations have been extensively researched, proven to be potent against wild-type HIV-1 and NNRTI-resistant viruses.54 The current formulation of DPV-VR (Ring 004) contains 25 mg of DPV54, which represents the M-IVR of Nel et al42, and DPV-VR model of Nel et al38 and Baeten et al39. In addition to M-IVR, Nel et al also included a second intervention consisting of reservoir-type of DPV-VR (R-IVR).42 This reservoir-type formulation was intended to increase its long activity by adding barium sulfate to the compound. DPV-VR was designed to provide a sustained release over 28-day period, thus aiming to increase patients adherence by administering the drug monthly.54 Pharmacokinetics analysis of DPV-VR showed that M-IVR was superior than R-IVR. Mean M-IVR concentration during the first 24 hours was roughly 50-fold higher than R-IVR. Although R-IVR needed longer time to reach maximum plasma concentration (M-IVR vs. RIVR, 8 hours vs. 10.5 days), its plasma concentration was consistently lower than M-IVR group. In addition, R-IVR reached significantly lower peak plasma concentration, AUC0– , and plasma concentration upon removal (day 28). Nonetheless, the main objective of R-IVR formulation–to increase its sustainable nature–was successful; as shown by Nel et al that only 3% of DPV content in R-IVR was released upon removal, compared to that of M-IVR which released 42% of its content.42 These findings indicate that further development of R-IVR has to be performed in order to provide better protection with the same or even longer duration of action. In general, DPV-VR successfully maintained sustained release for over 1 month. Nel et al showed that DPV-VR resulted in plasma concentration of higher than 100 pg/ml over the study period.42 Even after the ring was removed, it yielded terminal half-life of 6442-67.3541 hours (~2.5 days). Nonetheless, the high variability in pharmacokinetics parameters among the studies included suggest that further international, multicenter-based RCTs have to be conducted to confirm these findings. This study revealed that DPV-VR significantly reduced the incidence of HIV infection by 30.67%38 and 37.00%39. In addition, it is also associated with reduced risk of infection by approximately 30%, as shown by Nel et al38 (HR 0.69, 95% CI 0.49-0.99, p=0.04) and Baeten et al39 (HR 0.63, 95% CI 0.44-0.88, p=0.01). Moreover, the highly acceptable vaginal ring made it one of the most potentially desirable form of long-acting PrEP; as Montgomery et al

stated that most, if not all participants, were willing to continue using DPV-VR as a PrEP as it was easy and comfortable to use.14 Furthermore, DPV-VR were not negatively associated with sexual experiences. In fact, most of the patients and her partners did not feel the ring during sexual intercourse, and some even experienced increased sexual pleasure.55 Safety profiles of DPV-VR was also generally acceptable. The rate of any treatmentrelated AEs ranged from 50% to 75%.38,41,42 Nel et al38 reported 4% incidences of SAEs in patients receiving treatment while there was no SAEs reported in other studies.39,41,42 However, SAEs reported by Nel et al had no significant between-group differences in term of frequency. This same study by Net et al also reported 0.4% rate of product-related AEs, but those AEs were considered mild in severity.38 Some common AEs experienced by patients receiving DPV-VR treatment included headache (0.1-50%)39,41,42, vulvovaginal pruritus (012.5%)39,41,42, and vulvovaginal discomfort (12,5-37.5%)39,41. In the case of vulvovaginal discomfort and vulvovaginal pruritus, Nel et al41 assessed that it probably was not related to DPV-VR treatment. Headache was considered possibly related to IVR treatment regardless of the IVR content (in this case DPV or placebo) in which Nel et al42 reported the same rate of headache (37.5% M-IVR vs 37.5% R-IVR vs 37.5% placebo) with one subject in M-IVR treatment had a grade 3 headache. Nel et al41 in other study also showed similar rate of headache in both treatment and placebo groups (50% vs 37,5%). Baeten et al39 reported only one subject experiencing grade 2 headache in treatment group while there was no headache AEs reported in placebo groups. Other study using anastrozole/levonorgestrel IVR showed 9 subjects (17.3%) experienced headache and was reported as not related to the comedication.56 There was one subject receiving tenofovir IVR who experienced moderate headache in another study.57 Differences between placebo IVR and DPV-VR groups regarding rate of AEs in all studies were mostly considered not significant. DPV-VR was also well tolerated in which there was no AE-related withdrawal in all studies included.38,39,41,42 In addition to its efficacy, safety, and acceptability, DPV-VR was also cost-saving upon risk-prioritization and lowly associated with emerging drug-resistant HIV strains. A mathematical model study conducted by Glaubius et al revealed that only 2-4% of drug resistance cases were attributable to DPV-VR. Furthermore, the use of DPV-VR as PrEP even reduced total resistance by 1.5-1.8%.58 Moreover, Glaubius et al also stated that DPV-VR was cost-saving in nearly all simulations, with incremental cost-effectiveness ratio of lower than South Africa s gross domestic product ($6200) over lifetime analysis; hence, suggesting that

this approach is highly feasible and affordable.58 Furthermore, risk-prioritization of PrEP to female sex workers substantially increased its cost-effectiveness, characterized by decreased total costs and increased life-years. Overall, the implementation of DPV-VR as PrEP led to stable cost-effectiveness ratio, with increased impact and costs upon increasing coverage.58 Study strength and limitations The strength of our review relies in its design which only included RCTs, thus indicating its strong evidence. Furthermore, to the extent of our knowledge, this is the first systematic review evaluating the use of long-acting PrEP to prevent HIV infections in HIVuninfected/healthy patients; hence, serving as reference for further researches investigating similar issues. Nonetheless, the representativeness of this study may still be improved as the sample size included was small. In addition, there are only two Phase III RCTs investigating DPV-VR; thus, calling for future Phase III or higher RCTs which investigate the efficacy of DPV-VR to confirm these findings. Future applications The results of this systematic review may be further implemented to create HIV prevention strategies in order to overcome persisting incidences of HIV. This systematic review may also be the foundation for establishing guideline of long-acting PrEP to reduce new incidences of HIV infection. We recommend further studies done with larger sample size to reduce bias as some of the studies were of small sample size, particularly studies of long-acting injectable PrEP. Nonetheless, as the current published literatures only reviewed LAI CAB and DPV-VR, we also recommend further studies done with other PrEPs to gain more insightful knowledge of their clinical activities.

CONCLUSION In conclusion, this systematic review revealed that long-acting PrEP in the form of LAI CAB and DPV-VR yields excellent potential to prevent HIV infections. Both interventions showed promising pharmacokinetics properties with long terminal half-life and adequate drug plasma concentrations. LAI CAB dosing regimens of

400 mg resulted in plasma

concentrations of >4x PA-IC90 while DPV-VR successfully maintained drug concentrations for over one month. In accordance to its efficacy and pharmacokinetics, both interventions were generally safe with only mild AEs and few grade â&#x2030;Ľ3 AEs. ISR and headache was the most common AE experienced with LAB CAB and DPV-VR treatment, but only ISR was believed directly related to LAB CAB treatment while headache was believed related to vaginal ring

intervention. Overall, both interventions were also well-tolerated with minimal AE-related withdrawal which was regarded as not significant statistically. These summaries may serve as a basis for clinicians and policymakers in establishing strategies and guidelines to prevent HIV infections, thus helping to alleviate the devastating disease burdens caused by HIV worldwide. REFERENCES 1.

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Assessment of Factors Associated with Suboptimal Adherence of HIV Antiretroviral Therapy in Asia: A Systematic Review Jessica Audrey, Ayers Gilberth Ivano Kalaij, Fanny Michelle ABSTRACT Introduction Despite efforts done to battle human immunodeficiency virus (HIV) infection, it still remains as one of the leading cause of deaths worldwide. Asia sits as the second region with most HIV prevalence worldwide. Non-adherence to antiretroviral therapy (ART) is one of the factors which contribute to treatment ineffectiveness. Plenty of studies have tried to research on this problem, yet reviews regarding non-adherence factors in Asia are still lacking. Objective To analyze factors associated with ART suboptimal adherence in Asia Methods A systematic review was conducted through PubMed, Scopus, and CENTRAL, searching for observational studies which analyze factors contributing to ART nonadherence in Asia. Studies selected were then assessed for bias risk with STROBE’s criteria. Results The search yielded twenty observational studies with a total of 18,546 subjects, consisting of 16 cross-sectional studies and 4 cohort studies. Non-adherence to ART was associated with a number of factors. Personal factors, such as gender, age, and personal backgrounds, as well as socioeconomic factors, such as one’s education level and monthly income were significantly associated with adherence. Psychological health of HIV patients also affected their adherence to treatment. Furthermore, distance to health care facilities and patients’ relationship with health care providers were also important. Conclusions To conclude, addressing factors related to treatment non-adherence is important to enhance treatment effectiveness. Knowledge of these factors is hoped to help improve strategies and guidelines for ART adherence, especially in Asia, therefore helping to increase treatment effectiveness and reducing HIV mortality worldwide. Keyword: human immunodeficiency virus, antiretroviral therapy, adherence, Asia INTRODUCTION Despite various efforts aimed to address this problem, human immunodeficiency virus (HIV) still remains as one of the most prevalent yet incurable infectious disease. According to WHO, HIV has infected 75 million people worldwide and approximately, 32 million of them have died since the beginning of its epidemic.1 The treatment of antiretroviral therapy has been

initiated in countries and regions, due to the concern of the development of acquired immunodeficiency syndrome (AIDS) as the next phase of HIV infection. However, 37.9 million people worldwide were still living with HIV in 2018. It is also highlighted that HIV still remains as one of the leading causes of death worldwide as stated by WHO.1,2 A study of global, regional, and national prevalence of HIV showed that the highest prevalence of HIV was found in the region of Africa. In 2017, South Africa had the highest number of new infection with 0.28 million new cases per year.3,4 Thus, plenty of researches have been done in order to eliminate and conquer the HIV/AIDS epidemic in Africa. Surprisingly, next to Africa, Asia sits next as the region with the second highest HIV prevalence, claiming 16% of all HIV prevalence worldwide. Unfortunately, studies assessing HIV in Asia are still lacking.4 Currently, antiretroviral therapy (ART) is the first-line therapy in treating HIV patients, as it decreases the viral load and suppresses the virus.4,5 Even though ART coverage has increased by 90% across all age groups since 2008, HIV prevalence remains high as shown by the stagnant of change in its incidence.3,6 Non-adherence to ART is one major concern that contributes to this problem. Adherence to medication itself plays a crucial role in treatment outcomes, therefore, addressing factors related to adherence could be a breakthrough in making the treatment more effective.7 To the authors’ knowledge, currently no study has comprehensively reviewed the factors related to ART non-adherence specifically in Asian settings, though such review is desperately needed considering the high HIV prevalence in Asian population. Thus, this systematic review aims to assess ART non-adherence factors in Asian HIV patients. Through this endeavor, hopefully, the results of this review can help to improve guidelines of ART adherence in Asian population, as an integral part of achieving United Nations’ Sustainable Developmental Program target 3.3 in 2030, which is to ensure healthy lives regarding universal health coverage, via UNAIDS 90-90-90 strategy with the goal of reducing the mortality rate in HIV.4,5,7 METHODS Search strategy This systematic review of clinical trials is conducted based on PRISMA statement. We explored PubMed, Cochrane Controlled Register of Trials (CENTRAL), Scopus databases up to 10 November 2019 using the following keywords or terms: “ART OR antiretroviral

therapy”, “adherence”, “factors OR risk factors OR factors associated”, and “Asia”. We limited our literature search to studies with English or Bahasa Indonesia language, as these were the languages compatible with the authors. Inclusion and exclusion criteria Studies were screened according to the inclusion criteria as follows: (1) studies of factors influencing ART adherence with extractable outcomes, (2) observational study design, namely cohort, case-control, and cross-sectional studies, and (3) conducted in Asian countries. Afterwards, exclusion criteria were also set, which include (1) irretrievable full-text articles, and (2) inappropriate study types or design. Details of study search strategy are shown in Figure 1. Data extraction and risk of bias assessment Subsequently, we extracted data from our selected articles, which include author and year of publication, study design and settings, sample size, mean or range of age of samples, and outcomes as expressed by odds ratio of each factors. Articles were also assessed in terms of quality by using the STROBE’s criteria (Strengthening the Reporting of Observational Studies in Epidemiology). Quality assessment was done collaboratively by three reviewers until consensus were reached. Risk of bias assessment was provided in Appendix 1. RESULTS Study selection The process of literature searching and selection is illustrated in Figure 1. Initial search from PubMed, EBSCOhost, and Scopus yielded a total of 583 studies. Duplicates were removed, titles and abstracts were screened, and full-text articles were then assessed for eligibility. Thirty-eight studies were further excluded due to irrelevant study types, inappropriate location, language restrictions, not discussing factors related to drug adherence, and irrelevant outcomes. This resulted in a final of 20 studies to be included in qualitative synthesis, comprising of 16 cross-sectional and 4 cohort studies.

Figure 1. Diagram flow of literature search strategy

Study characteristics and outcomes Study characteristic included in this review are shown in Table 1. Overall, this review included a total of 18,546 patients. Out of the 20 included studies, 16 were cross-sectional studies and the remaining 4 were cohort studies. Study locations varied across Asia. Outcomes were factors which were significantly related to ART non-adherence, provided in odds ratio (OR) with their corresponding p-values.

Table 1. Study characteristics Author and Year (STROBE’s score) Kim J et al, 2018.8 (20.60/22)

Study Design Cohort Prospective

Location

Sample Size

Range/ mean of sample age

Korea

8501

0-50 years

Nguyen NT et al, 2016.9 (20.50/22)

Cross-sectional

Vietnam

1050

35.6 years

Yathiraj BA et al, 2016.10 (21.47/22)

Cross-sectional

South India

409

≥18 years

Jiamsakul A et Al, 2014.11 (21.36/22)

Prospective cohort

Asia (Thailand, Hong Kong,

1316

≤30 – 51+ years

Outcome Requiring prophylactic antibiotics Female gender Age of 0-19 and same or over 50 Age 30-39 Having a history of malignancy Lower socioeconomic status Being diagnosed in the earlier years Greater nicotine dependence Currently feeling anxiety Current smokers reporting current pain Living with spouse/partner Having more than a high school education Patient-Related Factors Females Not forget to take ART Not consuming alcohol Good family care Medication-Related Factors Absence of opportunistic infection The sense of feeling better after taking ART Health System-Related Factors Distance from hospital >25 km >2 assessments per patients per year

p value

1.70 1.60 1.60 1.40 1.60 2.10 1.60 to 3.80

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

1.10 1.60 1.92 0.45 0.36

<0.0001 0.049 <0.01 <0.01 <0.01 0.04

0.50 0.10 0.30 0.30

<0.05 <0.05 <0.05 <0.05

0.40 0.60

0.02

0.40 0.7

0.001 0.006

Injecting drug users

1.92

0.004

Homosexual exposure

0.52

<0.001

0.03

Malaysia, the Philippines, and Indonesia Negi BS et al, 2018.12 (21.47/22) Tran BX et al, 2018.13 (18.14)

Cohort Prospective

Pokhrel KN et al, 2018.14 (20.27/22) Wasti SP et al, 2012.15 (20.47/22)

Weaver ER et al, 2014.16 (19.80/22) SagaonTeyssier L et al, 2017.17 (18.13/22)

Nepal

305

40 years

Cross-sectional

Vietnam

1133

18 - ≥45 years

Cross-sectional

Nepal

682

36.3 years

Taking a nucleoside transcriptase inhibitor and protease inhibitor Time on ART 6 to 12 months

0.36

0.001

0.59

<0.001

Time on ART 12 to 18 months

0.40

<0.001

Time on ART 18 to 24 months

0.35

<0.001

Age ≥40s Disclosed HIV status Strong PTSD symptoms Self-employed Self-care problem Anxiety and Depression Farmers Harmful alcohol drinking

3.30 50.0 5.0 1.41 1.79 1.60 0.61 2.48 2.52

<0.042 0.001 <0.001 <0.01 <0.05 <0.01 <0.05 <0.001 0.005

Non-disclosure of HIV status

17.99

0.014

Alcohol use

12.89

<0.001

Being female

6.91

0.001

Being illiterate

4.58

0.015

Side effects

6.04

0.025

ART started ≤24 months

3.18

0.009

Travel time to hospital >1 hour

2.84

0.035

Some level of social support

0.328

0.018

Good level of social support

0.399

0.039

Health care outside capital city

6.15

<0.05

Psychosocial actors present

0.62

<0.05

Stigmatising events

1.13

<0.001

Women Cross-sectional mixed methods study

Nepal

Cross-sectional study

Indonesia

Cross-sectional study

Cambodia

282

261

1316

35.8 years

33.4 years

42 years

Wang X et al, 2007.18 (19.27/22)

Wang YY et al, 2018.19 (20.27/22) Venkatesh KK et al, 2010.20 (18.80/22)

Cross-sectional study

China

Cross-sectional study

China

Cross-sectional study

India

Wang H et al, 2008.21 (20.80/22) Lee S et al, 2016.22 (20.60/22)

Cross-sectional study

China

Retrospective cohort

Korea

Xu L et al, 2017.23 (20.47/22)

Cross sectional mixed methods

Thailand

181

516

198

308

247

568

47.8 years

34.4 years

41 years

42 years

12-19 years

Respect from health workers

0.25

<0.05

Paid for consultation

5.61

<0.001

Knowledge about side effects

0.124

<0.001

Belief towards ART

0.313

0.016

Reminder tools

0.287

0.010

Trust in doctor

0.128

0.027

Having confidence in ART

0.20

0.040

More homosexual sex partners

1.50

0.049

CD4 cell counts >500 cells per microliter

2.22

0.038

On HAART for >24 months

3.07

0.007

Reported alcohol use

5.68

0.001

Low general health perceptions

3.58

0.021

High distress

3.32

0.022

Active heroin use

2.50

0.040

Not using reminder

5.50

0.0001

ART-starting age <30 years

4.08

0.036

No non-HIV related comorbidity

2.94

0.046

Baseline CD4 cell count >300 cells/ÂľL

3.58

0.012

Age 16-19

0.575

0.037

Caregiver-assessed poor intellectual ability

2.886

0.004

1.649

0.039

2.100

0.003

Having grandparents as the primary caregiver Having other family members as the primary care giver

Muessig KE et al, 2014.24 (17.74/22)

Cross sectional

Pahari S et al, 2015.25 (18.74/22)

Cross sectional

Bhattacharya M et al, 2011.26 (17.74/22)

Cross sectional

Abdulrahman SA et al, 2017.27 (17.00/22)

Cross sectional

Guangzhou, China

813

West Bengal, India

128

New Delhi, India

Selangor, Malaysia

≥18 years

9.5 years

Self-reported easiness in asking doctors questions

0.510

0.012

Self-reported happy

2.420

0.004

Self-reported average happiness

2.716

0.002

Self-reported unhappy or very unhappy

3.849

<0.001

Having a boy/girlfriend

1.965

0.007

High school as last education

3.39

0.011

Middle school as last education

3.31

0.008

≤ Primary school as last education

4.52

0.002

Not cohabitating/married

1.49

0.049

Drinking alcohol several times a month

3.76

0.002

Drinking alcohol several times a week

2.31

0.001

1 to 3 years on ART

1.76

0.020

7-12 month of ART intake

7.8

0.03

Non-disclosure of HIV status to family members

4.9

0.02

Increasing duration of ART

1.08

0.01

Caregiver not educated beyond 5 grade

4.19

0.01

Orphan

3.57

0.03

Efavirenz-based regimen

3.65

0.04

Female gender

3.15

0.04

Chinese ethnic

2.01

0.044

Monthly income 3500-4999 RM

0.28

0.044

Monthly income >5000 RM

0.19

0.008

242

33.4 years

Notes: HIV, human immunodeficiency virus; ART, antiretroviral therapy; HAART, highly active antiretroviral therapy

DISCUSSION a. Analysis of the Study Based on the above included studies, we classified the factors into personal-related, socioeconomic, psychological, and healthcare-related factors Personal-related factors Some personal-related factors are associated with elevated risk of non-adherence to ART in HIV/AIDS patients. According to Kim J et al8, female gender was a risk factor for suboptimal adherence to ART compared to male (OR = 1.60), although most HIV-infected individuals were males.8 This study is in line with cross-sectional studies by Pokhrel14, Wasti15, and Bhattacharya26 which also found that being female increased non-adherence to ART by 2.52, 6.91, and 3.15 times respectively. However, one study by Yathiraj10 demonstrated a different outcome, showing that females were instead more adherent to ART (OR = 0.5). This may be due to the fact that many of the female participants in this study were widows, living with their families who might prompt to always remind them in terms of taking their medications regularly. Similarly, several previous studies also showed that males were more adherent than females.28-32 These findings indicated that gender correlation to ART adherence was still inconsistent and differed between studies, probably depending on study locations as cultures and gender views differed between countries and ethnic groups. Abdulrahman27, for example, in his study showed that Chinese tend to be less adherent to ART (OR=2.01), again implying the possible roles of social cultures toward personal adherence. Furthermore, age is another factor associated with adherence to ART. Xu23, in his study, found that younger patients under 19 years old (16-19 years) were more likely to be adherent to therapy (OR=0.575). On the other hand, study by Kim showed that patients being in their 20s and same or over 50s were significantly associated with non-adherence to ART than those in their 30s (OR 1.6 and OR 1.4 respectively).8 A plausible explanation for this is the difference in activity and memory of patients across age groups. The 20s patients are still that young that could have too much that they should handle which leads to forgetting of ART consumption. This is also supported by a study by Vinikoor33 which found that 16- to 29-year-old HIV patients were more likely to have health-neglecting behaviors in relation with the tendency of young adults to overwork. Yet, factors influencing adherence in each age groups were so diverse, such that it may be difficult to predict which group was most

likely to be non-adherent. It is highly dependent on the specific characteristics of the population, therefore, suggesting the need to comprehensively assess each population traits in order to effectively address problems related to adherence in specific regions. Social, economic, and environmental factors Socioeconomics status, including education levels and social environment, are found to be one of the major risk factors of non-adherence of ART in HIV/AIDS patients. Kim, in his study, found that lower socioeconomic status was a risk factor for non-adherence to ART (OR = 2.10).8 Lower socioeconomic status is associated with difficulties in dealing with the cost of medical treatment and transportation, prompting them to neglect treatment.34 Study by Abdulrahman27 further supported this claim by showing that higher monthly income was associated with optimal adherence (OR=0.28 and 0.19). A lower socioeconomic status is usually accompanied by lower educational level, thus, lacking awareness in the importance of regular medications which is often associated with low general health perceptions (OR=3.58), thereby negatively affects adherence.35 Muessig24 found that having high school, middle school, and less than primary school as last education increases non-adherence by 3.39, 3.31, and 4.52 times. This is consistent with a study by Nguyen9 included in the above review, which stated that having higher education is a protective factor which reduces the suboptimal adherence to ART (OR=0.36). These results emphasize the importance of educating the public on the importance of medication adherence in HIV/AIDS patients, especially those with a lower socioeconomic status.8,34 Social environment is also found to be the important in achieving optimal adherence. Several studies reviewed above demonstrated that living with spouse/partner (OR=0.45)9, good family care (OR=0.30)10, some level of social support (OR=0.328), and good level of social support (OR=0.399)16 are factors that often associated with decrease in non-adherence. Living surrounded by supportive family and caregivers could help to properly educate and remind patients to take their medications regularly. Moreover, good social support also motivates patients to achieve better health outcomes. In contrast, having other people other than parents as primary caregivers (OR=2.1)23, not married (OR=1.49)24, and being orphan (OR=1.965)26 were shown to increase non-adherence, again due to the lack of surrounding social support. Public perceptions and attitudes towards HIV/AIDS is also an especially important social factor. Stigmatising events were found to increase non-adherence to ART by 1.13

times.17 Internalizing stigma may happen when an HIV-infected individual accepts the stigmatizing beliefs held by a majority of the community and takes it as a valid belief. Therefore, HIV patients tend to keep their disease to themselves and delay disclosure until concealment is no longer possible. Concealment in turn may lead to treatment interruption, as the fear of disclosure and worrying about others finding out make them susceptible to skipping their medications when others are around.36 This is consistent with the findings from our review that non-disclosure is an important factor contributing to non-adherence, as shown by studies by Pahari25 and Wasti15 (OR=4.9 and 17.99 respectively). Thus, interventions aimed to improve social support towards HIV patients and targeting social influences are needed to ensure that treatment is effective. Psychological factors Aside from social factors discussed above, individual psychological states of patients were also found to contribute significantly towards treatment adherence. Five studies showed that feeling of anxiety (OR=1.6)9, pain (OR=1.92)9, post-traumatic stress disorder (PTSD) (OR=5.0)12, problem with self-care (OR=1.79)13, depression (OR=1.60)13, high distress (OR=3.32)20, and unhappiness (OR=3.85)23 were associated with increased risks of treatment non-adherence. Furthermore, people who were not mentally well were also at risk in falling into drug use or substance abuse, which again was related significantly to treatment nonadherence, as shown by several studies in our review.9,11,14-15,20-21,24 Conversely, a study by Sagaon-Teyssier17 also found that the presence of psychosocial actors was associated with lower non-adherence (OR=0.62), probably due to the psychological support given to HIV patients. Such adherence may probably arise from increased confidence and motivation to engage in their disease management as their depressive symptoms subsided. In fact, these results were consistent with other studies which found that psychosocial interventions can positively affect medication adherence of people living with HIV.37-38 This highlights the importance of properly assessing and addressing underlying mental problems in order to improve adherence. Healthcare-related factors Another factor that affects adherence to ART is health care provision. According to Wasti et al15, patients who needed to travel more than 1 hour to the hospital were more likely to be non-adherent to ART. This is supported by the finding that patients treated outside the capital city were also more likely to be non-adherent.17 Thus, this means that patients tend to

be adhere more to therapy if they can receive treatment easily. However, one study showed conflicting results; according to Yathiraj et al10, patients who needed to travel further distance (≥ 25km) in order to receive ART were instead more adherent to therapy. This is probably due to patients’ preference for a specific further health center, or perhaps, so that they could worry less about unintentionally disclosing their HIV status to nearby family, friends, or neighbors. Furthermore, the relationship between the patient and their health care provider also affects their adherence. According to Sagaon-Teyssier17, respect from health workers made the patients more likely to adhere to the therapy (OR=0.25). The patient’s trust and easiness to ask questions to the doctor affect their adherence as well.18,23 This implies the significance of doctors or other health care providers to constantly maintain a respectful and friendly attitude, as well as communicate effectively with their patients in such a way that they could easily understand and aware of the importance and possible side effects from their therapy.17 b. Study strengths and limitations The strength of this study lies on the fact that it comprehensively assesses the risk factors related to ART non-adherence and the relatively large number of samples. Moreover, study locations also vary across different countries in Asia. However, the exclusion of inaccessible full-text articles and studies with incompatible language may present as a limitation. c. Future application and research The result of the above systematic review can be further applied to formulate strategies to address problems related to ART non-adherence, thus improving effectiveness of treatment outcomes. Based on the above assessed factors, we suggest the implementation of the following approach: 1.! Assess patients’ characteristics and understand their personal and cultural backgrounds to identify possible personal factors to non-adherence 2.! Improve social support and abolish stigma towards HIV patients 3.! Properly address and identify patients’ mental health 4.! Facilitate improvement of HIV-related healthcare facilities and encourage a better doctor-patient relationship in dealing with HIV/AIDS problems

CONCLUSION To conclude, based on the above review, non-adherence to ART in HIV patients is associated with various factors. Our study showed that personal factors such as gender, age, and personal backgrounds, socioeconomic and environmental factors, psychological factors such as anxiety and depression, as well as healthcare-related factors were associated with suboptimal adherence to ART. Such non-adherence would then result in treatment ineffectiveness. We hope that the assessment of above risk factors could help formulate strategies and comprehensive guidelines to prevent HIV ART non-adherence in Asia. Moreover, knowledge regarding these factors could also raise the awareness of health workers to pay specific attention to patients who are at risk of being non-adherent, as well as encourage the public to have a proper perception and attitude towards people living with HIV. In doing so, it is hoped that non-adherence rate could decrease, increasing treatment effectiveness especially in Asia, thus helping to reduce mortality rate of HIV worldwide.

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in Coastal South India. Journal of the International Association of Providers of AIDS Care (JIAPAC). 2016;15(6):529-533. 11.!Jiamsakul A, Kumarasamy N, Ditangco R, Li PC, Phanuphak, Sirisanthana T, et al. Factors associated with suboptimal adherence to antiretroviral therapy in Asia. J Int AIDS Soc. 2014 May 16;17:18911 12.!Negi B, Joshi S, Nakazawa M, Kotaki T, Bastola A, Kameoka M. Impact of a massive earthquake on adherence to antiretroviral therapy, mental health, and treatment failure among people living with HIV in Nepal. PLOS ONE. 2018;13(6):e0198071. 13.!Tran B, Fleming M, Do H, Nguyen L, Latkin C. Quality of life improvement, social stigma and antiretroviral treatment adherence: implications for long-term HIV/AIDS care. AIDS Care. 2018;30(12):1524-1531. 14.!Pokhrel K, Gaulee PK, Neupane S, Sharma V. Harmful alcohol drinking among HIVpositive people in Nepal: an overlooked threat to anti-retroviral therapy adherence and health-related quality of life. Global Health Action. 2018;11(1):1441783. 15.!Wasti S, Simkhada P, Randall J, Freeman J, van Teijlingen E. Factors influencing adherence to antiretroviral treatment in Nepal: a mixed-methods study. PLoS ONE. 2012;7(5):e35547. 16.!Weaver E, Pane M, Wandra T, Windiyaningsih C, Herlina, Samaan G. Factors that influence adherence to antiretroviral treatment in an urban population, Jakarta, Indonesia. PLoS ONE. 2014;9(9):e107543. 17.!Sagaon-Teyssier L, Mmadi Mrenda B, Khol V, Ferradini L, Mam S, Ngin S et al. Adherence to PI-based 2nd-line regimens in Cambodia is not simply a question of individual behaviour: the ANRS 12276 2PICAM study. Tropical Medicine & International Health. 2017;22(11):1428-1435. 18.!Wang X, Wu Z. Factors associated with adherence to antiretroviral therapy among HIV/AIDS patients in rural China. AIDS. 2007;21(Suppl 8):S149-S155. 19.!Wang Y, Wang T, Yan H, Dâ&#x20AC;&#x2122;Amato R, Wang W, Li S. Evaluating the relationship between adherence to Highly Active Antiretroviral Therapy (HAART) and social and clinical characteristics in Chinese patients with HIV. AIDS Care. 2018;31(1):14-18. 20.!Venkatesh K, Srikrishnan A, Mayer K, Kumarasamy N, Raminani S, Thamburaj E et al. Predictors of nonadherence to highly active antiretroviral therapy among HIVinfected South Indians in clinical care: implications for developing adherence interventions in resource-limited settings. AIDS Patient Care and STDs. 2010;24(12):795-803.

21.!Wang H, He G, Li X, Yang A, Chen X, Fennie K et al. Self-Reported Adherence to Antiretroviral Treatment among HIV-Infected People in Central China. AIDS Patient Care and STDs. 2008;22(1):71-80. 22.!Lee S, Lee S, Lee S, Kim K, Lee J, Cho H et al. Predictors of poor retention in care of HIV-infected patients receiving antiretroviral therapy in Korea: five-year hospitalbased retrospective cohort study. Journal of Korean Medical Science. 2016;31(3):376. 23.!Xu L, Munir K, Kanabkaew C, Le Coeur S. Factors influencing antiretroviral treatment suboptimal adherence among perinatally HIV-infected adolescents in Thailand. PLOS ONE. 2017;12(2):e0172392. 24.!Muessig K, McLaughlin M, Nie J, Cai W, Zheng H, Yang L et al. Suboptimal antiretroviral therapy adherence among HIV-infected adults in Guangzhou, China. AIDS Care. 2014;26(8):988-995. 25.!Pahari S, Roy S, Mandal A, Kuila S, Panda S. Adherence to anti-retroviral therapy & factors associated with it: A community based cross-sectional study from West Bengal, India. Indian Journal of Medical Research. 2015;142(3):301. 26.!Bhattacharya M, Dubey A. Adherence to antiretroviral therapy and its correlates among HIV-infected children at an HIV clinic in New Delhi. Annals of Tropical Paediatrics. 2011;31(4):331-337. 27.!Abdulrahman S, Rampal L, Othman N, Ibrahim F, Kadir Shahar H, Radhakrishnan A. Socioeconomic Predictors of Adherence Behavior Among HIV-Positive Patients Receiving Antiretroviral Therapy in Selangor, Malaysia. Asia Pacific Journal of Public Health. 2017;29(4):304-314. 28.!Achappa B, Madi D, Bhaskaran U, et al. Adherence to antiretroviral therapy among people living with HIV. N Am J Med Sci. 2013;5(3):220–223 29.!Bam K, Rajbhandari RM, Karmacharya DB, Dixit SM. Strengthening adherence to Anti Retroviral Therapy (ART) monitoring and support: operation research to identify barriers and facilitators in Nepal. BMC Health Serv Res. 2015;15:188. 22. 30.!Aragone´s C, Sa´nchez L, Campos JR, Pe´rez J. Antiretroviral therapy adherence in persons with HIV/AIDS in Cuba. MEDICC rev. 2011;13(2):17–23. 26. 31.!Saha R, Saha I, Sarkar AP, et al. Adherence to highly active antiretroviral therapy in a tertiary care hospital in West Bengal, India. Singapore Med J. 2014;55(2):92–98. 32.!Uzochukwu BS, Onwujekwe OE, Onoka AC, et al. Determinants of non-adherence to subsidized anti-retroviral treatment in southeast Nigeria. Health Policy Plan. 2009;24(3):189–196.

33.!Vinikoor M, Joseph J, Mwale J, Marx M, Goma F, Mulenga L et al. Age at Antiretroviral therapy initiation predicts immune recovery, death, and loss to follow-up among HIV-infected adults in urban Zambia. AIDS Research and Human Retroviruses. 2014;30(10):949-955. 34.!Simoni JM, Huh D, Wilson IB, Shen J, Goggin K, Reynolds NR, et al. Racial/Ethnic disparities in ART adherence in the United States: findings from the MACH14 study. J Acquir Immune Defic Syndr. 2012 Aug 15; 60(5):466-72. 35.!Macdonell KE, Naar-King S, Murphy DA, Parsons JT, Harper GW. Predictors of medication adherence in high risk youth of color living with HIV. J Pediatr Psychol. 2010 Jul; 35(6):593-601. 36.!Katz I, Ryu A, Onuegbu A, Psaros C, Weiser S, Bangsberg D et al. Impact of HIVrelated stigma on treatment adherence: systematic review and meta-synthesis. Journal of the International AIDS Society. 2013;16:18640. 37.!Wagner G, Ghosh-Dastidar B, Robinson E, Ngo V, Glick P, Mukasa B et al. Effects of Depression Alleviation on ART Adherence and HIV Clinic Attendance in Uganda, and the Mediating Roles of Self-Efficacy and Motivation. AIDS and Behavior. 2016;21(6):1655-1664. 38.!Spaan P, van Luenen S, Garnefski N, Kraaij V. Psychosocial interventions enhance HIV medication adherence: A systematic review and meta-analysis. Journal of Health Psychology. 2018;:135910531875554.

Table 2. Studies quality assessment based on STROBE’s criteria Item No

Title and abstract

Kim J et al

Ngu yen NT et al

Yath iraj BA et al

Jiam saku lA et al

Negi BS et al

Trai n BX et al

Pok hrel KN et al

Was ti SP et al

Wea ver ER et al

Sagao nTeyss ier et al

Wan gX et al

Wan g YY et al

Vent akes h KK et al

Wan gH et al

Lee S et al

Xu L et al

Mue ssig KE et al

Paha ri et al

Bhat tach arya et al

Abd ulra hma n et al

Yes

(b) Provide in the abstract an informative and balanced summary of what was done and what was found

Yes

Recommendation (a) Indicate the study’s design with a commonly used term in the title or the abstract

Introduction Background/ rationale

Explain the scientific background and rationale for the investigation being reported

Yes

Objectives

State specific objectives, including any prespecified hypotheses

Yes

Methods Study design

Present key elements of study design early in the paper

Yes

Setting

Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-

Yes

up, and data collection Participants

(a) Cohort study— Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up

Yes

N/A

Yes

N/A

Yes

N/A

Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study— For matched studies, give matching criteria and number of exposed and unexposed Case-control study—For Yesmatched studies, give matching criteria and the number of controls per case

Variables

Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable

Yes

Data sources/ measurement

For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group

Yes

Bias

Describe any efforts to address potential sources of bias

Yes

Study size

Explain how the study size was arrived at

Yes

Quantitative variables

Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why

Yes

Statistical methods

(a) Describe all statistical methods, including those used to control for confounding

Yes

(b) Describe any methods used to

Yes

examine subgroups and interactions (c) Explain how missing data were addressed

Yes

(d) Cohort study— If applicable, explain how loss to follow-up was addressed

Yes

(e) Describe any sensitivity analyses

Yes

(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed

Yes

(b) Give reasons for non-participation at each stage

Yes

Case-control study—If applicable, explain how matching of cases and controls was addressed Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy

Results Participants

13*

Descriptive data

Outcome data

Main results

14*

15*

Yes

(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders

Yes

(b) Indicate number of participants with missing data for each variable of interest

Yes

N/A

Yes

N/A

Yes

N/A

Cohort study— Report numbers of outcome events or summary measures over time

Yes

N/A

Yes

N/A

Yes

N/A

Case-control study—Report numbers in each exposure category, or summary measures of exposure

N/A

Cross-sectional study—Report numbers of outcome events or summary measures

N/A

Yes

N/A

Yes

(a) Give unadjusted estimates and, if applicable, confounder-adjusted

Yes

estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized

Yes

N/A

Yes

N/A

Yes

Other analyses

Report other analyses doneâ&#x20AC;&#x201D;eg analyses of subgroups and interactions, and sensitivity analyses

Yes

Discussion Key results

Summarise key results with reference to study objectives

Yes

Limitations

Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and

Yes

magnitude of any potential bias Interpretation

Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

Yes

Generalisability

Discuss the generalisability (external validity) of the study results

Yes

Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based

Yes

TOTAL

20.6

20.5

21.47

21.36

21.47

18.14

20.27

20.47

19.80

18.13

19.27

20.27

18.80

20.8

20.6

20.47

17.74

18.74

17.74

Other information Funding 22

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.

AMINO | AMSA INTERNATIONAL COMPETITION 19/20

Accepting People with HIV through CHILL HIV (Human Immunodeficiency Virus) has become one of many diseases which raises a global concern. Until now, HIV has taken more than 32 million lives. HIV causes a huge number of mortalities because of its unique characteristic; once a person infected with this virus, they will suffer from it for the rest of their lives. There is no known cure yet for HIV infection.1 This particular disease raises a great deal of fear within the society, creating a stigma. Based on a recent research in 35% countries with data available, there are more than 50% of women and men with discrimination attitudes towards people with HIV. There are also reports stating that HIV patients are being denied by health services.2 Because of its sexual trademark, the public condemned HIV patients. Most people misunderstood HIV. They fear the disease so badly and start to isolate people with HIV in the community. Society does not understand the impact of their behaviors and what it feels like to live with HIV. People with HIV are being judged constantly, thus leading them to question their own values. “Internalized stigma” or “self-stigma” is a related condition when a person accepts all the negative stereotypes and apply those things to themselves which in turn, those things will affect their self-esteem, quality of life, and their compliance in treatment.3,4 According to World AIDS Day, UNAIDS (United Nations Program on HIV/AIDS) aims to eliminate HIV-related discrimination by 2020.2 Creators proposed an intervention in helping to eliminate this stigma. A livelihood intervention of HIV stigma could be done through: “positive changes in the patient’s self-evaluations” and also by “acceptance and compassionbased group therapy”.5,6 This intervention is shown in the public poster as an idea to help society to understand more about HIV, and hopefully, it will change the society’s misconception about people with HIV. Creators want to convey a simple algorithm that can be easily remembered called “CHILL”. First, CH is for Change mindset! Avoid the disease, not the person. People tend to avoid HIV patients and not the disease itself. By talking about HIV, in public or personally to the people with HIV, people will get used to them. This will create an opportunity to clear up the misunderstanding and help people to learn the truth about HIV which in turn, people will slowly change their thoughts about people with HIV.3 Second, I is for It’s safe to share plates and hug each other. It is true that HIV is transmitted through sexual contact. However, people should understand that it is okay to kiss, to hug, to shake hands, to share personal objects, and even to share food or water.1 Third, L is for Let’s build their confidence through peer-support. By inviting HIV patients in a group of peer-support, others

could help them build their confidence to live their lives in the future, instead of avoiding them in the society.6 Fourth, second L is for Let them prove their capability to do something better. People with HIV are still part of the community that need to make a living. They are still able to do the things they do before and even after they are infected with HIV, so others should give them a chance to do something better and useful for their lives.6 By doing CHILL, creators hope that people will contribute to reducing HIV stigma in society, and this should be applied to all people, including medical personnel, strangers, and their own family. Letâ&#x20AC;&#x2122;s accept HIV as any other diseases and letâ&#x20AC;&#x2122;s be chill around them!

Bibliography 1.

WHO.

HIV/AIDS

[Internet].

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CDC. Facts about HIV Stigma [Internet]. 2019 [cited 2019 Nov 12]. Available from: https://www.cdc.gov/hiv/basics/hiv-stigma/index.html

Szcześniak D, Kobyłko A, Wojciechowska I, Kłapciński M, Rymaszewska J. Internalized stigma and its correlates among patients with severe mental illness. Neuropsychiatr Dis Treat

[Internet].

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Tsai AC, Hatcher AM, Bukusi EA, Weke E, Lemus Hufstedler L, Dworkin SL, et al. A Livelihood Intervention to Reduce the Stigma of HIV in Rural Kenya: Longitudinal Qualitative Study. AIDS Behav. 2017;21(1):248–60.

Skinta MD, Lezama M, Wells G, Dilley JW. Acceptance and Compassion-Based Group Therapy to Reduce HIV Stigma. Cogn Behav Pract [Internet]. 2015;22(4):481–90. Available from: http://dx.doi.org/10.1016/j.cbpra.2014.05.006

It’s Now or Never: Stop the Stigma! Abstract There are approximately 37.9 million people with HIV and another 1.7 million people that is newly diagnosed by 2018. The HIV itself is pandemic (worldwide) and it is mainly spread in Africa, then to Latin America and Asia. It mostly affects adults but it does not mean that children won't be affected by HIV. It can’t be denied that people around the world are stigmatizing HIV-positive people. It is extremely important to abolish the stigma in the society in order to make the world a better place for those people living with HIV. In Indonesia itself, the number of people with HIV has increased every year. One of the main reasons for this trend is the use of unsterile needles, especially for injecting drugs. HIV and AIDS are still considered as a disease where people can’t really talk about, even to their family and health workers. This makes people with HIV and their families exceptionally vulnerable to the stigma and discrimination, which results in obstacles to get treated. Stigma itself can be categorized into two types, namely the one comes within yourself and the one comes from people around you. Internal stigma arises from fear in PLWHA (People Living with HIV/AIDS) and also as a result of internalization of external stigma. External stigma is obtained by people living with HIV in the form of discrimination, intimidation and neglection. Eventually, HIV-positive IDUs (Injection Drug Users) who are stigmatized will stop seeking for help, delaying treatment or even choosing to end their treatment. Their self-confidence to overcome their addiction problems will also be reduced due to the stigma they get. The stigma against PLWHA has a large impact on HIV/AIDS prevention and control programs including their quality of life. The population at risk will be afraid to get tested because if the results are revealed to be positive, it can cause them to be exiled. On the other hand, HIVpositive people are afraid to admit their HIV status and decided to postpone their treatment, which would definitely impact their health especially pregnant mother. The stigma arises because the majority of people don't understand about HIV themselves. They lack knowledge about the mechanism of HIV transmission, groups of people at risk and

how to prevent it in their everyday life, including the use of condoms. Stigma surely is one of the biggest obstacles faced to overcome HIV/AIDS. The most important efforts to tackle discrimination against HIV positive people is to widen society’s understanding of HIV and AIDS. Knowledge about HIV/AIDS greatly influences one's attitude towards people with HIV / AIDS. Apparently, the Indonesian Ministry of Health has proven that almost 75% of people who have minor knowledge about STIs (Sexual Transmitted Infections) and HIV/AIDS tend to stigmatize people with HIV. On the other hand, people who have enough knowledge about risk factors, transmission, prevention, and treatment of HIV/AIDS tend not to be afraid and do not give a stigma against people living with HIV. In fact, the majority of people have had information related to HIV/AIDS which they got from various sources. However, there are still many people out there who are still fixated on the stigma that has been circulating in the society. Up until now, our society are still stigmatizing people with HIV/AIDS and it is our job, as a society and as a medical student, to terminate those stigma in order to give people the knowledge that people with HIV is not what they think it is. HIV-positive people are not monsters and they deserve to live just like all normal people live. That is mainly the reason why we make the poster to educate the society about HIV’s basic knowledge. Starting from ourselves as an individual, then spreading the words to ‘avoid the virus but not the people’. There are a few things that can be done individually to change the stigma about PLWHA, such as being aware of our language choices and avoid stigmatizing words and supporting them to make use of the available services like counseling, HIV testing, medical treatment or referring them to a specialist. Doing as simple as listening and paying more attention to those people with HIV/AIDS could be a huge support for them. Starting from ourselves, we can then explain to the society about the real things about HIV/AIDS and help them go against the stigma. Providing testimonials of people living with HIV/AIDS and their friend or family’s experience living with HIV positive people. That way, the society will know that it is okay to live with people with HIV. The stigma against HIV positive people appears to be related to a person's lack of knowledge about the mechanism of HIV transmission and negative attitudes that are influenced by the HIV/AIDS epidemic in the community. Misunderstanding or lack of public knowledge

about HIV/AIDS often has an impact on people's fears of the people with HIV, leading to a rejection. Providing complete information, whether through counseling or outreach about HIV/AIDS to the community, plays an important role in reducing the stigma of People with HIV. With that, as a society, we can avoid the HIV virus but not the people with it. Keywords: HIV, AIDS, Stigma, HIV-positive people

BIBLIOGRAPHY ● Campaigns | Let's Stop HIV Together | CDC [Internet]. Cdc.gov. 2019 [cited 29 October 2019]. Available from: https://www.cdc.gov/stophivtogether/campaigns/index.html ● Data and statistics [Internet]. World Health Organization. 2019 [cited 12 November 2019]. Available from: https://www.who.int/hiv/data/en/ ● Global Statistics [Internet]. HIV.gov. 2019 [cited 29 October 2019]. Available from: https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics ● Handy F, Kaptiningsih A, Daili S. et all, PEDOMAN PELAKSANAAN PENCEGAHAN PENULARAN HIV DAN SIFILIS DARI IBU KE ANAK BAGI TENAGA KESEHATAN. Jakarta: Kementerian Kesehatan RI. 2014; 2015. ● HIV/AIDS [Internet]. Who.int. 2019 [cited 30 October 2019]. Available from: https://www.who.int/news-room/fact-sheets/detail/hiv-aids ● Pregnant Women, Infants, and Children | Gender | HIV by Group | HIV/AIDS | CDC [Internet].

Cdc.gov.

2019

[cited

November

2019].

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from:

https://www.cdc.gov/hiv/group/gender/pregnantwomen/index.html ● Prevention | HIV Basics | HIV/AIDS | CDC [Internet]. Cdc.gov. 2019 [cited 29 October 2019]. Available from: https://www.cdc.gov/hiv/basics/prevention.html ● When to Start Antiretroviral Therapy Understanding HIV/AIDS [Internet]. AIDSinfo. 2019 [cited 30 October 2019]. Available from: https://aidsinfo.nih.gov/understandinghiv-aids/fact-sheets/21/52/when-to-start-antiretroviral-therapy

Leave the Stigma and Welcome to the New Era World is facing a serious public health problem: Acquired Immune Deficiency Syndrome (AIDS), caused by Human Immunodeficiency Virus (HIV). HIV infection has killed 39 million people since its identification in 1980. By 2018, approximately 37.9 million people across the globe living with HIV infection. In fact, 36.2 million were adults and 1.7 million were children (<15 years old) (1). We can see that a lot of youths were infected by HIV. Suffering from a serious disease, each day is a day to fight for the people living with HIV. They, not only have to take a lot numbers of medication their whole life, but also have to deal with stigma and discrimination. Stigmatization was born by people s false beliefs. First, HIV is always associated with death and behaviors that some people disapprove (such as homosexuality, drug use, sex work, or infidelity). In he socie

s perception, HIV infection is the result of personal

irresponsibility or moral fault. Consequently, they deserve HIV as punishment for their deeds. Then, the fact that HIV is transmitted through sex made HIV probably not to best topic to be discussed, as sex is taboo for some culture(2). HIV-related stigma and discrimination refers to prejudice, negative attitudes, and abuse directed at people living with HIV and AIDS. In 35% of countries with available data, over 50% of people report having discriminatory attitudes towards people living with HIV (2). Fear of stigma and discrimination makes people reluctant to get tested, disclose their HIV status, and take antiretroviral drugs (ARVs). Stigmatization among women with HIV creates problems, such as loneliness, isolation, low self-esteem, identity crisis, low seeking care behavior, and nonparticipation in routine HIV testing. Stigma also interferes with medication adherence, insufficient service utilization, and eventually apathetic effects on morbidity and mortality(3). In fact, one in five people living with HIV avoided going to a clinic or hospital because they feared stigma or discrimination related to their HIV status. Furthermore, the denial does come along with the fear of it. One in every eight people living with HIV is being denied in health service because of stigma and discrimination(2). In the end, stigmatization only worsens the disease. Treating the disease requires a teamwork between the patients, health-care providers, and importantly, the whole society. Unfortunately, stigma builds the walls between them. New preventions and treatments of HIV would be useless unless the patient and the society themselves have concerns towards the disease. It would not be possible to prevent, detect, and treat HIV

without the willingness from the patients and support from people surrounding them. Abolishing stigma is the first step to fight this disease. Le s figh he s igma b follo ing hese simple s eps. Know the Facts In 1980 when it was first identified, very little was known about HIV transmission. This lack at knowledge made people scared of those infected due to fear of contagion. Hence, the first step to get rid of the stigma is by educating the society about HIV transmission. There are a lot of myths spreading around about how people can get HIV. By knowing the facts about HIV, it could save the society from worry and help to bust myths and misconceptions. HIV can only be passed only be these bodily fluids: blood, semen, vaginal fluid, anal mucous, and breastmilk. Hence, HIV infection occurs when infected bodily fluids get into our bloodstream by having unprotected sex; mother and child transmission during pregnancy, childbirth, or breastfeeding; injecting drugs with a contaminated needle; and receiving blood donations or organ transplants from the infected (4) The most important thing is that HIV is not transmitted that easy by simply having contacts with people with HIV. Even people living with HIV do not transmit HIV as long as they have an undetectable viral load (the amount of virus cannot be detected through blood test because it has been reduced by the effective treatment). Next, the most crucial information: HIV is not transmitted by touching someone who has HIV. We can not get HIV only by touching, hugging, or shaking their hand. Hence, people can not get HIV by sharing space with someone who is HIVpositive since the HIV is not able to survive in air. Little evidences prove that HIV is transmitted by coughs, sneezes, or spit. Furthermore, HIV can not be passed on through sharing food, drink, and cooking utensils. Likewise, HIV is not transmitted through toilet seats, tables, door handles, and sharing towels. It means that it is safe for sharing public facilities with people living with HIV. Last, insects are not able to transmit HIV. Even when an insect (such as mosquito) bites and sucks blood, it does not inject the blood of the last person it bit (4). Know that everyone is worthy People with HIV commonly have a bad perceptions about themselves. Stigmatization worsens those feelings. It is a crucial thing to remind people with HIV that they are still the same person, even after the HIV infection. Dealing with the truth of having HIV as a gift rather than a punishment hopefully will help people with HIV carry on their life. The society must provide

supports which strengthen the patients. Building an optimistic view may help them to continue their medications and give them an opportunity to have a better quality of life. Know the rights for people with AIDS People living with HIV are often subjected to human rights violation. The truth in the society is that when people were diagnosed with HIV, they seemed no longer be the whole human. They have limited access, namely for health access, education, socialization, and the opportunity to develop themselves. It is important to know that people living with HIV have similar rights like they had before the infection. They deserve what the other people do, without any differences. Speak up towards any discrimination or abuse Stigma leads to discrimination. However, people with HIV tend to stay silent about that. Hence, it is our duty to report any discrimination or abuse towards people with HIV. By speaking up, we will help to reduce the bad influence and stop discrimination or abuse towards people with HIV. A New Era of HIV Prevention HIV medicines have developed so well that HIV is now able to be prevented by taking specific medicines. Taking steps to protect ourselves against disease is called prophylaxis. 1. Pre Exposure Prophylaxis (PrEP) PrEP is able to stop HIV from taking hold and spreading throughout our body. When taken daily, PrEP is highly effective for preventing HIV from sex or injection drug use. PrEP should be considered if you are HIV-negative and in an ongoing sexual relationship with an HIV-positive partner. Studies proved that PrEP effectively reduce the risk of getting HIV from sex by about 99%, when taken daily (5). 2. Post Exposure Prophylaxis (PEP) PEP should be taken on emergency status: within 72 hours after exposure. Consider taking PEP if you think you may have been exposed to HIV during sex, shared needles and works to prepare drugs, or were sexually assaulted. Talk to emergency room doctor or health care provider immediately about PEP. PEP must be started within 72 hours after a recent possible to HIV, but, the sooner you start, the better. Every hour counts. When prescribed, PEP should be taken once or twice a day for 28 days. PEP is effective enough in preventing HIV when administered correctly(6). Finally, it is the time to end the stigma and start a new era of HIV prevention. HIV i a i

. S ig a i

.A d

e ha a c e, al ead .

Bibliography 1. UNAIDS. UNAIDS warns that HIV-related stigma and discrimination is preventing people form accessing HIV services. Available from: www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2017/october/201710 02_confronting-discrimination [Acessed 11 November 2019]

2. Avert. HIV Stigma and Discrimination. Available from: https://www.avert.org/professionals/hiv-social-issues/stigma-discrimination#footnote9_iywkrwu [Accessed 15 November 2019]. 3. Oskouie F, Kashefi F, Rafii F, Gouya MM. Qualitative study of HIV related stigma and discrimination: What women say in Iran. Electron Physician. 2017;9(7):4718 4724. Published 2017 Jul 25. doi:10.19082/4718 4. AVERT. Myths about HIV and AIDS. Available from: https://www.avert.org/hivtransmission-prevention/myths [Accessed 14 November 2019] 5. Centers for Disease Control and Prevention (CDC). PrEP. Available from: www.cdc.gov/hiv/basics/prep.html [Acessed 10 November 2019]. 6. Centers for Disease Control and Prevention (CDC). PEP. Available from: www.cdc.gov/hiv/basics/pep.html [Acessed 10 November 2019].

Preventing HIV/AIDS Transmission from Mother to Child with PLASENTA A. Background In this poster, we used an illustration of a pregnant woman to symbolize our main idea. The main idea is to use the concept of placenta as one of the barriers mothers use to protect their babies. We use the term ‘PLASENTA’ as it is how ‘placenta’ is spelled in our national language. Using the philosophy of how placenta works, we focus on the things we put for each letter spelled in ‘PLASENTA’ as the ways on how to prevent HIV/AIDS transmission from mother to child. In the US, by the end of 2016, there were 11,915 people who were living with HIV through perinatal transmission. Perinatal transmission is transmission of disease from mother to child during pregnancy, childbirth, and even breastfeeding. Pregnant women and their babies are at risk of this perinatal transmission because preconception care and planning services for families are often not provided in the HIV care settings, therefore there are still a lot of people who do not know any of these things. HIV-affected women are often not conscious of their pregnancies and most of them do not know the ways on how to prevent or safely plan a pregnancy, also the ways on how to reduce the risk of transmitting HIV to their babies. The risk of transmitting HIV to the baby is higher when the mother does not comply to her treatment throughout pregnancy and childbirth, or does not provide HIV treatment to her baby, or if she gets HIV during pregnancy. Other factors like social and economic factors may also make it even harder for some women with HIV to access healthcare and stay on their treatments as they should. Also, there are still some stigma from the society that there are absolutely no ways to prevent mother-to-child HIV transmission. B. Objectives Therefore, we, as member of Asian Medical Students’ Association, would like to diminish the stigma known amongst the society about mother-to-child HIV transmission and increase their knowledge on prevention and management of motherto-child HIV transmission perinatal transmission.

C. Content This poster contains an abbreviation to help pregnant woman understand how prevent HIV/AIDS transmission to her child during pregnancy until delivery. Those abbreviation is “PLASENTA” which includes eight things to do in preventing HIV/AIDS transmission from mother to child. “P” stands for PrEP (pre-exposure prophylaxis) if you have been exposed to HIV/AIDS from your partner. “L” stands for let’s check your blood to make sure that you and/or your partner be free of the HIV/AIDS. “A” stands for ART (anti-retroviral therapy) routinely as the doctor prescribed. “S” stands for stay healthy as a pregnant woman to always boost the immune system and give adequate nutrition to the fetus. “E” stands for educate yourself, your partner, also your family to avoid the stigma and hoax from the society. “N” stands for never forget to consult with your doctor means to always monitoring the fetus development and prepare the baby delivery. “T” stands for take HIV medicine to the baby until 4-6 weeks after delivery. Last, “A” stands for avoid breasfeed the baby because HIV/AIDS could transmit through breast milk while lactation period. Therefore, the baby should be given formulated milk to provide the nutritions. D. Conclusion In conclusion, HIV/AIDS transmission from mother to child during prenatal could prevent with some effort during the pregnancy and post delivery. The stigma in society is likely mistaken about HIV/AIDS and its transmission. The key in preventing HIV/AIDS transmission from mother to child is keep the mother and baby away from HIV exposure. In order to make sure of the status, serology examination could be taken by the mother and her partner. If it is unavoidable, get a prophylaxis and stay healthy could prevent the transmission. Also, get HIV medicine to the mother and baby could prevent transmission during perinatal. It shows that HIV/AIDS transmission from mother to child could be prevented. Therefore, in this opportunity, we would like to break the stigma in society about HIV/AIDS transmission, especially from mother to child.

References 1. WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Geneva: WHO Library Cataloguing in Publication Data; 2010. 2. CDC. HIV and pregnant women, infants, and children [Internet]. Atlanta; Centers for Disease Control and Prevention: March 2019 [cited 2019 Nov 12] Available from: www.cdc.gov/hiv 3. KEMENKES RI. Pedoman manajemen program pencegahan penularan HIV dan sifilis dari ibu ke anak. Jakarta: Kementerian Kesehatan RI; 2015.

Let’s PARTY Against HIV! Human Immunodeficiency Virus (HIV) strains tend to recombine , continuously evolve, and new emerging variants are being discovered. Based on Global Health Observation (GHO) data, since the beginning of pandemic, the number of people with HIV continues to increase and become a world wide concern. This is indicated by an increase of people living with HIV from 36.9 million in 2017 compare with 37.9 million in the end of 2018. According to United Nations Sustainability Development Goals (SDGs) in 2030 by means in goal 3, The United Nations Joint Programme on HIV/AIDS (UNAIDS) set an ambitious goal to end HIV as a public health threat through comprehensive strategies that include epidemiological input as the first step of the process. Globally, adolescent girls and young women face gender-based inequalities, exclusion, discrimination and violence. This fact put them at increased risk of acquiring HIV. Moreover, women death in reproductive age is the main problem caused by HIV worldwide. Untreated HIV patient can lead to more severe conditions called Acquired Immunodeficiency Syndrome (AIDS) where opportunistic infections can superinfect the host. The most common opportunistic infections are Mycobacterium tuberculosis, candidiasis, Pneumocystis pneumonia, Toxoplasma gondii encephalitis, Cytomegalovirus retinitis, etc. Mostly, a lot of laypeople have the wrong point of view of people living with HIV. The stigma circulating in the community also makes HIV patients feel discriminated because of their ignorance and makes things worse. HIV is not transmitted through air, water, tears, sweat, saliva, including sharing toilets, sharing dishes, drinking glasses, or engaging in close-mouth or social kissing. HIV also can’t be passed through healthy unbroken skin. The main route for its transmission is only through direct contact with certain body fluid, including blood, semen, rectal fluid, vaginal fluid, and breast milk. In fact, educating the community properly about HIV and how to cut its transmission to prevent new infection is much more important than just making bad stigma. To our knowledge, preventing is the best medicine. Thus, let’s PARTY Against HIV! Reduce the risk of HIV transmission through pre and post exposure prophylaxis (PrEP) and (PEP) medication if you’re at risk of having HIV before and after exposed to the virus although the laboratory test is HIV negative. Moreover, assisted medication treatment by antiretroviral treatment (ARV) is crucial to maintain viral load to a very low level that theoretically have effectively no risk of sexually transmitting HIV to their HIV-negative partners. When people living with HIV taking ARV regularly each day, it means they contribute to prevent new transmission and protect themselves as well. This effort also needs to be supported by responsible safe sex, not being heterosexual, using condom, and having precaution of sharing injected needle. In addition, the only way to know whether someone is HIV-positive or not is to

get tested. A regular laboratory test for undiagnosed HIV is also important to keep an eye on self-healthy status. The earlier to get tested, the earlier to be treated, the higher probability to live longer. Last but not least, yearly male circumcision program also beneficial to reduce the risk factor of having HIV.

Reference: 1. Furrer, Hansjakob. Opportunistic Diseases During HIV Infection-Things Arenâ&#x20AC;˛t What They Used to Be, or Are They? [Internet]. OUP Academic. Oxford University Press; 2016 [cited 2019Nov12]. Available from:

https://doi.org/10.1093/infdis/jiw086 2. Nikolopoulos GK, Kostaki E-G, Paraskevis D. Overview of HIV molecular epidemiology among people who inject drugs in Europe and Asia [Internet]. Infection, Genetics and Evolution. Elsevier; 2016 [cited 2019Nov13]. Available from: https://doi.org/10.1016/j.meegid.2016.06.017 3. WHO. HIV/AIDS [Internet]. World Health Organization. World Health Organization; 2019 [updated 2019 August 19; cited 2019 Nov 12]. Available from: https://www.who.int/gho/hiv/en/

4. HIV.gov. About HIV & AIDS [Internet]. U.S: Department of Health & Human Services; 2019 [updated 2019 June 24; cited 2019 Nov 12]. Available from: https://www.hiv.gov/hiv-basics/overview/about-hivand-aids/how-is-hiv-transmitted. 5. WHO. Health - United Nations Sustainable Development [Internet]. United Nations. United Nations; [cited 2019 Nov 12]. Available from: https://www.un.org/sustainabledevelopment/health/

ABSTRACT

H e

a I

def c e c V e ab e

fec

(HIV)

ha a ac

a d d ea e . Th

c de ce bec

e e

e d

sixth most deadly disease with over 37.9 million people in the world on 2018 are suffering from HIV/AIDS and 770.000 people died because of it (image 1). This virus spreads by contact with body fluid of person with HIV mainly when the person with HIV does sexual intercourse without using condom (unprotected) or through massal used drug injection. If HIV treated poorly, it can lead to Acquired Immunodeficiency Syndrome (AIDS). AIDS is a condition where CD4+ count is less than 200 cells. This incidence has always been a concern to every health services around the world so it is a must for a health service providers-soon to be or even society to know more about prevention, detection, and treatment of HIV/AIDS.

(image 1. Percent people died because of HIV ) HIV can be transmitted through sexual intercourse, either it's oral, vaginal, or anal sex, and blood (blood-borne pathogen). In general, oral sex has the fewest or even no risk for getting or transmitting HIV. Vaginal sex is more risky for getting or transmitting HIV than oral sex. While receptive anal sex is the riskiest type of sex for getting or transmitting HIV. So it is better to have fewer or even no receptive anal sex at all. Using condom while having sex is the simplest way to prevent from getting or transmitting HIV. It also can help to prevent other Sexual Transmitted Diseases (STDs), such as gonorrhea and chlamydia to be transmitted. However, even though condom is the simplest way to prevent HIV through its main transmission

sexual intercourse, there still be a chance of HIV transmissions especially for

some people who is at high risk on getting or transmitting HIV so they have to add other prevention method, like taking medicines to prevent and treat HIV. Besides using condom,

having fewer sex partners ca a

ed ce HIV a

a e. Th ca be d

e b ha

an abstinence, which means not having a sexual intercourse at some period of time. Another way to prevent HIV transmissions is being aware of heterosexual man or a

h d e

eg a

use condoms during sex with partner with unknown HIV status.

Different from people with unknown HIV status, people with HIV-negative who has a HIVpositive sex partner should encourage their sex partners to get and stay on treatment to prevent HIV transmissions. HIV medicine (Anti-Retroviral Therapy or ART) can make the viral load in the blood very low. This condition is known as an undetectable viral load. Someone who had ART can stay healthy for many years and have no risk in HIV transmissions through sexual intercourse.

Presentation Title: Don't Let the Stigma of HIV AIDS Scare You! Let's break the Stigma ! People on the move Research focus: The Stigma of HIV AIDS Presentation Type: Poster Presentation Abstract: Don't Let the Stigma of HIV AIDS Scare You! Let's break the Stigma ! People on the move The purpose of this Poster was to give education about The Stigma of HIV/AIDS. HIV (human immunodeficiency virus) is a virus that attacks cells that help the body fight infection and AIDS is the late stage of HIV infection. People living with HIV in 2018 is 37.9 Million, apparently woman and man living with HIV in 2018 is 18.8 Milion and 17.4 Milion. Risk Factor for HIV/AIDS is having unprotected anal or vaginal sex, another sexually transmitted infection, sharing contamined needle, receiving unsafe injection, and experiencing accidental needle slick Injuries. HIV/AIDS can transmitted from blood, breast milk, semen and vaginal secretion, and can't transmitted from kissing, hugging, shaking hands, and sharing personal objects as food or water.The first few months after initial infection, no symptoms or an influenza like illness, and serve illness of infection runs without treatment such as tuberculosis, meningitis, serve bacterial infections and cancers. Changing the HIV/AIDS stigma with TREE, protecT for anti disscrimination and anti violence, empoweR for go understanding and go medication, educatE for change the mindset and change the stigma, and IncludE for increase health care and increase good service.

Bibliography: News Room Fact Sheets detail HIV/AIDS. www.who.int. World Health Organization.Rwtrieved November 13, 2019 What Are HIV/AIDS www.HIV.gov. June 17, 2019.Retrieved November 14, 2019

DIRECT A Management and Prevention for HIV/AIDS BACKGROUND HIV/AIDS continues to be a major global public health issue. Based on World Health Organization (WHO) report, there were approximately 37.9 million people living with HIV at the end of 2018.

HIV is the virus that can lead to acquired immunodeficiency syndrome (AIDS). Unfortunately, there is still no cure of this disease. (CDC, 2019). To decrease the number of HIV in worldwide, It is important to have earlier diagnosis to determine whether if someone have HIV or not, and also how to conduct the proper medical care for patients with positive HIV. Many people with HIV/AIDS felt devastated ha he can li e normally like others. But, actually, there is a medicine called ART (Anti-Retroviral Therapy) that can make the viral load in the blood undetectable so HIV could not develop further to AIDS, so that PLWHA (People Living With HIV/AIDS) can live happily with long and healthy life and conduct minimal transmission of virus to others. Based on that, it is really important to educate the community regarding the ways to eliminate HIV/AIDS. Based on our poster, we would like show how to prevent and also how to manage the HIV so we can eliminate HIV/AIDS worldwide. OBJECTIVES To remind the importance of early diagnoses to prevent HIV/AIDS. To inform people diagnosed with HIV/AIDS that there is hope to live like normal people. By the increase in public awareness, we aim to decrease cases of HIV/AIDS.

DISCUSSION How to Eliminate HIV? 1. Diagnose all people with HIV as soon as possible after infection. HIV can be diagnosed through rapid diagnostic tests that provide same-day results F(WHO, 2019). 2. Treat the infection rapidly and effectively to achieve sustained viral suppression. We need to know how is the good medical care for HIV. There is called ART (AntiRetroviral Therapy) that can lead the viral undetected. 3. Protect people at risk for HIV using potent and proven prevention interventions, including PrEP, a medication that can prevent HIV infections. By eliminating HIV, we also able to eliminate AIDS. CONCLUSION Because HIV/AIDS is a major public health disease, it is important to know how to eliminate it. With the collaboration of prevention and management of HIV, the number of HIV/AIDS will decrease. REFERENCES Center

for

Disease

Control

and

Prevention,

2019.

HIV/AIDS.

https://www.cdc.gov/hiv/basics/whatishiv.html World Health Organization Indonesia, 2019. HIV/AIDS. Available at https://www.who.int/en/news-room/fact-sheets/detail/hiv-aids

Available

100

Treat For Life, Prevent To Live

Aim This poster aimed to educate people who has not been infected yet, because it is important for them to be aware of how protect themselves and prevent the transmission of HIV/AIDS.

Background Human Immunodeficiency Virus (HIV) disease or Acquired Immuno Deficiency Syndrome (AIDS) is serious global disease. HIV continues to be a major global public health issue, having claimed more than 32 million lives so far. However, with increasing access to effective HIV prevention, diagnosis, treatment and care, including for opportunistic infections, HIV infection has become a manageable chronic health condition, enabling people living with HIV to lead long and healthy lives. There were approximately 37.9 million people living with HIV at the end of 2018. However, not everyone is able to access HIV testing, treatment and care. Notably, the 2018 Super-Fast-Track targets for reducing new paediatric HIV infections to 40 000 was not achieved. Global targets for 2020 are at risk of being missed unless rapid action is taken. Due to gaps in HIV services, 770 000 people died from HIV-related causes in 2018 and 1.7 million people were newly infected.

Summary of the global HIV academic in 2018.

101

From the results of this study, it is concluded that the prevalence of AIDS is high in 2018. So, it is important to prevent it, because preventive measures such as stringent law can help to prevent community from HIV infection. We hope through this poster, people will extremely understand about "how dangerous HIV/AIDS", so they always be aware to avoid HIV infection.

Brief Research Methodology Official Website : World Health Organization

Keywords : HIV/AIDS, Treatment, Prevention

Authors University of Jambi Winalda Eka Santi Dhea Anisa Yuri Lubis Marlin

102

103

106

AMINO | AMSA INTERNATIONAL COMPETITION 19/20

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AMINO | AMSA INTERNATIONAL COMPETITION 19/20

Scientific Paper Competition World Immunization Week 2020 COMPREHENSIVE ASSESSMENT OF FACTORS ASSOCIATED WITH COMPLIANCE TOWARDS VACCINATION IN SOUTHEAST ASIA: A SYSTEMATIC REVIEW Ayers Gilberth Ivano Kalaij*, Michael Sugiyanto**, and Ahmad Fadhil Ilham*** * ** ***

Second Year Medical Student, (kalaijayers@gmail.com)

Second Year Medical Student, (michael.sugiyanto@yahoo.co.id) Second Year Medical Student, (fadhililhamad3@gmail.com)

Abstract Introduction: WHO reported that in 2014, global vaccination coverage is 86%. However, around 19.9 million infants and children did not receive routine vaccination and 60% of them live in 10 Asian and African countries. That fact implies that there are gaps in vaccination coverage among regions in the world. It is believed that the compliance towards childhood vaccination is influenced by many factors. Objective: To analyze the factors associated with compliance towards childhood vaccination in Southeast Asia. Methods: A systematic review was conducted through PubMed, Scopus, and Cochrane Database Library, searching for observational studies which analyze factors affecting compliance with childhood vaccination in Southeast Asia. Studies selected were reviewed and assessed with STROBE c i e ia. Results: Sixteen observational studies were included, with a total of 41,956 subjects, consisting of 15 cross-sectional studies and one case-control study. We find that certain parental personal-related factors such as age ethnic and religion, and place of residence were significantly associated with acceptance. Children and family status-related factors are also found to be a predictor. We also find that socioeconomic factors strongly affected their compliance to immunization. Furthermore, place of child bi h, acce i i ai i heal hca e facili ie , a d heal hca e facili ie e e al important. Conclusion: The knowledge regarding these factors is expected to help in establishing strategies to increase the compliance towards childhood vaccination in Southeast Asia, as well as reducing mortality rate in children worldwide.

Keywords: Childhood Vaccination, factors, Compliance, Southeast Asia Introduction The future of a nation hugely depends on

by infectious diseases.1 Because of that

the well-being of its younger generation.

high number, vaccines are considered as a

Children that grow and develop optimally

valuable health investment as they can

will make a great generation. In 2018,

reduce the burden of disease caused by

around 25 children under five years old die

infectious disease. Vaccines are widely

per 1000 live births. Based on the data

recognized

from the Indonesian Ministry of Health,

intervention that can be made in reducing

around 36% of child deaths were caused

mortality

121

as and

the

most

morbidity

effective related

infectious disease in children. In 1974,

decades. If this trend continues to persist,

Expanded Program on Immunization (EPI)

the

was initiated by the

Health

immunization coverage by 2020 and to

Organization (WHO) to provide universal

end deaths caused by vaccine-preventable

coverage on immunization to all children

infectious disease by 2030 are at risk of

failure.4

the

world.

infectious

World

Among

diseases

the

were

targeted

tuberculosis,

factors

measles. Now, more vaccines had been and

children

have

100%

global

Numbers of studies have proved that many

pertussis, polio, tetanus, diphtheria, and developed

goals

can

affect

the

immunization

coverage program in a country. Those

are

factors can be health system factors, such

vaccinated than ever before. EPI had

as problems in vaccine supply, cost of

increased global immunization coverage

vaccination, and lack of information about

from 74% in 2000 to 86% in 2014.

vaccination status in a region; provider

Consequently, the annual child mortality

factor, such as poor knowledge

dropped from 9,6 million in 2000 to 5,9

indications and contraindications of a

million in 2015.3

vaccine and poor communication with the

Despite this progress, the World Health

parents; and parental factors, such as poor

Organization

understanding

(WHO)

reported

that

about

receive routine vaccination. Around 60%

compliance to the vaccination schedule,

of the children live in 10 countries in Asia

and socioeconomic problems.6 One of the

and Africa.3,4 This implies that although

rising problems regarding vaccination

the global immunization coverage has

coverage in Southeast Asian countries is

surpassed 80%, the coverage may differ

vaccine hesitancy, which is defined as the

significantly in various regions. One of

delay

those countries is Indonesia. Based on the

vaccination

2018 Indonesian Basic Health Research

vaccination services.4,7 Vaccine hesitancy

(Riset Kesehatan Dasar or Riskesdas),

can be caused by many factors such as

only 57,9% of children received full

misinformation about vaccines, belief in

immunization,

the

below

the

world

coverage of 85%.5 The effects of this low

adverse

vaccination,

far

benefit

approximately 19.9 million infants did not

fear

the

acceptance

religion

despite

effect,

refusal

availability

culture,

and

of in

safety

concerns.

coverage is real in Indonesia. Currently,

WHO has listed vaccine hesitancy as one

Indonesia experiences the re-emergence of

of ten global health threats in 2019.8

diphtheria, a disease that has been gone for

Eradication 122

vaccine

hesitancy

essential

increase

immunization

coverage in Southeast Asian countries. To

"factors i ai

associated", [MeSH

and ]

achieve that, factors affecting compliance

Vaccination [MeSH Terms] OR Vaccine

with the vaccination should be identified.

[MeSH

Through identifying those factors, the

literature search was the availability of

appropriate strategy can be arranged to

full-text articles and the studies with

effectively tackle this problem, therefore

English or Bahasa Indonesia language, as

creating a healthier generation. This

there were the languages compatible with

review aims to identify the factors

authors.

affecting

compliance

with

childhood

] .

Li i a i

Study eligibility criteria

vaccination in Southeast Asian countries. Hopefully this review can help in the

Studies were screened according to the

attempts to eradicate vaccine hesitancy

following criteria, including the type of

and eventually achieve 100% global

study,

vaccination coverage.

reference standards. All observational studies

participants, namely

index

text,

cross-sectional,

and case-

control, and cohort studies that met the

Methods

criteria were included in this review.

This systematic review was conducted

Review, case report, case series, and

based on the Preferred Reporting Items for

conference abstract were excluded studies.

Systematic Reviews and Meta-Analyses

Included studies must have a full-text

(PRISMA) protocol which can be accessed

version, written in English or Bahasa

through http://www.prisma-statement.org/.

Indonesia, and conducted in Southeast Asian countries. The study must assess

Information sources and search strategy

factors

influencing

compliance

The literature search was performed by

childhood vaccination to be included in

three independent reviewers with multiple

this study. Samples consisted of all

electronic databases, such as PubMed,

mothers and childrens associated with

Scopus, and Cochrane Library up to 5

outcome

April 2020. The keywords used in the

compliance. The reference standard is the

Malaysia OR Singapore OR Cambodia OR

acceptance of childhood vaccination, and

Thailand OR Philippines OR Myanmar

also determines the odds ratio of the

OR Laos OR Vietnam OR Brunei OR

correlation between those two variables.

", fac

I d

vaccination

literature that describes factors related to

child e ,

childhood

e ia OR

"Ea

OR " i k fac

123

Study selection Literatures keywords

compliance

was

identified

described

the

using

childhood

vaccination.

Otherwise, if OR is less than one, the

the

factor is related to less likely done

childhood vaccination. Articles were also

section. Following the database search,

assessed in terms of quality following

duplicate removal was performed using

STROBE

EndNote X9 software. Screening of titles

c i e ia (S e g he i g

Reporting of Observational Studies in

and abstracts of studies was carried out

Epidemiology) of combined observational

according to criteria of accessibility by

study which includes 22 criteria where 1

two independent reviewers. The planned

point is given for every criterion met.

procedure was illustrated in Figure 1.

Quality

assessment

was

done

collaboratively by three reviewers and concluded after consensus were reached. Risk of bias assessment was provided in Appendix 1. Results Search results and study selection Articles from the literature search were selected based on the study eligibility criteria set above. Initial search from PubMed, Cochrane Library, and Scopus resulted a total of 3934 studies. Duplicates Figure 1. Diagram flow of literature search

were removed, titles and abstracts were

strategy

screened, and full-text articles were then

Data extraction and quality assessment

assessed for eligibility. Fifteen studies

Subsequently, the following data was

were further excluded due to irrelevant

extracted from the included studies: author

study types, not discussing factors related

and year of publication, study design and

settings, sample size, mean or range of age

restrictions, inappropriate location, and

of samples, and outcomes as expressed by

irrelevant outcomes. The search yielded in

odds ratio of each factor. The results of the

a final 16 observational studies3,4,7,9

study were stated as odds ratio with their

consisting of fifteen cross-sectional studies

corresponding p-values. If OR is more

and one case-control study to be included

than one, the factor is related to good

124

childhood

vaccination,

qualitative

language

synthesis.

Table 1. Study characteristics Author and Year (STROBE score) Bondy, 200815 (20.47/22)

Study Design

Cross sectional

Location

The Philippines

Sample Size 1324

Range/ mean of sample age 29 years old

Method of analysis

Outcome

Bivariate Analysis Multinomia l logistic regression Linear regression

Maternal education: complete secondary Maternal education: higher Cebuano ethnicity Lower middle wealth index Middle wealth index Four or more antenatal visits

Efendi, 202016 (20.5/22)

Multi-stage cluster sampling cross-sectional study

Indonesia

3,231

12-23 months (child)

Bivariate analysis and binary logistic regression

First child Mother antenatal care fewer than four times The lowest economic status Delivered at non-health care facilities Health professional as labor helper

Herliana, 20173 (19.47/22)

Cross-sectional

Indonesia

14401

30 months (childre n) 15-49 years (mother )

Multilevel logistic regression

Living in Maluku or Papua Living in Sumatera Living in Bali and Nusa Tenggara Children age 24-35 months

125

OR [95% CI]

p value

3.2

0.020

4.9 2.8 2.1 2.7 5.2

0.006 0.039 0.023 0.039

2.842 [1.643-4.915] 0.445 [0.338-0.586] 0.630 [0.465-0.854] 0.667 [0.549-0.811] 1.561 [1.189-2.049] 0.51 [0.37-0.70] 0.66 [0.54-0.81] 1.41 [1.06-1.85] 0.80 [0.70-0.92]

<0.001 <0.001 <0.001 <0.01 <0.001 <0.01 <0.001 <0.001 0.016 0.002

Children age 36-47 months Children age 48-59 months 2nd to 4th child 5th child or more Family members more than 10 Uneducated mother Poor economic condition No antenatal care No postnatal care Born at public health institution Joint maternal care between wife and husband How, 201617 (19.67/22)

Kalok, 20207 (21.27/22)

Cross-sectional

Singapore

Kuala Lumpur, Malaysia

162

1081

21 years

18 years

Logistic regression model 5-point Likert scale sensitivity analyses Multiple logistic regressions

0.71 [0.63-0.83] 0.73 [0.63-0.85] 0.84 [0.74-0.97] 0.59 [0.45-0.78] 0.68 [0.52-0.90] 0.46 [0.27-0.82] 0.63 [0.50-0.79] 0.30 [0.19-0.48] 0.66 [0.59-0.74] 1.82 [1.56-2.12] 1.16 [1.04-1.31]

<0.001 <0.001 0.016 <0.001 0.006 0.008 <0.001 <0.001 <0.001 <0.001 0.010

Perceived benefits

5.24 [2.89-9.52]

<0.001

Non-muslim

0.15 [0.03-0.85]

0.03

126

Kien, 201618 (12.39/22)

Cross-sectional

Vietnam

2,639

12-23 months (child)

Chi-square Test (descriptive characteristi c) Multivariab le analysis with logistic regression

Maternal education level secondary or below

Source of information of vaccination date by local authority

0.7 [0.5-0.9] 0.6 [0.4-0.9] 0.5 [0.3-0.9] 1.087 [1.008-1.172] 17.430 [1.827-166.280]

Source of information of vaccination date by megaphone

0.204 [0.065-0.637]

Non-Muslim

0.559 [0.421-0.852] 0.435 [0.277-0.685] 0.625 [0.433-0.901] 0.376 [0.142-0.996] 0.588 [0.402-0.859] 0.434 [0.277-0.678]

Ethnic minority group Lower maternal education (primary level or less) The lowest economic status

Kitamura, 201319 (16.06/22)

Krishna, 201920 (19.56/22)

Cross-sectional

Laos (Lao Pe le Democratic Republic

Selangor, Malaysia

213 pairs

1015

N/A

Mostly 30-39 years

Bivariate analysis Chi square test (categorical variable) S de test (continuous variables) Multivariate binary logistic regression

0.28 [0.16-0.47]

Older maternal age

Maternal education diploma or below Have 3-4 children Have 5 or more children Child age 2 years or below Travelling time to health facility 30 minutes or above

127

<0.001

0.02 <0.01 0.04 0.031 0.013

0.006

0.004 0.011 0.012 0.040 0.006 <0.001

Lim, 201721 (16.22/22)

Cross-sectional

Malaysia

10,140

25-39 years

Bivariate analysis of sociodemog raphic variables Multivariate logistic regression model

Have a delayed immunization schedule Self-employed mothers Head of households who are working in the private sector Head of households who are working in the self-employed High household income (>RM6,500) The Indians Bumiputeras Households with primary education Households with secondary education

Mohd Azizi, 20179 (15.72/22)

Nozaki, 201910 (15.39/22)

Cross sectional

Stratified twostage clustered sampling crosssectional study

Malaysia

Myanmar

545

904

32.3 years

12-23 months (child)

X2 test (univariate analysis) Multivariate logistic regression Bivariate analysis with surveyweighted logistic regression

First pregnancy

Unemployed parents

Middle or high economic status Older maternal age (â&#x2030;Ľ35 years) Greater maternal education (secondary level or higher) Maternal literacy

128

0.364 [0.254-0.521] 0.60 [0.42-0.86] 0.76 [0.60-0.97] 0.63 [0.48-0.83] 0.72 [0.50-1.03] 1.85 [1.11-1.78] 1.38 [1.06-1.78] 2.56 [1.36-4.84] 2.28 [1.25-4.17] 0.25 [0.11-0.57] 0.51 [0.27-0.92] 3.18 [2.26-4.47] 2.50 [1.52-4.11] 1.52 [1.10-2.09] 1.68 [1.14-2.49]

<0.001 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.001

0.027

<0.001 <0.001 0.012 0.009

Mother antenatal care more than four times Maternal tetanus vaccination before delivery Home birth Healthcare facility visit during last 12 months Greater paternal education Skilled paternal occupation Multivariate analysis with backward step-wise logistic regression Phimmasane, 201011 (17.6/22)

Cross sectional

Laos (Lao Pe le Democratic Republic

584

30.9

Chi2 test (discrete variables) T test (continuous variables) Multivariate analyses

Middle or high economic status Older maternal age (â&#x2030;Ľ35 years) Mother antenatal care more than four times Maternal tetanus vaccination before delivery Low education of the father High income level Wide interval between pregnancies Belief that children must be vaccinated Knowing age of vaccination Vaccination at hospital

129

3.01 [2.09-4.34] 3.68 [1.99-6.81] 1.67 [1.19-2.33] 1.59 [1.13-2.24] 2.10 [1.49-2.97] 1.60 [1.10-2.32] 2.64 [1.85-3.78] 2.87 [1.62-5.10] 1.87 [1.28-2.73] 3.26 [1.82-5.85] 0.26 [0.11-0.64] 1.01 [1.01-1.02] 1.14 [1.01-1.13] 11.11 [2.22-100] 3.7 [1.26-11.11] 5 [1.16-20]

<0.001 <0.001 0.003 0.008 <0.001 0.014 <0.001 <0.001 0.001 <0.001 0.003 0.008 0.030 0.003 0.01 0.03

Sopian, 201712 (19.27/22)

Cross-sectional

Vicerra, 201813 (16.93/22)

Kota Bahru, Malaysia

Philippines (Luzon, Visayas, and Mindanao)

280

3,951 (Luzon: 2,034; Visayas: 631; Mindanao: 1,286)

43.5 years

15-49 years (mother )

Multiple logistic regressions Wald statistic simple logistic regression test Binomial logistic regression HosmerLemeshow Test F-Static

Other children in the family were vaccinated

2.77 [1.16-6.66]

0.02

Age of respondents

1.09 [1.04-1.14]

<0.001

Good knowledge

16.32 [7.32-36.4]

<0.001

Greater maternal education (tertiary education)

Middle socioeconomic status Father education (secondary level)

Xeuatvongsa, 201714 (19.7/22)

Multi-stage cluster sampling Cross-sectional study

Laos (Lao Pe le Democratic Republic

317 Pairs of Children And Caretakers

12-35 months

Bivariate Analysis Chi-square test S de t test

Maternal ethnicity (Non Laolum) Paternal ethnicity (Non Laolum) Maternal education (more than primary) Paternal education (more than primary) Maternal occupation (not farmers) Paternal occupation (not farmers)

130

Luzon: 2.14 [1.41-3.26] Visayas: 2.59 [1.06-6.34] Mindanao: 1.89 [1.17-3.05] Visayas: 2.37 [1.09-5.18] Mindanao: 1.73 [1.25-2.39] 0.34 [0.20-0.60] 0.32 [0.19-0.54] 1.66 [1.05-2.61] 2.16 [1.34-3.48] 2.60 [1.57-4.33] 2.05

Luzon: <0.001 Visyas: <0.05 Mindanao: <0.05 <0.05 <0.001 <0.01 <0.01 0.03 <0.01 <0.01 <0.01

[1.26-3.33]

Yufika, 20204 (17.2/22)

Cross-sectional

Aceh and West Sumatra Province, Indonesia

956

Majorit y 20-39 years

Two-step logistic regression analysis, S ea a rank correlation (For correlations among subdomains )

Time taken to reach the nearest health facilities Received vaccination in hospital setting Vaccination as part of an outreach activity in village Vaccination within birthplace of the children Source of information about vaccination date by medical staff Source of information about vaccination from the vaccination card

0.60 [0.37-0.96] 2.42 [1.53-3.84] 0.48 [0.30-0.78 2.15 [1.34-3.45] 1.65 [1.01-2.71] 2.02 [1.17-3.50]

Parents work in healthcare sector

4.38 [2.44-7.69]

131

0.03 <0.01 <0.01 <0.01 0.03 0.01

<0.001

The average STROBE score for those 16

independent predictor for good compliance

studies is 17.92, which indicates this

to childhood vaccination (OR=2.87 [1.62-

review is consisted of relatively good

5.10]).

studies.

Kitamura19 which also stated that mothers

Study characteristics and findings The data extracted and characteristics of

with

Outcomes

were

significantly

across

Asia.

factors

which

were

long term than the natural disease so that

childhood

older mothers choose to vaccinate their children. Similarly, a cross-sectional study in Malaysia by Sopian12 also found that

p-values. Results of quality assessment c i e ia

acceptance

implies that immunization is cheaper in the

odds ratio (OR) with their corresponding STROBE

good

significantly

age is correlated with retirement age which

vaccination compliance, given in terms of

ba ed

with

were

This is due to the fact that older maternal

41,956 subjects were included in the study. varied

age

with

immunization (OR=1.087 [1.008-1.172]).

Overall, this review included a total of locations

older

associated

included studies are shown in Table 1.

Study

This study is in line

older age groups of parents increase the

e e gi e i

proportion of acceptance (OR=1.09 [1.04-

detail in the appendix on the last part of

1.14]).

this paper.

Better

exposures

and

higher

awareness were the contributing factors among older parents. These findings

Discussion Based on

indicated that older maternal age was the

included studies, we

significantly associated with immunization

classified the factors above into parental personal-related

children

and

status-related,

socioeconomic,

acceptance.

family

Furthermore, ethnic and religion were

and

found to be other factors associated with

healthcare-related factors.

acceptance

Parental personal-related factors

maternal ethnicity and paternal ethnicity

related with compliance in childhood Three

parental

immunization.

Xeautvongsa14, in his study, found that

Some parental personal-related factors are vaccination.

(Both are non-Laolum ethnicity) decrease

personal-

compliance rate in childhood vaccination

related factors including age, ethnic and

by 0.34 and 0.32 times respectively;

religion, and place of residence are

however, these findings were explained

associated with factors of compliance in

more in studies by Kien18, Kalok7, and

childhood

Krishna20 which found that minority ethnic

vaccination.

According

Nozaki , older maternal age was an

and religion (described as non-muslim)

132

groups are less likely to be vaccinated than

Children and family status-related factors

the majority groups (OR=0.7 [0.5-0.9],

Children and family status related factors

0.15 [0.03-0.85], and 0.559 [0.421-0.852]

found in our literature search are children's

respectively). On the other hand, the

age, birth order, number of family

majority

the

members, and vaccination status of other

Indians, Bumiputeras, and Cebuano are

children in the family. First, study by

immunization

Herliana3 stated that the older the child age

(OR=1.85, 1.38, 2.8 respectively). This

is, the less compliant the parent are with

indicates that immunization obstacles are

the vaccination schedule and this is

rather linked to culture and ethnicity, as

showed in age of 24-35 months and age of

the health system tends to be tailored to

36-47 months (OR=0.8 [0.70-0.92] and

the culture and predominance of ethno-

0.71 [0.63-0.83] respectively). However,

medical beliefs among the ethnically

other study by Krishna20, showed the

dominant group. These findings also

significant association between younger

explained that childhood immunization

children

may have correlation between certain

compliance. This study stated that mothers

locations.

who have children below 2 years were less

Place of residence is also found to be

likely to have their children immunized

important

immunization

(OR=0.588 [0.402-0.859]) as there are

compliance. A study by Herliana 3 has

huge amounts of conflicting information

found that people living in Bali and Nusa

ha c ld

Tenggara have the highest odds of being

decision regarding their perception that

immunized than people living in Sumatra

younger children are more susceptible to

or Maluku or Papua with the OR 1.41,

complications as their immune system are

0.66, and 0.51 respectively. A plausible

still growing. The different outcomes

explanation of this is that Maluku and

could be due to the different age interval

Papua region is located in the easternmost

that used in studies, so the overall

part of Indonesia and is economically

correlation

deprived. In addition, eligible children in

immunization

this area most likely lived in remote areas

inconsistent.

without access to health services. Not

Birth order is also important factor and

surprisingly, access to be immunized has

older

also been an obstacle.

compliance to vaccinate them as stated by

ethnicity

likely to

illustrated accept

achieving

age

child

(<2

ega i el

between

years)

i fl e ce

child

compliance

and

correlated

the

age

and

was

still

with

the

Efendi16 (first child, OR=2.842 [1.643-

133

4.915]). Herliana3 (2nd to 4th child,

occupation and income, and parental

OR=0.84 [0.74-0.97], 5th child or more,

knowledge

OR=0.59 [0.45-0.78]). Other studies also

vaccination. Economic status is related to

showed that larger families will be less

compliance in childhood vaccination, as

compliant with vaccination. Study of

shown in study by Herliana3 that found the

Herliana3 stated that family members more

association

than 10 people (OR=0.68 [0.52-0.90]),

condition and decrease of compliance

while study of Krishna20 stated that 3-4

(OR=0.63 [0.50-0.79]). This study was

children and also more than 4 children

supported by studies of Kien18 and

(OR=0.625

0.376

Efendi16 which reported lowest economic

[0.142-0.996] respectively) as the factors

status as factors related to noncompliance

of immunization noncompliance.

(OR=0.5 [0.3-0.9] and 0.63 [0.465-0.854]

A possible explanation for this is the lack

respectively). Besides, there are three

of urgency to vaccinate the child as the

studies showing middle economics status

previous children did not experience

as a factor that increases compliance. They

vaccine-preventable

are study by Nozaki10 which assess both

[0.433-0.901]

and

diseases

with

and

between

economic

middle

Azizi9 stated that mothers expecting their

(OR=2.64 [1.85-3.78]), study of Vicerra13

first child will be four times more vaccine-

which assess middle socioeconomic status

hesitant

even

in Visayas (OR=2.37 [1.09-5.18]), and

though other studies proved that a higher

study of Bondy15 which assess lower

child degree is likely to be vaccinated.

middle wealth index (OR=2.1) and middle

Factors associated with higher compliance

wealth index (OR=2.7). These findings

with

intervals

indicate that lower economic groups are

between pregnancies (OR=1.14 [1.01-

more likely to be noncompliant while good

1.13]) and vaccination of other children in

compliance are more likely seen in higher

the family (OR=2.77 [1.16-6.66]), as

economic groups. These may explain

stated by Phimmasane11. A possible factor

better

related to these two factors is the

immunizations was in higher economics

knowledge about planning an ideal and

groups, as well as ability to complete

healthy family.

childhood immunizations, while the lowest

Socioeconomic factors

economic groups are more limited to the

Socioeconomic factors include economic

access.

status,

vaccination

parental

[0.11-0.57])

are

wide

education,

parental

134

access

high

poor

about

without vaccination. However, a study by

(OR=0.25

and

perception

economic

information

status

about

Parental education is another important

and these were compared with those

socioeconomic factor. Higher parental

without

education is a factor of compliance

education level as low or high education

increase according to several studies.

may be caused by different educational

Vicerra

tertiary

systems of each country where studies are

education in Vicerra13 (OR=2.14 [1.41-

held. Thus, these findings indicate that

3.26]), Bondy15 showed maternal complete

parents with lower education are more

secondary education (OR=3.2) and higher

likely to be less compliant.

education (OR=4.9), and Xeuatvongsa14

The possible explanation for these findings

showed

is the fact that education lead to better

showed

higher

(OR=1.66

maternal

[1.05-2.61])

education

and

paternal

education.

Differences

ledge ega di g acci a i

. Pa e

education (OR=2.16 [1.34-3.48]) as the

knowledge about immunization is related

factors

compliance.

to good health-seeking behavior and

Kalok,

becomes a major determinant in their

Phimmasane

decision to vaccinate children. Parents

showed low parental education as a factor

with lower education were more likely to

associated with decrease of vaccination

be hesitant towards immunization because

supporting

Subsequently, Herliana,

all

studies

Krishna,

and

Kalok7

compliance.

maternal

lack of knowledge on vaccination may

below

explain negative attitudes towards it.

(OR=0.28 [0.16-0.47]), Herliana3 showed

These studies are also supported with other

uneducated mother (OR=0.46 [0.27-0.82]),

fi di g

Krishna20

knowledge

education

showed

secondary level

showed maternal

education

hich and

a ed

perception

about

diploma or below (OR=0.435 [0.227-

vaccination are also important in the

0.685]), and Phimmasane11 showed low

compliance. Phimmasane11 and Sopian12

education of the father (OR=0.26 [0.11-

showed good knowledge is related to

0.64])

compliance (OR=3.7 [1.26-11.11] and

Lim21

16.32 [7.32-36.4] respectively), while

the

noncompliance. demonstrated

factors A

that

study

related by

households

with

good

perception

and

belief

about

secondary education (OR=2.28 [1.25-

vaccination as the factors are shown by

4.17]) and also household with primary

How17

education (OR=2.56 [1.36-4.84]) increase

Phimmasane11 (OR=11.11 [2.22-100]).

the immunization compliance, but in this

Several studies also demonstrated relation

study, primary and secondary education

between

are described not as low education status

vaccination

135

(OR=5.24

parental

[2.89-9.52])

occupation

compliance.

and

Positive

correlation between occupation and the

(OR=0.63 [0.48-0.83] as the factors related

compliance only found in study of

to incomplete children immunizations.

Xeuatvongsa14, which demonstrated non-

These groups may be less compliant

farmer maternal occupation (OR=2.60

compare to those parents who were

[1.57-4.33])

employed in the government because the

and

non-farmer

paternal

occupation (OR=2.05 [1.26-3.33]). In this d , he

employees

are

usually

ecified

educated, which influence their contact to

and it also stated that parental occupation

sources of information and are more

was often considered as a determination

accessible

for level of socioeconomic status but some

Government

studies found no association between

supportive of the policies and it may

parental occupation and vaccination status.

commonly have association with high

There are also studies that demonstrated

immunization coverage. There is also

high income level as factors determining

study from Yufika4 which showed that

compliance. Study of Phimmasane11 in

parents working in the healthcare sector is

Laos

levels

a factor related to good compliance

(OR=1.01 [1.01-1.02]) as factors related to

(OR=4.38 [2.44-7.69]). Healthcare sector

compliance, while study of Lim21 in

is associated with this immunization and

Malaysia

parents who work there may have good

showed

government

high

showed

income

different

outcomes

healthcare

sectors

knowledge

higher income was instead related to

immunization and also easier access to

noncompliance.

healthcare facilities. Another study is

these

importance

maternal

study locations and operational definitions

delivery according to Nozaki10 (OR=3.26

the

[1.82-5.85]) which also associated with

significance of income as a vaccination

compliance. This study may support the

determining factor is yet to be defined.

previous finding which correlates with

income

category,

In addition, Azizi9 showed unemployed

vaccination

outcomes may be affected by different each

tetanus

the

also

(OR=0.72 [0.50-1.03]) suggesting that Difference

about

are

facilities.

ledge

before

parents (OR=0.51 [0.27-0.92]) and Lim21

vaccination.

showed self-employed (OR=0.60 [0.42-

Healthcare-related factors

0.86]), head of households who are

Healthcare is another factor that affects the

working in the private sector (OR=0.76

decision-making

[0.60-0.97]), and head of households who

According to Herliana3, infants who were

are

born at public health institution are more

working

the

self-employed

136

immunization.

likely to get vaccination (OR=1.82 [1.56-

more likely to be compliant. These

2.12]), while another study from Efendi16

findings are also supported reminder of

showed infants who were born at non-

information is important, which may be

health care facilities are the opposite

determined by how the information is

(OR=0.667 [0.549-0.811]). Maternal visit

delivered. Compliance will increase if

is also important. Mothers who did

information is delivered by local authority

antenatal care visits of more than four

(OR=17.430 [1.827-166.280]) according

times are more likely to have good

to study of Kitamura19, and also by

compliance to vaccination according to

medical staff (OR=1.65 [1.01-2.71]) and it

studies

Nozaki10

(OR=1.87

and

[1.28-2.73]

Bondy15

and

also increase with the use of vaccination

5.2

card (OR=2.02 [1.17-3.50]). Otherwise,

respectively). In line with the studies,

i f

Efendi16

effective for immunization compliance

showed

mothers

who

did

i g

ega h

antenatal visit fewer than four times

(OR=0.204

(OR=0.445 [0.338-0.586]) and Herliana3

adequate source of information becomes

showed

d a e a al

important. Several factors lead to delay in

care visit (OR=0.30 [0.19-0.48]) and

immunization schedule, and this may also

postnatal care visit (OR=0.66 [0.59-0.74])

associate with risk of not receiving

as the factors related to noncompliance of

complete

childhood vaccination.

according to Krishna20 (OR=0.364 [0.254-

Other factors such as longer time taken to

0.521]).

reach the nearest health facilities is related

Another healthcare-related factor is the

to noncompliance according to study of

facilities. Study by Xeuatvongsa14 showed

Xeuatvongsa14 (OR=0.60 [0.37-0.96]) and

that receiving vaccination in hospital

Krishna20 (OR = 0.434 [0.277-0.678])

settings (OR=2.42 [1.53-3.84]) and within

while availability of health professional

birthplace of children (OR=2.15 [1.34-

during labor is related to compliance

3.45]) are factors related to vaccination

according to study of Efendi16 (OR=1.561

compliance, while vaccination as part of

[1.189-2.049]). All of these findings are

an outreach activity in village is factor

possibly caused by the function of

related to noncompliance (OR=0.48 [0.30-

healthcare visit and doctors education to

0.78]). Availability of vaccination in

provide information about the importance

hospital settings are also shown in studies

of immunizations for children and also to

of Bondy15 and Phimmasane11 to increase

remind the schedule, so parents become

compliance (OR=2.42 [1.53-3.84] and 5

h did

137

[0.065-0.637]).

immunizations

Therefore,

children,

[1.16-20] respectively). These findings

providers in educating the public to

recommended

prevent

the

administration

the

preventable-diseases

childhood vaccination in good facilities in

vaccinating their children, thus increasing

order

the immunization coverage. We suggest to

increase

compliance.

The

recommendations of immunization from

a e

the

understand their personal backgrounds to

World

Health

Organization

and

a ie

cha ac e i ic

national government are important as ideal

identify possible

immunizations

Thus,

childhood vaccination, improve education

adequate healthcare facilities are needed to

of the parents towards immunization,

ensure

especially mothers, improve social and

for

children.

availability

ideal

personal

a d

factors to

immunizations.22

economic support and abolish stigma and

Strength and Limitations of the review

rejection towards childhood vaccination,

The

strength

this

review

and

facilitate

improvement

comprehensively reviews studies with

immunization-related healthcare facilities

large samples in total. Review with large

and encourage healthcare facilities to

samples is important in assessing factors

promote immunization since the children

related to the compliance with vaccination.

were born in hospital settings. However,

Also, this review assesses various groups

more researches need to be conducted in

of factors, such as socioeconomic factors,

order to explore more applicable risk

child-family related factors, and health

factors, as there are only few risk factors

care facility-related factors. However, this

currently known and the fact that the

review also has some limitations. It only

factors were location specific.

included studies written in English so it is still possible that literature that is not

Conclusion

written in English contains information

Although global vaccination coverage in

needed to compose this review. Full text

2018 is 86%, there are gaps in vaccination

availability is also the limitation of this

coverage among regions in the world.

review.

Based on the review, parental compliance

Recommendation for everyday practice

in childhood vaccination, especially in

The result of the above systematic review

Southeast Asia is associated with various

can be further applied to formulate

factors. This study showed that parental

strategies to address problems related to

personal-related factors such as parental

childhood vaccination and help guidelines-

age and ethnicity, children and family

making process to help primary health care

status-related factors such as birth order

138

and

number

socioeconomic

family

factors,

members,

References

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healthcare-related factors such as facilities

Indonesia Expanded Programme on

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Furthermore,

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We have nothing to declare.

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study

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[Internet].

Conflict of Interest

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We declare that we have no competing

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Appendix 1. S die Ite m No Title and abstract

Introduction Background/rati onale

Objectives

Methods Study design

Setting

ali

a e

Bon dy et al

Efen di et al

Herli ana et al

How et al

Kalo k et al

Yes

Explain the scientific background and rationale for the investigation being reported State specific objectives, including any prespecified hypotheses

Yes

Present key elements of study design early in the paper Describe the setting, locations, and relevant dates, including periods

Yes

Recommendation (a) Indicate the d de ig i h a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found

e Kien et al

ba ed

STROBE c i e ia Sopi an et al

Vicer ra et al

Yes

Phi mma sane et al Yes

Yes

Kita mur a et al Yes

Kris hna et al

Lim et al

Yes

Yufi ka et al

Xeua tvon gsa et al Yes

Yes

Noza ki et al

Yes

Moh d Azizi et al No

Yes

23 143

Yes

Participants

of recruitment, exposure, followup, and data collection (a) Cohort study Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study For matched studies, give matching criteria and number of exposed and unexposed Case-control study For Yesmatched studies, give

Yes

N/A

24 144

Variables

Data sources/ measurement

Bias

Study size

Quantitative variables

Statistical

matching criteria and the number of controls per case Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Describe any efforts to address potential sources of bias Explain how the study size was arrived at Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why (a) Describe all

Yes

25 145

methods

Results Participants

statistical methods, including those used to control for confounding (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) Cohort study If applicable, explain how loss to follow-up was addressed Case-control study If applicable, explain how matching of cases and controls was addressed Cross-sectional study If applicable, describe analytical methods taking account of sampling strategy (e) Describe any sensitivity analyses 13*

(a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing

Yes

26 146

Descriptive data

Outcome data

14*

15*

follow-up, and analysed (b) Give reasons for non-participation at each stage (c) Consider use of a flow diagram (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders (b) Indicate number of participants with missing data for each variable of interest (c) Cohort study Summarise followup time (eg, average and total amount) Cohort study Report numbers of outcome events or summary measures over time Case-control studyâ&#x20AC;&#x201D;Report numbers in each exposure category, or summary measures of exposure Cross-sectional studyâ&#x20AC;&#x201D;Report numbers of

Yes

N/A

Yes

N/A

Yes

N/A

Yes

27 147

Main results

Other analyses

Discussion Key results

Limitations

outcome events or summary measures (a) Give unadjusted estimates and, if applicable, confounderadjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses Summarise key results with reference to study objectives Discuss limitations of the study, taking

Yes

N/A

Yes

28 148

Interpretation

Generalisability

Other information Funding 22

into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Discuss the generalisability (external validity) of the study results Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based TOTAL

Yes

20.47

20.5

19.47

19.67

21.27

12.39

16.06

19.56

16.22

15.72

15.39

17.6

19.27

16.93

19.7

17.2

29 149

Immunogenicity and Safety Profile of Various Microneedle Array Patches as a Potential Novel Vaccine Delivery System to Enhance Vaccine Efficacy: A Systematic Review Raya Makarim Penantian, Vincent Kharisma Wangsaputra, Muhammad Alifian Remifta Putra

ABSTRACT Introduction: Vaccination plays a big role to alleviate and even eliminate preventable-diseases with an abundance of evidence that prove its effectiveness. However, vaccine uptake has not reached the target due to several multifactorial challenges, resulting in a need for strategies to optimize the potential success of vaccines. This systematic review aims to evaluate the immunogenicity and safety profile of vaccines delivered through microneedle array patches, which may aid to solve the challenges of low vaccination coverage. Methods: Relevant studies were selected from PubMed, Scopus, ProQuest, Oxford Academic and Wiley Online Library and analysed using the PRISMA statement. Included studies were assessed using the OHAT Risk of Bias Rating Tool for Human and Animal Studies. Results: The literature search yielded 11 studies, 10 of which are animal trials and 1 clinical trial. Immunogenicity was assessed using three aspects, namely IgG titer, hemagglutination-inhibition and inflammatory mediators. Safety profiles were investigated by looking for post-vaccination symptoms and a scoring system for clinical trial. Conclusion: Microneedle array patches show promising immunogenicity and safety profile as compared to common forms of vaccine delivery system used at the moment. The immunogenicity induced by microneedle vaccination is superior or at least comparable to other delivery systems that were used as control and the adverse effects were greatly minimised as well. Further clinical trials are needed to confirm the utilisation of microneedle array patches in a large scale. Keywords: vaccine, microneedle, immunization, vaccination, delivery system

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INTRODUCTION Vaccination is the most effective public health intervention that humankind ever made in history. Vaccination may induce the formation of immunity in individuals, further generating the ability to prevent development, progression and manifestation of diseases in the first place. Each year, basic immunization was able to save 3 million children's life in the world from numerous vaccine preventable diseases (VPDs) such as the diphtheria, pertussis, tetanus, measles, and many other diseases.1,2 Since the initiation of the Expanded Programme of Immunization (EPI) in 1974, creation of Gavi, the vaccine alliance in 2000, also the establishment of Global Vaccine Action Plan (GVAP) in 2012, global vaccination coverage has significantly increase with mortality rates in the children due to VPDs have been dramatically reduced.1,2 Even with this outstanding fact, world vaccine coverage is facing stagnancy and no increase was recorded during this several years. As of 2018, there are over 86% or 116.3 million children in the world are vaccinated with DTP3, while 14% or 19.4 million children are still at high risk for VPDs. Around 60% of unvaccinated children are coming from 10 developing countries with low immunization coverage: Angola, Brazil, Ethiopia, the Democratic Republic of the Congo, Indonesia, India, Pakistan, Nigeria, Vietnam and the Philippines.3,4 Challenges that continue to persist and remain including the inequities in vaccine uptake in several regions which may cause the continued outbreaks and occurence of VPDs. The achievement of global immunization coverage is being jeopardized by many factors such as the different socio-economic status, urban-rural settings and also geographical barriers, which all lead to inequalities of immunization coverage.Thus, new immunization strategies and innovation are much needed to break the status quo. Not only new socio-economic approaches such as better understanding of vaccine hesitancy, vaccine acceptance and encouraging active participation of communities, but also the development of new vaccine product and delivery technologies are much needed.3,4 Low vaccine efficacy which causes the need for booster dose produce gaps in immunization coverage. Recently, discovery of Microneedle Array Patches (MAP) as the novel vaccine delivery system shows promising potential as it may elicit enhanced immune responses or better immunogenicity that may substantially reduce vaccine doses. MAPs enable researchers to create vaccines that have high efficacy, which could become a solution toward low immunization coverage due to low vaccine efficacy. Not only higher immunogenicity, the MAPs offer the

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potential of improved vaccine thermostability, safer profile, more acceptable delivery system, easier usage and even cost-effective administration of vaccines compared to conventional injection by regular needle and syringe (N&S).5,6 To the best of writer’s knowledge, there is still no systematic review that discusses the immunogenicity and safety profile of numerous MAPs which are currently being tremendously developed. Thus, this systematic review aims to give current updates on immunogenicity and safety profiles of numerous MAPs that potentially become novel vaccine delivery systems which may become a solution for low immunization coverage. METHODS Search strategy The authors conducted this systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement.7 Papers were identified by reviewing through 5 different online databases, namely PubMed, Scopus, ProQuest, Oxford Academic and Wiley Online Library using the following keywords to filter the studies: ‘microneedle’ OR ‘microneedles’ AND ‘vaccine’ OR ‘vaccines’ AND ‘immunisation’ OR ‘immunization’ AND ‘vaccination’ OR ‘vaccinations’ AND ‘delivery system’. The search was limited to studies from 2015-2020 and no language restrictions were implemented. A detailed illustration of the literature search is shown in Figure 1. Inclusion and exclusion criteria In terms of study selection for diagnostic and prognostic marker(s), the following criteria of inclusion were applied: (1) study design, animal trial or clinical trial; (2) study population, animals or human; (3) study outcome, immunogenic properties or safety profiles; (4) language used in the original article is in English; (5) latest relevant studies, published within the last five years. The exclusion criteria were as follows: (1) publications with incomplete information and/or no retractable data; (2) types of articles: conference abstracts, letters, comments; (3) overlapping or duplicate publications; (4) different outcome of interest (no outcomes on immunogenicity).

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Data extraction and risk of bias assessment In extracting data from included studies, several information were included: (1) authors and year of publication; (2) study characteristics, including the study design and aim or purpose of the study; (3) subject characteristics, including the subject species, median age of sample, sample size, and specific disease that observed in the sample; (4) interventions and comparators; (5) outcomes related to immunogenicity (immunogenicity-related indicators; IgG titer - total IgG, IgG1, IgG2a; Hemagglutination Inhibition/HAI titer; inflammatory mediators - IFN-Îł, IL-6 and other cytokines, along with type of sample and data extraction method), safety profiles, with each of studies probability (p) value. Risk of bias (RoB) assessment of included studies were performed using the Office of Health Assessment and Translation (OHAT) RoB Rating Tool for Human and Animal Studies 2015.8 OHAT RoB rating tool is a specialized risk of bias rating tool that presents a parallel approach to evaluating risk of bias for both human and non-human animal studies, in order to facilitate consideration of risk of bias from different elements and evidence streams with common categories and terms. It consist of 11 risk-of-bias questions or domains, with each question is applicable to 1 or up to 6 study design types (CaS: Case Series/Case report, CaCo: Case-Control, Co: Cohort, CrSe: Cross-sectional, EA: Experimental Animal, HCT: Human Controlled Trial). Questions are further grouped into 6 types of bias: attrition/exclusion, confounding, detection, performance, selection, and selective reporting. RoB assessment are rated by selecting from 4 possible answers: low RoB (include specific examples of relevant low RoB practices), probably low RoB (indirect evidence of low RoB practices), probably high RoB (indirect evidence of high RoB practices or insufficient information such as not reported/NR about relevant RoB), and definitely high RoB (direct evidence of high RoB practices such as specific examples)8 Data extraction and RoB assessment were conducted by three independent reviewers (RMP, VKW, and MARP), and any discrepancies were resolved by creating consensus between all authors. Appendix 1 provides further details on the RoB assessment.

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RESULTS Study Selection The selection process for the included studies in this systematic review is presented in Figure 1. Initial search from 5 online databases, namely PubMed, Scopus, Proquest, Oxford Academic, and Wiley Online library, yielded a total of 823 studies. After duplicates were removed, a number of 791 studies were screened titles and abstracts, resulting in 101 full-text articles to be assessed for eligibility. Furthermore, 90 studies were excluded due to the fact that 25 did not provide extractable data, 37 did not provide outcomes of interest (i.e. immunogenicity or safety profiles), 19 showed inappropriate study design, 9 were irretrievable. Finally, the whole process resulted in 11 trials to be included in the qualitative synthesis, consisting of 10 animal trials9-18 and a randomized phase I clinical trial in human subjects.19

Figure 1. PRISMA flow diagram of literature search strategy for this systematic review.7

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Study Characteristics The detailed main characteristics of studies included in this review are shown in Table 1. The trials were published between 2015 and 2020. Study locations varied, with the continents of origin ranging from North America, Asia, Europe, and Australia. Amongst all of the 11 included studies in this systematic review, 10 were animal trials with BALB/c mice or macaques as the subjects, along with a randomized clinical trial in human subjects. The studies also covered a wide range of vaccines for diseases, with influenza as the most studied one (4 out of 11). Samples are mainly obtained from serum of the subjects with ELISA as the predominant standard protocol to measure the outcome of interest.

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Table 1. Study characteristics

156

157

158

Abbreviation: AAV – aluminum-adjuvanted monovalent hepatitis B vaccine (AAV); AFV - adjuvant-free hepatitis B vaccine (AFV); BALB/c - Bagg Albino Laboratory mice; BCG-ID - Bacillus Calmette–Guérin intradermal; BCG-MN - Bacillus Calmette–Guérin microneedle ; DEN – dengue virus; dMNP - dissolvable microneedle patches (dMNPs); DT+TMC - diphtheria toxoid (DT) and N-trimethyl chitosan (TMC); ELISA – Enzyme linked immunoassay; ELISPOT - enzyme-linked immune absorbent spot (ELISpot); HAI hemagglutination inhibition assay (HI or HAI); IgG – Immunoglobulin G; IN – Intranasal; LB-MSN-DT - DT was loaded into MSNs and the nanoparticle surface was coated with a lipid bilayer (LB-MSN-DT); MN – Microneedles; M2e5x VLP - M2e5x virus-like particles; MNA - Microneedle array; MR – Measles Rubella; npMNAs - nanoporous MicroNeedle Array; PBS - Phosphate-Buffered Saline

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Study Outcome Table 2 shows a summary of the data extracted from the included studies. There are ten studies on animals with a variety of species used, ranging from rodents such as mice to primates with rhesus macaque as an example, and one phase 1 randomized clinical trial. These studies provide evidence for the potential use of MAN in vaccination against a wide spectrum of pathogens. A third of these studies used vaccines that are commonly used in children immunization programs including Hepatitis B virus (HBV), Measles and Rubella (MR), Diphtheria and Tetanus as well as bacteria such as Mycobacterium tuberculosis (BCG vaccine)..Four studies assessed the efficacy of vaccines delivered via microneedles for influenza virus, a vaccine commonly to adults and children on an annual basis. Other studies researched using the Dengue virus (DENV) and

Ebola virus (EBOV), expanding the possibility of

microneedles to even be used in vaccinati on specific to a region. The immunogenicity of each vaccine was assessed by using three parameters: IgG titers, hemagglutinin inhibitor (HAI) and levels of inflammatory mediators at particular days postadministration of the vaccine. Furthermore, the authors investigated the safety profile of MAN by looking for the consequences of MAN experienced by the subjects as stated in the studies in order to analyze the risk of adverse effects. The data that were selected were all statistically significant with a p value of at least <0.05.

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Table 2. Reported outcomes related to immunogenicity and safety profile

161

162

163

164

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Abbreviation: AFV - aluminium-free vaccine; anti-HBs - anti-Hepatitis B; BALB/C - Bagg Albino; BCG-MN - Bacillus CalmetteGuerin-micorneedle; DIV – Divalent Inactivated Vaccine; DT - diphteris toxoid; DT+IMQ - diphteria toxoid+imiquimod; DT+TMC diphteria toxoid + N-trimetyl chitosan; HA - hemaglutination assay; IFN-γ - interfreon gamma; IgG - immunoglobulin; IL2 - interleukin 2; IL-4 - interleukin 4; IL-6 - interleukin 6; IM - intramuscular; MAP-FA-15 - micronnedle array patches forearm; MN - microneedle; npMNAs - nanoporous microneedle patches; PBMCs - peripheral blood mononuclear cell; PBS - phosphate buffer saline; SC subcutaneous; sGP-MN - soluble glycoprotein microneedle; TT - tetanus toxoid; TT+IMQ - tetanus toxoid+imiquimod; VSMN - virus specific microneedl

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DISCUSSION Current problems in conventional vaccination In the status quo, the usage of conventional needle and syringe (N&S) for vaccines has several limitations such as low efficacy that lead into need of booster dosage, storage problems in which vaccines are needed to storage in a limited range of temperature (low thermostability) and it needs trained personnel to perform the injection. Moreover, administration by injection may cause pain along with stress, especially in case of the children vaccination. In case of pediatric vaccination programs, the reasons behind incomplete vaccination coverage is mainly due to the poor compliance.5,6 Most of the vaccinations that are available are either subcutaneous (SC) injection or intramuscular (IM) injection. Looking at the aspect of immunogenicity, both subcutaneous and muscle contain less antigen presenting cells (APCs) compared to the skin tissue which is commonly regarded as the ideal sites for vaccination. Realizing this common lack of vaccines triggers researchers on discovering alternative routes of administration that are currently widely investigated for attempts to find effective and safer vaccines such as oral, pulmonary, nasal and transcutaneous delivery of vaccines.20,21 The transcutaneous become a major source of interest for many researches due to skin is a highly accessible site and has unique immunological characteristics. Based on various research, it was known that effective immune response can be elicited via the skin with variou approaches that have already been tried. One of the successful examples of transcutaneous vaccination is scarification of smallpox immunization in humans.22 The presence of APCs concentrated in the epidermis and dermis able to induce appropriate immune response after cutaneous immunization. Another primary reason in choosing the transcutaneous route is that it may generate safe immune stimulation, as it is able to avoid direct contact between general circulation with the potent component of the vaccine such as its adjuvant that is slightly toxic. The main problem in transcutaneous rate is that the uppermost layer of the skin, which is known as the stratum corneum, play role as a barrier for diffusion, thus become a major obstacle in increasing effectivity of transcutaneous immunization (TCI) such as vaccination through pre-treated or intact skin. Currently, the main challenges that still remain for cutaneous immunization such as ability to enhance transport of antigens through the skin barrier, along with increased immunogenicity of

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topical vaccines. Microneedle array patches became one of the major innovations for the vaccine delivery system which traditionally used N&S.23-25 Microneedles as a breakthrough in vaccine delivery system Microneedles promote painless TCI by significantly reducing the needles size so that these needles are barely perceptible. The concept of MAP for drug delivery has been promoted by Gerstel and Place in 1976, and in the 1990s the fabrication techniques that support the production of MAP are available in a cost-effective manner.26, The term microneedles itself can be defined as usage of needles shorter than 1 mm. Microneedles need to be able to pierce through stratum corneum, which theoretically is about 15 to 20 Îźm-thick before reaching the viable epidermis that contains APCs. Although with these properties, one thing that needs to be noted is that skin is an elastic tissue, with heterogeneous components and slightly stretched condition. Thus the structural and mechanical properties of the skin may differ significantly according to the skin type, hydration level, body location, and age among individuals.27-29 In order to ensure its effectiveness and reproducible piercing even with various obstacles and factors, microneedles commonly fabricated much longer than 20Îźm but it may be compensated with use of an applicator that is able to reduce the microneedle length needed. Other parameters such as insertion depth, microneedle tip geometry, microneedle diameter, and microneedle density may influence the skin perforation ability and antigen delivery.30-32 Various methods have been proposed in order to fabricate numerous types of microneedles. Microneedle technology itself currently under active research and different strategies were developed for usage of microneedle arrays in the case of transdermal drug delivery, covering the TCI. Generally, there are four common types of microneedle, which are the solid, hollow, coated and dissolvable microneedle, with each having its own advantages and disadvantages.33-35 Immunogenicity properties of various microneedle patches From among 10 animal trials and 1 human clinical trial study, the overall result of immunogenicity properties of various microneedle patches that are being used for vaccine delivery systems of different diseases shows significant improvement compared to conventional N&S or other route vaccines. The study measures the immunogenicity based on the total IgG, IgG1, IgG2a, HI titer with sample being used as serum with ELISA and HAI assay as the main method of assessment.

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In following discussion, writer will discuss research based on the increase, or decrease on its immunogenicity along with the effect of MAPs in generation of inflammatory mediators -

Studies that showed increase in immunogenicity

The animal trial conducted by Shin, et al. (2015)9 using 44 BALB/C mice as the subjects was aimed to compare which administration route (microneedle or intranasal) elicited better immune response and protection against influenza (inactivated 2009 A/H1N1). It was shown that immunogenicity of microneedle (MN) group significantly improved in comparison to the intranasal (IN) group, with the following details of total IgG titer was 3.67-fold higher, IgG1 titer was 25-fold higher, and IgG2a titer was 20-fold higher in MN group. Hemagglutination Inhibition titer also supported the result, in which on the second week, the HA titer for MN showed 4-fold increase compared to IN vaccine. In week 4, the HA titer for MN was approximately 6-fold higher compared to IN. For p values of the data, all conclude that the result is significant with p<0.001 for total IgG and IgG1, p<0.005 for IgG2a and HA titer week 2, p<0.05 for HA titer week 4.9 Supporting the potential MAP usage for influenza vaccine, another research conducted by Zhu, et al. (2018)15 also showed significant results in improvement of immunogenicity using the MNPs in comparison to conventional IM. The study which was conducted in female BALB/c mice, intended to compare the immunogenicity by using the tricomponent influenza (Aichi, PR8 and M2e) MNPs combination compared to DIV (Aichi and PR8) IM and tricomponent IM. Study revealed that usage of MNPs showed an overall significant increase in IgG1 specific isotypes for PR8 (p<0.001), and Aichi specific isotypes (p<0.05), and also total IgG showed significant increase for M2e specific (p<0.05) in tricomponent MNPs compare to DIV IM or tricomponent IM.15 Other research that also supported the improvement of influenza vaccine immunogenicity using MNPs was conducted by Kim MC, et al. (2019)17 and Foster AH, et al. (2020)19. Based on Kim MC, et al.â&#x20AC;&#x2122;s research in female BALB/c mice, it showed that total IgG to human M2e with SM2e5x MN Booster (OD= 1.6) vs S-M2e5x IM Booster (OD= 1.25), gave 28% increase in total IgG.17 Ratio of IgG2a/IgG1 in S-M2e5x MN Booster (1.45) vs S-M2e5x IM Booster (0.3), also significantly higher.17 HAI titers against homologous virus (A/California, H1N1) as a measure of virus neutralizing functional antibodies were detected at high levels in the immune sera of the S-

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M2e5x MN, S-M2e5x IM, and split MN groups.17 Meanwhile Forster AH, et al. (2020)19, conducted one of the first clinical trial for influenza vaccination with MNPs based delivery performed on human subjects. The study was divided into two parts, part A and part B, both of which showed improved immunogenicity as indicated by microneutralization titre response that was 14482 in MAP-FA-15 group as compared to 5120 in IM-QIV-15 group after 22 days. HAI titer for part A showed MAP-FA-15 (320) vs IM-QIV-15 (160) after 10 days, while Part Bâ&#x20AC;&#x2122;s HAI titer were MAP-FA-15 (320) vs IM-QIV-15 (160) after 22 days.19 The potential of MAP is not limited only for the usage in influenza vaccine, another implementation includes VPDs, such as the diphtheria, pertussis, tetanus, measles, rubella, and hepatitis B. Amongst studies conducted by De Groot, et al. (2017)11; Du G, et al. (2018)12; Joyce JC, et al. (2018)13; Choi, et al. (2019)16, the highest increase in titer was demonstrated 42 days post-administration of diphtheria toxoid vaccine by Du G, et al.12, with 1.75-fold increase in total IgG and IgG1 in LB-MSN-DT group compared to the DT+TMC (control).12 Furthermore, MN can also be implemented for vaccination against diseases that are specific to a region. In this systematic review, the authors found two studies on TB and EBOLA. A research to investigate the use of MN to deliver BCG vaccine BALB/C mice was conducted by Chen et al. (2017)10 In this experiment, it was shown that the titers of total IgG, IgG1, and IgG2a were all higher using MN in comparison to the control (MN only and PBS). In addition, a study by Liu Y, et al. (2018)14 on BALB/C mice assessed the administration of EBOV vaccine using sGP-MN and sGP-IM demonstrated that the IgG titer was 8-fold higher in sGP-MN 2 weeks after the vaccine was given. Additionally, both delivery systems were added with adjuvant which greatly raise the induction of antibodies up to a level of 25,000 ng/mL on average. However, study by Choi, et al. (2019) showed higher mean anti-HepBs response by 215 mIU/ml in IM AFV control group in comparison to dMNP group. To put in other words, the mean antiHepBs response was 1.98-fold higher in the control group.16

170

Studies that showed similar or comparable immunogenicity

Turvey, et al. (2019)18 compared the use of dengue virus (DENV) using a solid poly MN array against SC injection on AG129 mice. The results show that there is no considerable difference in the total IgG antibody titer between the MN and the SC group, although it is worth mentioning that in both groups, IgG titer exceeds the seroprotective threshold level.18 -

Studies that showed effects in inflammatory mediators

Chen, et al. (2017)10 discovered that the percentage of IFN-γ + CD4+ is 25-fold higher when a BCG vaccine was administered via MN patches as compared to that found in the control group (MN and PBS). Likewise, the percentage of IFN-γ + CD8+ in the MN group was twice as much as in the control group. Study by Zhu, et al. (2018)15 using tricomponent MNPs combination also showed significant increase of IL-4, IFN-γ for Aichi, PR8, and 4M2e peptides in comparison to the other methods of delivery (DIV IM and tricomponent IM). In addition, the study by Choi, et al. (2019)16 showed an increase of IFN-γ in dMNP group with 105 SFCs/106 PBMCs higher than in IM AFV (control), 5 weeks after the booster dose for hepatitis B vaccine was given. As for the IL-2 and IL-4 levels, they were observed to be similar in both groups. However, a study by Kim MC, et al. (2019)17 showed 1.17-fold higher inflammatory IL-6 cytokines in S-M2e5x IM control group (410 pg/ml) in comparison to S-M2e5x MN group (350 pg/ml).17 Safety profile of various microneedle patches (RMP) According to the World Health Organization (WHO)1,2, there is a growing worldwide concern on the topic of vaccine hesitancy, whereby people refuse to accept vaccination for a multitude of reasons, despite the preexisting strong evidence that the advantages of a vaccine overweigh the possible risks. As a result, the vaccination coverage has not reached the ideal target. which hinders the success of vaccines as it is highly dependent on the population to increase and maintain the uptake of vaccines. One of the reasons that cause people to have doubts in vaccination is the potential of adverse effects that come along with vaccination such as fever, hematoma etc. A breakthrough in the vaccine delivery system is crucial to combat the doubts that some of the population have in terms of safety profile.

171

Joyce, et al.13 experimented on infant rhesus macaques by vaccinating the macaques at 3-4 weeks of age. After 15 minutes of application to the inner thigh, there were mild puncture marks at the puncture sites of MAN but these marks disappeared after one hour. Moreover, other mild symptoms were reported such as transient erythema but no other adverse effects were seen throughout the study including edema or bleeding. Choi, et al.16 also experimented using rhesus macaque but administration of Hepatitis B vaccination was used. Likewise, no adverse reactions were observed, further strengthening the evidence that microneedle is a safer alternative. In humans, microneedle patches are generally safe and tolerable, and have a better safety profile than either intramuscular or subcutaneous injection. As mentioned previously, the size and depth of microneedles allow them to be inserted into the skin without stimulating the nerve free endings as much, unlike what an IM or SC injection induces. In this way, MNA allows vaccine delivery in the least painful way and thus, it could alleviate the nerve phobia that some people, especially children, might experience. The clinical trial by Forster, AH et al.19 on influenza virus via MAN shows incredible safety profile results, by performing a pain assessment using a pain score. Forster AH et al uses a pain scoring system with a scale of 0 to 10, in which 0 means no pain and 10 is the worst pain possible. It was found that subjects that were given MNA reported having a pain score of only 0-2, regardless on the site of application.19 In addition, other post-vaccination signs at the site of vaccination such as erythema and eschar formation as well as edema were also assessed in the same trial. Using a scale of 0 to 4 for erythema and edema separately, in which 0 means no edema or no erythema and 4 means severe erythema (beet redness) or severe edema (edmea with a height of more than 1 mm and spread beyond the exposure area). Generally, subjects given with a MAN have a total score of 0 to 3, showing a good response with regards to side effects.19 Study strengths and limitations Given that the method of vaccine delivery through microneedle shows superior novelty in comparison to other conventional routes of administration, to the best of our knowledge, this systematic review becomes the first one to evaluate the immunogenicity and safety profiles through this means of delivery. This fact is also supported by the studies used in the review, all of which are within the last five years. This contributes to the strength of our review and consequently

172

also provides benefits by serving as reference for further researchers when investigating similar issues. Additionally, the study locations vary across the world, ranging from at least 4 different continents with wide coverage of numerous vaccine-preventable diseases, that allows its impactful utilization as delivery. As in other studies, our systematic review also has several limitations. One major limitation is the fact that most studies included are animal trials with only one study using human subjects. Furthermore, most studies did not clearly provide information in terms of randomization and blinding during study, which might present as study bias. The exclusion of inaccessible full-text articles and studies with incompatible language may further account for the limitation. Future application and research The result of this systematic review could be further brought into application to be considered as one means of vaccine delivery, which could serve as a way to overcome the current problems associated with adherence to undergo immunization process through vaccination due to numerous factors as explained in the status quo, such as hesitancy, fear of needles, et cetera. We do also recommend further studies to be conducted with bigger sample size to further confirm the results and its applicability in the society of today. Additional research about safety profiles, efficacy, immunogenicity could also be performed with even wider coverage of vaccine preventable diseases. Despite the drawbacks mentioned in the previous section, we strongly believe that the result of this review would provide insightful and useful implications, serving as a basis to encourage further studies in this field.

173

CONCLUSION To sum up, this systematic review revealed that vaccines delivered via microneedle array in the form of patch have several advantages over traditional forms of vaccination (subcutaneous and intramuscular injections). In terms of immunogenicity, the majority of studies show that it is superior to either SC or IM by comparing the level of IgG titer that is induced upon vaccination. Other immunogenicity aspects that were assessed include hemagglutination-inhibition assay and inflammatory mediators. Those studies that show comparable immunogenicity between different forms of vaccine also indicate that MN can be a potential alternative. Moreover, studies that assess the safety profiles provide evidence that MN has a better safety profile than SC or IM, which has the potential to tackle vaccine hesitancy as one of the biggest challenges in vaccination. Overall, the authors believe that microneedle vaccination has a massive potential to be explored further and eventually be used in clinical practice to help achieve the Sustainable Development Goals. REFERENCES 1. World Health Organization. Immunization coverage [online]. Geneva, Switzerland: World Health Organization; 2019. Available at:

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6. Hao Y, Li W, Zhou X, Yang F, Qian Z. Microneedles-Based Transdermal Drug Delivery Systems: A Review. Journal of Biomedical Nanotechnology. 2017; 13(12): 1581–1597. 7. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul;6(7):e1000097. 8. National Toxicology Program. OHAT Risk of Bias Rating tool for Human and Animal Studies

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27. Leone M, Mönkäre J, Bouwstra JA, Kersten G. Dissolving microneedle patches for dermal vaccination. Pharm Res. 2017 Nov;34(11):2223–40. 28. Kraan H, van der Stel W, Kersten G, Amorij J-P. Alternative administration routes and delivery technologies for polio vaccines. Expert Review of Vaccines. 2016 Aug 2;15(8):1029–40. 29. Rodgers AM, Cordeiro AS, Donnelly RF. Technology update: dissolvable microneedle patches for vaccine delivery. MDER. 2019 Sep;Volume 12:379–98. 30. van der Maaden K, Luttge R, Vos PJ, Bouwstra J, Kersten G, Ploemen I. Microneedlebased drug and vaccine delivery via nanoporous microneedle arrays. Drug Deliv and Transl Res. 2015 Aug;5(4):397–406. 31. Weldon WC, Martin MP, Zarnitsyn V, Wang B, Koutsonanos D, Skountzou I, et al. Microneedle vaccination with stabilized recombinant influenza virus hemagglutinin Induces Improved Protective Immunity. Clin Vaccine Immunol. 2011 Apr;18(4):647–54. 32. Becker PD, Hervouet C, Mason GM, Kwon S-Y, Klavinskis LS. Skin vaccination with live virus vectored microneedle arrays induce long lived CD8+ T cell memory. Vaccine. 2015 Sep;33(37):4691–8. 33. Li N, Wang N, Wang X, Zhen Y, Wang T. Microneedle arrays delivery of the conventional vaccines based on nonvirulent viruses. Drug Delivery. 2016 Nov 21;23(9):3234–47. 34. Schipper P, van der Maaden K, Romeijn S, Oomens C, Kersten G, Jiskoot W, et al. determination of depth-dependent intradermal immunogenicity of adjuvanted Inactivated polio vaccine delivered by microinjections via hollow microneedles. Pharm Res. 2016 Sep;33(9):2269–79. 35. Fernando GJP, Zhang J, Ng H-I, Haigh OL, Yukiko SR, Kendall MAF. Influenza nucleoprotein DNA vaccination by a skin targeted, dry coated, densely packed microprojection array (Nanopatch) induces potent antibody and CD8 + T cell responses. Journal of Controlled Release. 2016 Sep;237:35–41.

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Appendix 1. Studies quality assessment based on OHAT Risk of Bias Tool 2015

Study (Year; Author)

Selection Bias

Performance Bias

Attrition/Exclusion Detection Bias Bias

Selective Other Reporting Bias Bias

Q1: Q2: Q5: Randomization Allocation Identical concealment experimental conditions

Q6: Q7: Incomplete Blinding outcome data during study

Q8: Confidence in exposure characterization

Q9: Q10: Confidence Outcome in outcome reporting assessment

Q11: Other potential threats to internal validity

2015; Shin, et al.

2017; Chen, et al.

2017; De Groot, et al.

2018; Du G, et al.

2018; NR Joyce JC, et al.

178

2018; Liu Y, et al.

2018; Zhu, et al.

2019; Choi, et al.

2019; Kim MC, et al.

2019; Turvey ME, et al.

2020; Forster AH, et al.

179

Breaking the Myth of Vaccine (DTP & MMR) and Its Preservative Substances Induced Neurodevelopmental Disorder : a Systematic Review, Meta-Analysis, and Epidemiological Review Nathanael Ibot David 1*, William Wiradinata 1 1

Faculty of Medicine, Brawijaya University, Malang, Indonesia *nathanaelibot@gmail.com; +62 81286928218 ABSTRACT

Introduction: Vaccine is one of the greatest achievements in the history of medicine. Routine immunization programs have been proven to be saving the lives of millions of children from the exposure of vaccine preventable diseases, such as measles, pertussis, and influenza. The concerns of parents led by myths and misconceptions about vaccines, causing them to withdraw their child from vaccination programs, are detrimental to their own safety and others around them from vaccine preventable disesases. The objective of this review study is to examine the correlation of vaccines and its preservatives to the occurence of neurodevelopmental disorders. Methodology: Authors conducted this review study based on PRISMA guidelines. Studies were searched g e ec Pee a

c da aba e e , a d Vacc e

e a g gf

de e

e a D

de ,

MMR ,

DTP ,

e ea 2000-2020. Studies included assessedthe effect of

MMR and DTP vaccines, including its preservatives, on neurodevelopmental disorders. Quality among studies were evaluated using the Newcastle-Ottawa Scale. Statistical analysis were done using the Mantel-Haenzel method and fixed effects model. Results: The utilization of MMR and DTP vaccines related to autism as a part os ASD yielded a result of odds ratio (OR) = 0.86, (95% confidence intervals (CI) 0.80 to 0.93, P < 0.0001). The analysis on thimerosal exposure results in an odds ratio (OR) = 1.69 (95% confidence intervals (CI) 1.52 to 1.88, P < 0.00001). Conclusion: MMR and DPT vaccines are not correlated to autism as a part of ASD. The use of MMR and DPT vaccine in children below 18 months and 36 months of age is also not correlated to autism as a part of ASD. On the other hand, thimerosal as a preservative seem to have some correlation with autism as a part of ASD. The complication rate caused by vaccine preventable disease is far more diverse and high in number compared to AEFI caused by vaccine usage. Further research is needed to confirm this finding. Keywords: DTP, MMR, neurodevelopmental disorder, preservative, vaccine

180

181

I. INTRODUCTION

downtrend in high and middle income countries (HMICs)2,4. A low scope on

Vaccine is one of the greatest achievements

immunization surely could lead to a failure

in the history of medicine. The discovery of

in maintaining society's herd immunity. A

smallpox vaccine by Edward Jenner in 1798

high vaccination rate of 95% is required to

brought attention and greatly spurred the

achieve herd immunity and prevent future

growth of vaccine research1,2. Based on

possible outbreaks1,4. This aims to protect

epidemiological studies, vaccines are known

the

to be highly effective in preventing certain infectious preventable

diseases,

especially

diseases,

â&#x20AC;&#x201C;

people

who

are

bone

marrow

organ transplant recipient, post splenectomy

complication and sequelae3,4. One of the good health and well being

immunocompromised,

their

Sustainable Development Goals (SDGs)

contraindicated to be vaccinated, such as the

vaccine-

including

other

patients,

â&#x20AC;&#x201C;

and

premature

babies6.

The

evidence of vaccines impact on herd

could be

immunity were displayed on the diminishing

attained through the utilization of vaccines.

numbers on pertussis incidence rate from

Until this day, World Health Organization

48.000 cases in 2012 to 24.231 cases in

(WHO) has been seriously promoting

2013 in the USA. After studies were

vaccine usage in order to achieve this goal5.

conducted

Routine immunization programs have been

regarding

this

massive

improvement, it is shown that immunization

proven to be saving the lives of millions of

of adults and adolescents played a pivotal

children from the exposure of vaccine

key by reducing the transmission rate of

preventable diseases, such as measles,

pertussis1.

1,3

pertussis, and influenza . Looking at it from a public health perspective, vaccines

Regardless of the efficacy of vaccines, the

does a great job in minimizing expenditures

employment

caused by preventable diseases2.

obstructions in the form of myths spreading

vaccines

faced

many

in society7. Inadequate information about

Although the efficacy of vaccines has been

vaccines were being widely spread through

proven to be outstanding, some of the

many sources, such as newspapers, websites,

countries in the world haven't experienced

movies, testimony-based medicine, journals,

its full benefits, especially low and middle

even

income countries (LMICs), also there is a

influencers

organizers,

182

(celebrities, mommy

bloggers, bloggers

opportunists).

The

impact

this

Disorder, Fifth Edition (DSM-V), ASD is a

misconception is massive, giving birth to a

set

group known as "antivaccine"

characterized

â&#x20AC;&#x201C;

that exists

neurodevelopmental by

deficit

disorders in

social

since the 1700s in the beginning of smallpox

behaviours and non verbal interaction, such

vaccine

as reduced eye contact, facial expression,

â&#x20AC;&#x201C;

with a slogan: "Green Our

Vaccines"8. influence

Proof is

immunization,

the

antivaccine

decreasing

turns

out

that

Wakefield's

publication that suggests a link between

outbreak in Texas and New York, from 34

MMR vaccine and ASD didn't present the

cases in 2004 to a staggering 189 cases in

actual facts. On a later day, Wakefield were

2013, due to the weakening of herd

discovered proposing a patent for a measles

immunity1. There are two popular myth

vaccine that he made and receiving a sum of

being held and popularized by "antivaccine"

money from a lawyer, allegedly suing a

group. The first myth is a film aired in 1982,

company

titled "DTP: Vaccine Roulette" (WRY-TV),

Samples used in his study were also not

claiming that there is a connection between

randomized, further questioning the validity

DTP

neurodevelopmental

of the study. The validity of Wakefield's

disorders (NDD)9. The second myth being a

study were also put into test by a meta-

journal published in the Lancet, authored by

analysis in Vaccine, conducted in 2014 and

Andrew

the

involving 1.3 million people as study

correlation between MMR vaccine and

population, reporting no difference in the

autistic syndrome disorder (ASD). Due to

incidence rate of autism between vaccinated

these misconceptions, many rationalizations

and unvaccinated children11. The film "DPT

appeared, for instance, fears about vaccine

: Vaccine Roulette" were also put to the test

safety, religious objections, and scepticism

and based on research, DTwP (whole cell)

about science8.

vaccine are often causing adverse effects,

and

Wakefield,

life10.

measles

vaccine

followed

rate

and body gesture in the first three years of

exploring

producing

MMR

vaccines.

causing the FDA to withdraw DTwP (whole

Now, there are plenty of parents who are

cell) vaccines and replacing it with DTaP

withdrawing their children from vaccination

(acellular) vaccines. Based on a safety

programs due to beliefs that vaccine will

standpoint, the use of acellular vaccine is not

potentially induce ASD6. Based on the

a risk factor in causing ASD, showing no

Diagnostic and Statistical Manual of Mental

183

evidence of encephalopathy and febrile

studies in order to determine : (1) the

seizures as AEFI (Adverse Effect Following

correlation between MMR & DPT vaccines

Immunization)1.

to the occurence of autism as a part of ASD; (2) the correlation between thimerosal as a

Other than vaccines itself, other substances

vaccine preservative to the occurence of

found in vaccines were being suspected as a

autism as a part of ASD; and (3) the

potential causing agent of ASD in children.

comparison of morbidity and mortality rates

Vaccines contain many various substances, such

preservatives

antifreezing

agent

between vaccine preventable diseases and

(thimerosal),

(ethylene

AEFI.

glycol),

colouring substances, gelatin, glutamate in varicella vaccine, antibiotics (neomycin, streptomycin), involved

and the

other making

(formaldehyde residue)6. There concern

regarding

II. METHODS

substances

thimerosal

Authors conducted this systematic review

vaccine

acc d g

is some as

of the review12. Items deemed essential for transparent reporting of a systematic review

children. Based on this condition, studies

such as title, introduction, methods, result,

were conducted by the FDA and it is thimerosal

ae e

diagram and checklist to improve the quality

preservative causing a negative effect in

discovered that

e PRISMA

and discussion were

may cause

included in

the

checklist.

mercury toxicity in children below six months. This finding caused the massive

1. Eligibility Criteria

withdrawal of vaccines in 2001, but its

This review includes cohort, case control,

correlation with ASD is still unproven.

and epidemiological studies published in

Although researches and improvements have

2000-2020 investigating the relation of

been made in vaccines, authors felt that

MMR and DPT vaccines, including its

there is a need to break the myth and

preservatives,

misconception among the people with a

disorders. Studies not available in English

systematic study to answer this problem

and published before 2000 were excluded.

based on data. Authors conducted a review 2. Search Strategy

on case control, cohort, and epidemiological

184

neurodevelopmental

The authors searched through electronic

studies included with emphasis of statistical

literature using databases and search engines

results obtained.

such as PubMed, Cochrane, Science Direct, Scopus, Researchgate, and Google Scholar 4. Risk of Bias Assessment

from the year 2000-2020. Keywords used in e d

ea c de

OR ,

( D

e a

The quality of this study was assessed by

NDD ) AND ( Mea e ,

two reviewers with the same portion by

e e : ( Ne be a

de e

e a, e

MMR )

, ea

OR T

the

Newcastle-Ottawa

Scale.

Assessment of studies using instruments in

OR DPT )

AND ( Vacc e ) AND ( P e e a AND ( T

using

AND

the form of questionnaires. (see appendix 1

e )

and appendix 2)

e a * ).

The wildcard term (*) was applied to increase the sensitivity of the search

5. Statistical Analysis

strategy.

were

Meta-analysis were conducted with Mantel-

observational studies that evaluated the

Haenzel method as the statistical method,

effect of MMR and DPT vaccines, including

with the effect measure being Odds Ratios

its preservatives, on neurodevelopmental

(ORs) and Risk Ratios (RRs) with 95%

disorders. Two reviewers evaluated the

confidence intervals (CI). Fixed Effects

journals independently and discrepancies

Model (FEM) were used and P

between the two authors were resolved by

considered statistically significant. Bias in

discussion.

studies used in the meta-analysis were

The

studies

included

0.05

evaluated using a funnel plot. 3. Data Extraction and Analysis III. RESULTS

Eligible studies were reviewed and the f

g da a

ee e

1. Study Identification and Selection

ac ed : a

After conducting a search of studies and

name, year of publication, the place where

examining the contents that have been

the study was performed, study design,

collected from various databases, a total of

number of samples,sample characteristics, and

studied

substances.

The

1576 studies were found. During the

authors

screening process, 1163 duplicate studies

analyzed and summarized the outcomes of

were reported to be found. In total, 413

185

synthesis, 12 of the studies are also included in quantitative synthesis (meta-analysis)1519,21,22,24-26,27,30

Authors

reached

full

agreement for inclusion of studies included in this review (see Figure 1.) 2. Risk of Bias Assessment Authors examined the studies using the Newcastle-Ottawa Scale (NOS) tool for cohort and case control studies. The risk of bias in all of the studies are mostly in the low and unclear risk of bias category (see Table 1. see Table 2.) 3. Study Characteristics Figure 1. Flowchart of study identification and selection based on PRISMA

Authors summarized the characteristics and properties of each study included (see appendix 3, 4, and 5)15-30.

studies

underwent

title

and

abstract

4. Meta-analysis of Primary Outcome

screening that result in the exclusion of 243 studies. The exclusion criteria based on non-

Authors investigated the correlation between

english

journal,

and

non

MMR & DPT vaccines to the occurance of

and

its

autism as a part of ASD according to data

preservatives. The remaining 170 studies

collected from 8 studies15-19,24-26. Data

were screened by its full-text article, of

resulting from this meta-analysis shown to

which 155 studies were excluded due to

be significant (odds ratio (OR) = 0.86, 95%

failure meeting the inclusion criteria. After

confidence intervals (CI) 0.80 to 0.93, P<

assessment of studies by comprehensive

0.0001;

reading, the remaining 16 studies were

heterogeneity showed that the data may

synthesis15-30.

represent moderate heterogeneity (P = 0.01,

addressing

non-NDD,

MMR,

DPT,

included

qualitative

Besides

being

included

see

Figure

2.).

Tests

for

I2 = 60.0%). Qualitative observations based

qualitative

186

Table 1. Risk of bias table of case control bias item from NOS questionnaire)

d e (a

dge e

d e ab

eac

on the funnel plot resulted showed that data collected has a low risk of reporting bias

analysis evaluating the results from cohort

(see Figure 2.).

and case control study design separately.

In analyzing the correlation between MMR

After studies were separated on the basis of

and DTP vaccination to the occurence of

study design, 3 studies with cohort design24-

autism as a part of ASD in children, authors

were interested in conducting further

were found. Meta-analysis were done into

Table 2. Risk of bias table of cohort item from NOS questionnaire)

d e (a

and 5 studies with case control design15-19

dge e

187

of studies about each risk of bias

those 2 groups and the following data was

On the other 3 studies utilizing the cohort

extracted :

study design24-26, another significant result

Figure 2. Metaanalysis of Primary outcome A. Forest Plot B. Funnel Plot

In 5 studies using the case control study

was found (odds ratio (OR) = 0.85, 95%

design15-19, a significant result was found

confidence intervals (CI) 0.77 to 0.93, P =

(risk ratio (RR) = 0.97, 95% confidence

0.0006;

intervals (CI) 0.94 to 1.00, P = 0.03; see

heterogeneity showed that the data may

Figure 3.). Tests for heterogeneity showed

represent substantial heterogeneity (P =

that the data may represent substantial

0.06, I2 = 64%). Based on the funnel plot

heterogeneity (P = 0.04 , I2 = 59%). Based

generated, qualitative observations are made

on the funnel plot generated, qualitative

and the results found that the data collected

observations are made and the results found

is at some risk of reporting bias (see Figure

that the data collected is at a low risk of

4.).

see

Figure

4.).

Tests

for

reporting bias (see Figure 3.). 5. Meta-analysis of Secondary Outcome

188

Regarding

the

suspicion

the

= 96%). Based on the funnel plot generated,

correlation between thimerosal as a vaccine

qualitative observations are made and the

preservative to the occurence of autism as a

results found that the data collected is at a

part of ASD, authors conducted an analysis

low risk of reporting bias (see Figure 6.).

on studies that assessed the impact of

Next, based on the 4 studies mentioned

vaccines preserved with thimerosal. Based

before, authors conducted further analysis

in the data collected, 4 studies reported a

evaluating the results from cohort and case

correlation of this event21,22,27,30. Analysis

control study design separately. After

done by authors through meta-analysis of

studies were separated on the basis of study

these 4 studies yielded significant results

design, 2 studies with cohort design22,27 and

(odds ratio (OR) = 1.69, 95% confidence

2 studies with case control design21,30 were

intervals (CI) 1.52 to 1.88, P < 0.00001; see

found. Meta-analysis were done into those 2

Figure 6.). Tests for heterogeneity showed

groups and the following data was extracted

considerable heterogeneity (P < 0.00001, I2

Figure 3. Metaanalysis of Primary outcome (Case control only)

A. Forest Plot B. Funnel Plot

189

In 2 studies using the case control study

incidence of complications

caused by

design21,30, a significant result was found

vaccine preventable diseases compared to

(risk ratio (RR) = 2.24, 95% confidence

the incidence of AEFI. According to the data

intervals (CI) 2.05 to 2.45, P< 0.00001; see

found, it could be understood that the

Figure 7.). Tests for heterogeneity showed

incidence of complications

considerable heterogeneity (P< 0.00001, I2 =

vaccine preventable diseases were high in

98%). Based on the funnel plot generated,

numbers, compared to the incidence of

qualitative observations are made and the

AEFI with a miniscule scale of numbers.

results found that the data collected is at a

The incidence data

low risk of reporting bias (see Figure 7.).

presented in a table (see appendix 6).

caused by

are systematically

On the other 2 studies utilizing the cohort study design22,27, another significant result

7. Subgroup analysis

was found (odds ratio (OR) = 1.40, 95%

a. Assessment

confidence intervals (CI) 1.24 to 1.57, P< 0.00001;

see

Figure

7.).

Tests

based

age

vaccination using MMR and DTP

for

vaccines

heterogeneity showed that the data may represent substantial heterogeneity (P =

Authors

0.19, I2 = 41%). Based on the funnel plot

vaccination age using MMR and DTP

generated, qualitative observations are made

vaccines to the occurence of autism as a part

and the results found that the data collected

of ASD. Analysis was done based on age of

is at some risk of reporting bias (see Figure

vaccination using MMR and DTP vaccines,

7.).

which is below 18 and 36 months old.

order

acquire

comprehensive

7,31-41

data

old vaccinated with MMR and DPT vaccines15,17,19, data resulting from this

were

meta-analysis shown no correlation between

obtained from various places in the world to illustrate

the

difference

between

On 3 studies with children below 18 months

epidemiological

Epidemiological

effect

control studies, it is found that :

qualitative analysis, authors also added through

the

authors based on the data obtained from case

understanding, besides quantitative and information

analyzed

According to the meta-analysis done by

6. Meta-analysis of Tertiary Outcome In

also

the use of MMR and DPT vaccines on

the

190

children below 18 months old to the occurance of autism as a part of ASD (risk ratio (RR) = 0.98, 95% confidence intervals (CI) 0.94 to 1.02, P = 0.30; see Figure 5.) Tests for heterogeneity showed that the data may represent moderate heterogeneity (P = 0.11, I2 = 54%). Based on the funnel plot generated, qualitative observations are made and the results found that the data collected Figure 4. Meta-analysis of Primary outcome (Cohort only) Forest Plot (Left) amd Funnel Plot (Right)

is at a low risk of reporting bias (see Figure 5.). Based on the data on 3 studies with children below 36 months old vaccinated with MMR and DPT vaccines15,17,19, data resulting from this meta-analysis shown no correlation between the use of MMR and DPT vaccines on children below 18 months old to the occurance of autism as a part of ASD (risk ratio (RR) = 0.98, 95% confidence intervals (CI) 0.96 to 1.01, P = 0.18; see Figure 5.). Tests for heterogeneity showed considerable heterogeneity (P < 0.0003, I2 = 88%). Based on the funnel plot generated, qualitative observations are made and the results found that the data collected is at a low risk of reporting bias (see Figure 5.). b. Assessment based on thimerosal dosage and age of vaccination using vaccines

191

thimerosal

preserved

Authors also conducted an analysis on the

heterogeneity (P< 0.00001, I2 = 97%).

effect of thimerosal dosage and age of

Based

vaccination

preserved

qualitative observations are made and the

vaccines to the occurence of autism as a part

results found that the data collected is at a

of ASD. Analysis was done based on

low risk of reporting bias (see Figure 8).

using

thimerosal

the

funnel

plot

generated,

thimerosal dose differences and age of vaccination

using

thimerosal

preserved

vaccine, which is 12.5 µg in children below

IV. DISCUSSION

1 month of age and 25 µg in children below

Vaccine had already become an irreplacable

2 months of age. According to the meta-

part of human life and history, especially in

analysis done by authors based on the data

the field of medicine. Regardless of the

obtained from case control studies, it is

controversial debates that emerges about the

found that :

negative

preventing morbidity and mortality from

result was found (risk ratio (RR) = 1.89,

millions of children in the world. The hope

95% confidence intervals (CI) 1.73 to 2.06,

is, with such splendid results, the masses

P< 0.00001; see Figure 8.). Tests for

would be inclined to enroll in vaccination

considerable

programs as a preventive measure from the

heterogeneity (P< 0.00001, I2 = 97%). Based

the

funnel

plot

vaccines,

declared that vaccines are truly successful in

children below 1 month21,22, a significant

showed

epidemiological data published by WHO

On 2 studies with 12.5 µg of thimerosal in

heterogeneity

effects

public health sector1,6 .But in reality, there is

generated,

a downtrend in vaccine usage. The decrease

qualitative observations are made and the

in the scope of vaccination are beginning to

results found that the data collected is at a

be felt by many people, especially with the

low risk of reporting bias (see Figure 8.).

increase of decentralized, yet spread out

Based on the data on 2 studies with 25 µg of

thimerosal in children below 2 month21,22, a

acc e

e e . T

c d

surely becomes a concern, because the ideas

significant result was found (odds ratio (OR)

ead b

e a

acc e

e e

= 1.84, 95% confidence intervals (CI) 1.69

based on myths and misconceptions, and it

to 2.01, P< 0.00001; see Figure 8.). Tests

could be found in many forms of media8.

for

heterogeneity

showed

considerable

192

Figure 5. Metaanalysis of subgroup (Cohort only) Forest Plot (Left) amd Funnel Plot (Right)

A. Child MMR

<18 Months B. Child MMR < 36 Months

B Figure 6. Meta-analysis of Secondary outcome Plot (Left) amd Funnel Plot (Right)

193

The effect of antivaccine movements is not

On the process of proving the hypothesis

about the correlation of vaccine use and

immunization, but a global threat by

ASD, internationally publicized studies were

potentially making the way for dangerous

analyzed.

vaccine preventable disease outbreaks. With

studies15-19,24-26, the results (odds ratio (OR)

a wide scope of immunization of 95%, the

= 0.86, 95% confidence intervals (CI) 0.80

function of herd immunity in guarding the

to 0.93, P < 0.0001; see Figure 2.) refuted

vulnerable and contraindicated to vaccines

the correlation of vaccine usage to ASD.

can go on. A narrow scope of immunization

This finding is opposite to 3 studies15,18,25

will also ensure the weakening of herd

that obtained results that vaccination are

immunity, ensuring the exposure of vaccine

correlated to ASD. Despite that, based on a

preventable diseases to the vulnerable and

wide study, indicated that the vaccinated

contraindicated

potentially

children are experiencing a 14% drop in

leading to a high incidence rate followed by

ASD rate. Based on this finding, it is proven

morbidity and mortality1. Therefore, there is

that there are no correlation between ASD

a need for adequate information, proper

and the use of vaccines. Further analysis on

understanding by healthcare workers, and

cohort studies gave a result of (odds ratio

the awareness from the people in order to

(OR) = 0.85, 95% confidence intervals (CI)

gain proper trust in vaccination8.

0.77 to 0.93, P = 0.0006; see Figure 4.) and

small

meaning

the

vaccines,

efforst

among

people

(RR) = 0.97, 95% confidence intervals (CI)

about

0.94 to 1.00, P = 0.03; see Figure 3.). This

vaccines, researchers did a great role to

finding shown that in both cohort and case

search for proofs about the benefits and uses f acc e . Af e Wa ef e d there

are

some

evidence

b ca about

of 8

in case control studies a result of (risk ratio

In order to eradicate the myths and misconceptions

By the meta-analysis

control studies, there is no correlation

between vaccine usage and ASD.

the

correlation of ASD and vaccine usage

Next, based on available data, an analysis

through a multicentre approach for over 2

were conducted to investigate the potential

decades42.

healthcare

of ASD after vaccination adjusted to the age

workers need to present evidence about

of children when they were vaccinated.

vaccines through a valid and credible study.

Meta-analysis of 3 studies15,17,19 with the

This

shows

that

vaccination age of <18 and <36 months was

194

Figure 7. Meta-analysis of secondary outcome (thimerosal induce NDD) from Case control study (up) and Cohort study (down)

done. The results were (risk ratio (RR) =

on 4 studies21-22,27,30 , the results (odds ratio

0.98, 95% confidence intervals (CI) 0.94 to

(OR) = 1.69, 95% confidence intervals (CI)

1.02, P = 0.30; see Figure 5.) for the <18

1.52 to 1.88, P < 0.00001; see Figure 6.)

months group and (risk ratio (RR) = 0.98,

shown

95% confidence intervals (CI) 0.96 to 1.01,

increasing the risk of ASD by 69%. Further

P = 0.18; see Figure 5.) for the <36 months

analysis on cohort study design group

group. Both results indicates no correlation

yielded a result of (odds ratio (OR) = 1.40,

between vaccine usage to ASD.

95% confidence intervals (CI) 1.24 to 1.57,

that

thimerosal

exposure

are

P < 0.00001; see Figure 7.) and in case

Other than the public concern about the

control study design group, a result of (risk

rumors circulating about vaccines and ASD,

ratio (RR) = 2.24, 95% confidence intervals

thimerosal as a vaccine preservative is also

(CI) 2.05 to 2.45, P < 0.00001; see Figure

being suspected as a potential cause for

7.). This finding shows that both in cohort

mercury intoxication that could lead to ASD

and case control study design, thimerosal

in children. Based on the meta-analysis done

exposure are correlated to ASD.

195

Next, based on the available data, further

order to recognize that the incidence of

analysis were done on thimerosal dosage

AEFI are lower than the complications of

and age of vaccination using thimerosal

vaccine preventable diseases. According to

preserved vaccines to the occurence of

the analysis of epidemiological studies

autism as a part of ASD. Analysis were done

conducted

on 2 studies21,22 with the dichotomization

incidence rate of complications per 1000

into 2 groups, the first one being 12.5 µg in

cases

in children less than one month of age, and

diseases are much higher compared to AEFI

the second one being 25 µg in in children

caused by vaccines. Furthermore, beside the

less than two month of age. Results on the

higher incidence rate of complications in

12.5 µg in in children less than one month of

vaccine

age group being (risk ratio (RR) = 1.89,

manifestation of complications are more

95% confidence intervals (CI) 1.73 to 2.06,

variable in vaccine preventable diseases

P < 0.00001; see Figure 8.), and on the 25

(moderate-severe) compared to AEFI (mild-

µg in in children less than two month of age

moderate).

group being (odds ratio (OR) = 1.84, 95%

around many countries, the

caused

vaccine

preventable

diseases,

the

V. LIMITATION

confidence intervals (CI) 1.69 to 2.01, P <

In this systematic review and meta-analysis,

0.00001; see Figure 8.). This shows that the

a degree of heterogeneity were sometimes

exposure of thimerosal with specific dose

found

and time in both groups indicate a

the

data

when

conducting

quantitative research. This was possibly

correlation to ASD.

caused by the differences in the year where

After analyzing the data quantitatively,

the study data were extracted. Some of the

authors took a look into epidemiological

studies analyzed were also not quite explicit

studies. Plenty of parents are concerned and

in presenting the data, making the data

withdrew their child from immunization

extraction process more difficult. A lack of

programs due to receiving many information

studies published in the range of 2015-2020

of AEFI on each vaccination. This is not to

were apparent, so studies across 2000-2020

be disputed, since each human bodies has

were included.

their own unique immune reactions, but a

VI. CONCLUSION

further examination must be conducted in

196

In this systematic review and meta-analysis,

Further researches are needed to confirm

we could understand the importance of

this finding.

vaccines as a precaution against disease. Of

The complication rate caused by vaccine

course, the urgency of vaccines does not

preventable disease is far more diverse and

only revolve around oneself, but also others.

high in number compared to AEFI caused

Through an analysis of studies, results

by vaccine usage. Besides that fact, a key

shown that MMR and DPT vaccines are not

component in breaking the myths and

correlated to autism as a part of ASD. The

misconception on vaccine usage is a

use of MMR and DPT vaccine in children

comprehensive understanding of the facts

below 18 months and 36 months of age is

presented so we could actively follow and

also not correlated to autism as a part of

participate vaccination programs to ensure

ASD. On the other hand, thimerosal as a

freedom from vaccine-preventable diseases

preservative seem to have some correlation

on the next generations to come.

with autism as a part of ASD.

Figure 8. Meta-analysis of subgroup (thimerosal dose dependent induce NDD) from Case control study 12.5 Âľg < 1 month age (up) and Cohort study 25 Âľg < 2 month age (down)

197

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APPENDIX

Appendix 1. Newcastle-ottawa scale quality assessment scale case control studies questionnaire

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Appendix 2. Newcastle-ottawa scale quality assessment scale cohort studies questionnaire

204

Appendix 3. Table summary of the characteristics and properties of Case control studies

205

Appendix 4. Table summary of the characteristics and properties of Cohort studies

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Appendix 5. Table summary of the characteristics and properties of Epidemiological studies

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Appendix 6. Rate of complication in vaccine-preventable disease vs. AEFI of Vaccine

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Appendix 7. Table summary of the vaccine adverse event

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Women Empowering Peer Group: A Literature Review to Determine an Effective Way to Fight the Antivaccine Movement for Mother in Developing Countries Achmad Januar Er Putra Medical Clerkship, corresponding e-mail: januar.putra04@gmail.com I.

Introduction and Objectives: Vaccination is one of the way to provide immunity in a person. Vaccine is included in

the term of active immunity, which means the substance from the vaccine will interact with human immune system and produce an immune response. This response mimic the true disease, but not overt clinically and later not went to the potential complications1. Vaccination also produce the immunological memory which is similar to the memory of the disease caused by the specific microorganisms. This memory again will not appeared to the clinical symptoms. This memory then protect the body from infection because the body already have weapon to overcome those causative agent. Vaccine offers the benefit to a person by giving them the protection for a longer time, or even for an entire life1,3. The result of vaccine in a person will known as the individual immunity. This means that the individual which already undergo the process of vaccination will have the specific protection towards disease, or the vaccination-preventable disease. If the person were vaccinated reach the number of threshold, vaccination will protect the community. This protection knows as the herd immunity. He d imm ni

doe n mean all he indi id al in he

community have to be vaccinated, but the most people-which were immune, will have the ability to protect the people-at-risk2,3. As this, the vaccination will give the benefits toward the comm ni , e en fo ome ho e ha en

ake hi p oce

Many countries has planned their vaccination program and specific target as one of their strategic plan to build their nation. WHO wrote the urge of vaccination which included in SDGs (Sustainable Development Goals). It was implemented in SDG 3: Ensure healthy lives and promote wellbeing for at all ages. There are several goals within this point of SDG. Vaccine takes place in goal 3.8, which stated as achieve universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all4. As it is written at the SDGs, so all of the countries which become the member UN as the head of WHO, have to apply the SDGs. One of the countries which could be mentioned is Indonesia. Indonesia with its Ministry of Health planned a detailed vaccination schedule for baby and newborn. This program were given freely as an integral part of the basic right for every baby living in Indonesia. However,

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the ministry official report, known as Riskesdas (Riset Kesehatan Dasar)-Basic Health Research shows that the vaccination coverage or UCI (Universal Child Immunization) is mostly below the target. The data from 2014 surveys shows that the percentage of UCI in Indonesia is 83%, or 12% below the target taken by the ministry of 95%5. More, the statistic published by the Ministry of Health in Indonesia shows that the percentage of MMR vary year by year. The data shows that the percentage rises from year 2008 to 2012. In 2012, the percentage of vaccination reached by 99.3%. While, the percentage from 2013 until 2018 showed the regression from 95.8% becoming 89.8%6. There are many reasons why the number is decreasing from year to year. One of them is the massive campaign from the group of person who called them as an antivaccine. This group shared fake news about vaccines, including the misinformation and vaccine-related complications such as autism. Searching engines such as Google reported the proportion of antivaccine website of 41% by 20147. This number showed that more people who accessed the searching engine about vaccine get the probability to be propagated and analyze the wrong information by half of the total results. This would led to the increase in the percentage of unvaccinated people around the world. The objective of this paper is to determine the condition of antivaccine and several ways which can be applied to increase the percentage of vaccination coverage among specific population. II.

Method This scientific paper is written as a literature review. The literature were selected from

the searching tools, such as Google scholar, PubMed, or Lancet. The selection process included he ke

ch a

accine , imm ni

, an i accine , maternal mortality . The journal

date of publication were limited maximally until year 2009 of publication. Not only journal, this paper contain several numbers from official reports, such as from the ministry of health or bureau of health in certain countries, WHO, and CDC. In deducing a conclusion within this scientific paper, we are using the related information from the journals and official report. Those information then summarize into several important data. III.

Results Antivaccine Movement Fear of vaccination movement, or famous for antivaccine was not established within

previous years. This activity moves back from the 18th century with one of the well-known

211

people, Reverend Edmund Massey from England, whom called vaccine as the diabolical operation or the sinful practice of inoculation. Even a well-known scientist, Benjamin Franklin, reject the concept of vaccination but later he excused it after his 4 years old son died from smallpox. Not only by the statements of several scientists, some theological experts might said that the vaccination as the works of devil. The development of this movement was shaped after two events, those are DPT [sic]: Vaccine Roulette and a paper by Andrew Wakefield. The first was a film produced in 1982 which gave a brief definition and relationship between DTP (diphtheria, tetanus, and pertussis) vaccine with the neurodevelopmental disorders. While the second was a paper published by Andrew Wakefield in Lancet, 1998. He published a paper which defined and gave the relationship between MMR (measles, mumps, and rubella) vaccine with autism; although later the paper was taken out8,9. As mentioned before, the rise of antivaccine movement was due to the paper published by Andrew Wakefield. Later, the journalist and investigators found out that he was not mentioned the funding from litigants against vaccine manufacturer. Lancet then retracted the study and mentioned that the paper was utterly false. However, the myths and misinformation was already spread all across the world, especially Western Europe and North America and produce in the reducing of some vaccination rate. Those reducing rate are MMR vaccination rate in UK which was dropped from 92% in 1992 to 84% in 2002. Even in some parts of London the rate was lower, i.e. 61% in 2003. The percentage were far-lower than minimum percentage to prevent the measles outbreak. This condition was producing several outbreaks in UK and this country reporting the first death due to measles from the year of 1992 9. In USA, the rate of MMR vaccination was below the standard for herd immunity, which is 94.3% over 95%. Although the rate was high enough, the outbreaks had been occurring in several parts of this country, mostly attacked the underimmunized individuals10. As the paper of Andrew Wakefield was retracted, the decreasing percentage of vaccination rate is still happening until now8-10. The vast development of internet and social media could develop this antivaccine movement also. The technology now could make the layperson to access much information from the search engine about medical condition and healthcare information. At the previous, many medical textbook, journals, and factsheets were only accessible by medical professionals, but now everyone can easily access and read it through the social media. It comes to two sides. The first one it could be beneficial for medical professionals to educate people as they are already know a little about health literacy, while it would have the bad consequences also. Many information on the internet were not 100% true and correct, they would contain some hoax, fake news, and misinformation about something, like vaccine. As in YouTube there is

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32% of its content who have cons for vaccination and surprisingly they have higher rating. A study on Canadian internet showed that 60% of them were promoting anti-vaccine sentiments. Some websites were also containing some statements from many famous person, such as celebrity and politician. An analysis done in several countries deduced that the percentage of anti-vaccine websites are ranging from 10% to 40% of all results in internet. The research suggests that the relation between antivaccine and celebrity statements toward vaccine was significantly higher when compared to the all search results about vaccine. The diagram below ho ing he ignificance of celeb i ie

a emen

abo

accine,

hich i

ignifican l

appears in antivaccine movement compared to the total results. The complementary and alternative medicine shared the highest percentage of antivaccine statement where the percentage also outnumbered the percentage of pro-vaccination7,8.

Figure 1. Vaccine stance in several grouping7. Note: each colour represents each group; blue for pro, gray neutral, and red for antivaccine. In further research, there are myths developed in the community. First myth was known so popular for a long time that is the causal of autism by MMR vaccine. The hypothesized of this study by Wakefield stated that the MMR vaccine will create a reaction in the gut of person whose got vaccinated. The reaction was named as ileo-caecal lymphoid nodular hyperplasia. It will led to the release of brain-damaged peptides which contributed to the development of autism or ASD (autistic spectrum disorders). Wakefield only make this hypothesis from 12 children. Later, this hypothesis was refused by twenty studies as there is no specific findings of that peptides and no gastrointestinal findings which support Wakefield hypothesis. Not only that, other myths will also come to a surface such as encephalitis-associated with DTP vaccine; thimerosal, a substance as vaccine preservative by inhibiting bacterial and fungal growth, which mentioned to be toxic in central nervous system; multiple administration of vaccine will

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disturb the human immune system; and adjuvant ingredients may be harmful to the vaccine recipient. All of those myth later identified and there are no scientific reason for those myth as many research could break it off11. Vaccine Diplomacy The vaccine diplomacy aimed to decreasing the gap between the level of vaccinated children or person to the target. This activity held to erase the shortage of vaccine supply because of war, political uncertainty, and the rising of antivaccine movements. As stated, the way to dismantle the information about antivaccine may be challenging and difficult. Countering this movement is essentially needed to build the confidence among people in vaccination. By 2019, World Health Organization (WHO) declared the antivaccine movement as threat to the global public health. This will lead the US, other countries and UN agencies to develop a strategic partnership in combatting the antivaccine12. Many strategies have been used to increase the vaccination rate. CDC in cooperation with state and grantees launched a program to moved healthcare personnel from a state with low immunization rates and unawareness to one in which a personnel has the characteristics such as full of knowledge, concerned, motivated to change the immunization practices, and capable of sustaining new behaviours. The approach by CDC is known as AFIX in acronym13. AFIX consists of 4 (four) main activities: Assessment of the immunization coverage of public and private providers, Feedback of diagnostic information to improve service delivery, Incentives to motivate providers to change immunization practices or recognition of improved or high performance, and eXchange of information among providers. This AFIX approach is now being used in US for both public and private vaccination providers. Medical professionals, government and NGOs are recommending this program. AFIX has special characteristics such as focused on outcomes, providers, and the blend of advanced technology and personal interaction13. Other editorial stated that the problem of antivaccine could not be tackled by giving cautions or lecturer about the vaccine, as what the society done for stopping the tobacco, but by giving an information or education about the consequences of being un-vaccinated. This method was giving a better outcome rather than giving lecture to the parents about vaccine misinformation. The application of this method further could be separated into two approaches. The first scope is from the individual level. The better way to make the parents believe the consequences of not vaccinating the children was based on doctor-patient relationship. Patients ill gi e hei

o he ph ician if he can li en o he pa en

con en . A he pa en

trust, the physician could give explanation about the condition of unvaccinated children. The second could be the perspective from the society. It is better for a medical practitioner to clearly

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show a message of the consequences of being unvaccinated in public rather than confrontationally speaks for antivaccine movement14. A qualitative investigation in Australia was finding out about several strategies which were concluded by several bodies, those are government health departments, local health services, advocacy groups, professional associations and technical/scientific organizations. They resulted in strategies which might be used to promote vaccination. Those are using the facts and evidence, humanizing the threat of disease, and creating safe spaces. As mentioned, communicating the audience about facts and evidence would make them easier to get the message and information. Humanizing the threat of disease could be done by giving the real example of someone experience who died or even getting the limitation caused by the vaccinepreventable disease. Creating safe spaces would be very helpful to layperson as they can ask much information as they want to answer their doubt about vaccine. This would be effective for them to be included in several groups such as Facebook were they can ask freely without any harassing statement from other15. Other study found out a holistic analysis in making a better outcome in vaccination. It includes the chain between healthcare policy makers; and the public, healthcare workers, community leaders, the media. The healthcare policy makers are responsible for making the policy environment such as vaccine funding, training for the medical practitioners, making any information and education for people, and also giving administration and monitoring about their program. The policy would cover every single description of being vaccinated, which is mean that there will be also specific laws or code related to the vaccination. The public including medical professional would accept and obey the law from the policy makers, approach the issues of vaccination based on the local culture, and boost their strategy to bond with their community16. The Success in a Health Problem Reduction Not only vaccination rate, several health problems were also has their problem. One of them which everyone know is the maternal and infant mortality rate although in several parts of the world they can handle it, some still dealing with it. There are several ways which every country or agents did to overcome the huge number of maternal and infant mortality rate. Women

empo e men

a becoming an effec i e

o comba he ma e nal and infan

mortality rate. Women empowerment could come in three aspects such as participation in economic decision-making, health decision-making, and autonomy in mobility. The study showed if the women were giving a better empowerment, there was a better outcome in the infant mortality. The infant mortality for high empowered women would come in 7 (seven) times lower than the low empowered women group. This number was statistically significant

215

with p value < 0.0517. O he li e a

e implied ha

omen

empo e men

o ld al o come

in 17 indicators. Those 17 indicators later re-grouped into 4 bigger groups, i.e. labor force participation, disagreement with reasons to justify wife, decision-making po e , and omen knowledge level. Two big group were having significant effect to the reducing the number of maternal and infant mortality. Decision-making power were including visiting family, own heal h ca e, h band

ea ning and ho ehold p cha e. Women

kno ledge le el

education level and access to media. These factors were affecting the number of maternal and infant mortality. The results showed that if the women had already finish their primary education, the number of ante-natal care will almost 3 (three) times higher compared with less or no educational background. The number in several developing countries were similar. In rural area of India, the number will be 3 (three) times higher; Bangladesh has 5.4 times greater in group of women who finish her secondary education; and Timor Leste shows that if the mother were not having any formal educational background would have 54% of probability to go to antenatal care fewer than the recommendation18. Many other research or quasi-experimental showed the positive effect of empowering women for the growth and development of the baby and motivation of the mother. It is stated that providing the training to mother can be useful and acted as an effective method in the process of weight-gain in premature and low-birth weight newborns, and shorten the duration of infan

ho pi ali a ion. The n mbe of

eigh gain

e e 3.95 g am compa ed o he

decrease of weight in 0.9 gram. The length of stay at the hospital were 15.45 days and 20.95 days respectively. The knowledge of mother to get in touch with the health personnel and the presence of skilled birth attendant would also significantly decrease the number of maternal mortality ratio. The mother will notice the emergency after she got trained and educated by the medical professions, so the number of death will be suppressed. The increasing participation of women in national politics also resulted in the reduced number of maternal deaths, as the women will allocate greater investments and technology for combatting the maternal deaths problem in their community19-21. The women empowerment still has a large scope to discuss. Many ways which may be done to increase the level of empowerment in women, especially mother. One of the effective way is by having the peer group special for mother. This peer group was an effective way because it can give a reduction in the number of maternal and infant mortality. By having peer group, the maternal death was reduced by 30% compared to the group who doe n have the peer group. At low cost setting, community-based intervention could reduce the neonatal and maternal mortality. This way was effective also by the presence of medical doctor and

216

midwives as the leader and communicator so the group would still on the track and minimize the misinformation. Women s peer group would have a better benefit than only the information sharing from the practitioner. They also have their solidarity and trust among each other22-24. IV.

Discussion From several results we have found and synthesize at the previous chapter, hereby we

discussed several points related to the appropriate theme. Vaccination was known as a way to develop an immunity in human body. If a person already get the vaccine, they will develop an individual immunity. A group of person with it individual immunity will develop a communal immunity, which is well-known as the herd immunity. This herd immunity will give the benefit not only for the person whose already get the vaccination, but for population-at risk also. Herd immunity will only effective if the vaccination rate goes beyond the threshold, mostly more than 95% of the person already vaccinated. This condition seems to be difficult to approach today as there is a massive movement against vaccination, famous as antivaccine. This group spreads about vaccine myths and misinformation and produce many propaganda about the bad of vaccination. They was dominating the social media with almost half of the information there were behind their control. They even related the wrong information or even a research about vaccination and spread that hoax to the public, so the community would believe them and decided not to vaccinate their children. As this happened, there are many outbreak of vaccinepreventable disease in several parts of the world. A promising way to combat this antivaccine movement could adapt the ways of reducing the number of maternal and infant mortality in several parts of the world. It was mostly successful for them to reduce the ratio or rate by low and middle income setting. The women empowerment seems to be effective for fighting the antivaccine. Women, especially mother has a crucial role in the family sustainability. They could empower themselves by getting enough information and education in dealing with their problems, and this results in reducing the maternal and infant mortality. One of the way to empower women is by including them in the peer group. As several studies show the drastic reduction in number of those maternal and infant mortality. By having their own peer group, everyone would share the same paradigm and issues related with their health, so they would give more attention and concern for their problem. Antivaccine movement and misinformation could be tackled by the mother also by their shared information through the peer group, by the guidance of medical practitioner, such as the local midwife or a medical volunteer who have the same vision to combat the antivaccine.

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Conclusion From the result we have discussed, we conclude that the women empowerment through

the peer group would be an effective way to educate and motivate women, especially mother to get the right and true information about vaccination. The mother then would have the decision to vaccinate their children and even promote about the true of vaccination to other mother. This would hopefully increase the rate of vaccination and hereby the outbreak of vaccine-preventable disease could be prevented, especially in developing countries. References: 1. Hamborsky J, Kroger A, Wolfe S. Epidemiology and Prevention of Vaccine-Preventable Disease. 13th Ed. Washington D.C.: Centers for Disease Control and Prevention, 2015:3-4. 2. Metcalf CJE, Ferrari M, Graham AL, Grenfell BT. Understanding Herd Immunity. Trends in Immunity. 2015; 36(12):753-755. 3. Tortora GJ, Funke BR, Case CL. Microbiology: An Introduction. 10th Ed. San Francisco: Pearson Education Inc. 2010:405-407. 4. World Health Organization. Towards a Global Action Plan for Healthy Lives and WellBeing for All. Geneva: WHO. 2018:13. 5. Kementerian Kesehatan Republik Indonesia. Situasi dan Analisis Imunisasi. Jakarta: Badan Litbangkes Kemenkes RI. 2014:2-5. 6. Kementerian Kesehatan Republik Indonesia. Situasi Campak dan Rubella di Indonesia. Jakarta: Pusat Data dan Informasi Kemenkes RI. 2018:3-8. 7. Arif N, Al-Jefri M, Bizzi IH, Perano GB, Goldman M, Haq I, Chua KL, Mengozzi M, Neunez M, Smith H, Ghezzi P. Fake News or Weak Science? Visibility and Characterization of Antivaccine Webpages Returned by Google in Different Languages and Countries. Front. Immunol. 2018, 9:1215. 8. Hussain A, Ali S, Ahmed M, Hussain S. The Anti-vaccination Movement: A Regression in Modern Medicine. Cureus. 2018; 10(7): e2919. 9. Olive JK, Hotez PJ, Damania A, Nolan MS. The state of the antivaccine movement in the United States: A focused examination of nonmedical exemptions in states and counties. PLoS Med. 2018; 15(6): e1002578. 10. Danielson L, Marcus B, Boyle L. Countering Vaccine Misinformation: Special Feature. AJN. 2019, 119(10):50-55.

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11. Clift K and Rizollo D. Vaccine myths and misconceptions. Journal of the American Academy of Physician Assistants. 2014, 27(8):21-25. 12. Hotez PJ. Immunizations and vaccines: a decade of successes and reversals, and a call for accine diplomac . Int. Health. 2019:1-3. 13. Hamborsky J, Kroger A, Wolfe S. Epidemiology and Prevention of Vaccine-Preventable Disease. 13th Ed. Washington D.C.: Centers for Disease Control and Prevention, 2015:3437. 14. Swingle CA. How Do We Approach Anti-Vaccination Attitudes?: Editorial. Missouri Medicine. 2018, 115(3):180-181. 15. Steffens MS, Dunn AG, Wiley KE, Leask J. How organisations promoting vaccination respond to misinformation on social media: a qualitative investigation. BMC Public Health. 2019,19:1348. 16. Hardt K, Bonanni P, King S, Santos JI, El-Hodhod M, Zimet GD, Preiss S. Vaccine strategies: Optimising outcomes. Vaccine. 2016, 34:6691-6699. 17. S i aning ih H and Wicak ono F. Impac of Women Empo e men on Infan Mo ali in Indonesia. Kesmas: National Public Health Journal. 2017; 11 (4):185-191. 18. Sebayang SK, Efendy F, Astutik E. Women s Empowerment and the Use of Antenatal Care Services in Southeast Asian Countries. DHS Working Paper No. 129. Rockville, Maryland, USA: ICF. 2017:7-14. 19. Mohammaddoost F, Mosayebi Z, Peyrovi H, Chehrzaa MM, Mehran A. The effect of mo he

empo e men p ogram on p ema

e infan

eigh gain and d a ion of

hospitalization. Iranian J Nursing Midwifery Res. 2016; 21:357-62. 20. Bhalotra S, Clarke D, Gomes J, Venkataramani A. Women s Poli ical Voice and Ma ernal Mortality. IZA Discussion Paper. Bonn: Institute of Labor Economics. 2017:2-15. 21. Lan CW and Tavrow P. Compo i e mea

e of

omen

empowerment and their

association with maternal mortality in low-income countries. BMC Pregnancy and Childbirth. 2017, 17(Suppl 2):337. 22. Heys M, Gram L, Wade A, Haworth EJN, Osrin D, Sagar K, Shrestha DK, Neupane RP, Adhikari D, Adhikari RK, Budhathoki B, Manandhar D, Costello A. Long-term impact of community based participatory women s group on child and maternal mortality and child disability: follow-up of a cluster randomized controlled trial in rural Nepal. BMJ Glob Health. 2018, 3:e001024. 23. Howell EA. Reducing Disparities in Severe Maternal Morbidity and Mortality. Clin Obstet Gynecol. 2018; 61(2):387-399.

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24. Cameron L, Suarez DC, Cornwell K. Understanding the determinants of maternal mortality: An observational study using the Indonesian Population Census. PLoS ONE. 2019; 14(6): e0217386.

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COMBATING MYTHS: NO EVIDENCE BETWEEN AUTISM AND MMR VACCINE Anita Dominique Subali INTRODUCTION Despite the availability of a safe and effective vaccine, more than 140,000 people died from measles in 2018, mostly among children under the age of five.1 Measles is caused by paramyxovirus and is highly contagious which passed through direct contact and through the air. The virus primarily infects the respiratory tract before spreads throughout the body. It may lead to severe complications and even death, which cause an avoidable burden on the health care system. Measles remains a significant cause of death and disability, especially in low-income countries.2 Measles is a serious and potentially fatal disease. On the other hand, it can be prevented through vaccination. The vaccine commonly delivered as a combined measles-mumps-rubella (MMR) vaccine. MMR vaccine has been proven to be effective at protecting people against measles, mumps, and rubella, and preventing the complications caused by these disease.3 In 20002018, measles vaccination has successfully prevented an estimated 23.2 million deaths worldwide.2 Vaccination has been one of the safest and effective interventions in public health for the primary prevention towards infectious disease, which result in both individual and herd immunity. Childhood vaccinations which have been recommended around the world are based on preventive and protective effect of vaccines.4 Despite the benefits of vaccines, over the past decades, much concern has been raised regarding the potential links of childhood vaccinations with the development of autism and autism spectrum disorders (ASD). MMR vaccine becomes one of vaccines that have received most attention. The hypothesized association between the MMR and autism continues to produce concern and challenge in vaccine acceptance almost 2 decades after the first controversial, which later retracted Lancet paper in 1988. This rising awareness of autism incidence, prevalence, and postulated causation of vaccinations during childhood has resulted to an increased distrust and a possibility for the resurgence of vaccine-preventable disease.5 The scientific based evidence of causal relationship between the autism and MMR vaccines are being review in this articles. METHODS

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A literature search was performed in the Google scholar, NCBI, and ScienceDirect databases. Three keyword searches were performed in the databases: measles, MMR vaccine, MMR vaccine and autism. Multiple up to date journals were assessed to find appropriate information to arrange the literature review. This study included articles published in the last ten years (dated 2010-2020) with study design such as cohort, systematical review, and meta-analysis. Four articles were selected and will be reviewed in this study. RESULT AND DISCUSSION Measles: The Burden of Disease Measles, being one of the most contagious diseases which spread through airborne transmission (person-to-person through sneezing or coughing), is caused by a virus in the paramyxovirus family. The virus infects the respiratory tracts following the subsequent spread throughout the body. Measles is characterized by a prodromal phase-10 until 12 days after exposure with the clinical manifestations such as fever (often high) and malaise, which followed by measles classical triad: cough, coryza, and conjunctivitis. The rash commonly could be found around 14 days after exposure, originated as a maculopapular eruption on the head and expands towards the trunk and extremities. Measles pathognomonic are Koplik spots, the blue-white plaques on the mucous membranes of the mouth.5 Measles may end up serious in all age groups. However, the probability to suffer from measles complications increases children younger than 5 years of age and adults older than 20 years.2 Complications due to measles including diarrhea, ear infection (otitis media), bronchitis, vision loss,5 some may suffer severe complications such as pneumonia and seizures. Severe complications brings the need to be hospitalized and could end up with poor prognosis. One specifically feared and life-threatening complication can be post-infectious encephalitis, whereas a particularly serious long-term consequence is represented by subacute sclerosing panencephalitis (SSPE). SSPE is a significantly rare but fatal disease of the central nervous system due to measles virus infection acquire in the earlier life. SSPE generally develops 7 to 10 years after the onset of measles, despite the person may looked fully recovered from the illness.1 In each 1 million persons worldwide, there are 36 cases of measles being reported each year, which causes death for 134,200 people annually. In fact, one or two children in each thousand died due to measles. One out of every 20 children with measles developed pneumonia, the most common killer due to measles in young children. About one child out of every 1,000 who get 2

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measles ended up with encephalitis, leading to convulsion and leaving the child deaf or with intellectual disability.2 Measles Vaccine as a Leading Solution It is true that measles is a serious and potentially fatal disease. However, it can be prevented through vaccination. The vaccine is frequently delivered as a combined measles-mumps-rubella (MMR) vaccine. MMR consists of attenuated (weakened) live virus vaccine. After the vaccine administration, the virus harmless infection induces immunity, building immune system to combat future infections.3 MMR vaccine is confirmed to be effecting at protecting people against measles, mumps, rubella, and preventing complications due to the diseases.2 In fact, one dose of MMR vaccine is 93% effective against measles, with two doses of it increases the effectiveness against measles until 97%.3 The measles vaccine was first introduced in 1963. Before the introduction and widespread vaccination, major epidemics occurred for approximately every 3 years and there are estimated 2.6 million deaths each year due to measles.3 Acceleration of MMR immunization have had a significant impact on reducing measles death. During 2000

2018, 23.2 million deaths could be prevented by measles vaccination. The

World Health Organization stated that global measles deaths have decreased by 73% from an estimated 536,000 in 2000 to 142,000 in 2018.1 The Debate: Vaccine Induces Autism Despite its preventive and protective effect, there has been an enormous debate regarding the possibility of a link between childhood vaccination and the subsequent development of autism and autism spectrum disorders (ASD). The measles, mumps, rubella (MMR) vaccine and thimerosal-containing vaccines, for instance diphtheria, tetanus, pertussis (DPT or DT) vaccine are the vaccinations receiving the mos attention.6 In recent decades, this problem becomes a major public health issue with the increase of vaccine preventable diseases in the community as a result of the fear of the association between vaccination and autism. Awareness increment of autism incidence, prevalence, and the postulated causal relationship of childhood vaccinations has led to both an increased distrust in the trade-off between the benefits of caccine versus the potential risk; and also the possibility of the resurgence of vaccine-preventable-diseases.6 Autism itself is a serious, life-long developmental disorder which characterized by marked impairments in social interactions; communication skills; and repetitive, restrictive, or stereotyped 3

223

behaviors, interests, and activities. Autism includes the more severe end of autism spectrum disorder. There are a wide variety of what causes autism, but only few cases has a specific identified cause. Autism is strongly related with genetic component and associated neurological defects which may occur early in embryonic development. Despite the fact that a diagnosis of autism may not be made until later in life: when communication delays and characteristic behaviors become apparent, the underlying neuropathology of autism is generally present at birth in the majority of the cases.5 In a few cases, a child may appear to be developing completely normally but then regress and develop autistic characteristics. These cases of regressive autism is, at least theoretically, are being adopted as a biologically plausible link with vaccination and autism.5 The Pioneer of the Conspiracy Wa efie d

e ea ch a hi idea hi e-b

e . Wa efie d

e ea ch

ea e

and inflammatory bowel disorder evolved into this hypothesis that measles vaccination, MMR vaccine in precise, could lead to a new syndrome of gastrointestinal pathology and neurodevelopmental regression. The Lancet publicized this idea in a report in 1998. This article was a descriptive report consisting 12 children who had a history of inflammatory bowel disease with eight of whom suffering from autism. Parent or physician of the eight children reported e i g

f he chi d

beha i a

a h

e i d af e

he MMR Vacci e

administration; which suggesting the link of vaccine induced autism.5 Nevertheless, this study had significant flaws, markedly that the report did not offer strong proof of causal association. Moreover, the history of MMR receipt was based on parental recall, which is the major source of memory bias.7 Nonetheless, because these parents belief of MMR being responsible for their children

a i

, it is not surprising that they reported a temporal association between MMR

vaccination and the development of autistic symptoms. Furthermore, there are also ethical concerns about this study based on its funding and the fact that the patients were not randomly enrolled. Due to these ethical concerns, the article is retracted by the Lancet in 2010.7 Regardless of its limitations, the articled had successfully generated intense both media and public attention, which results in decreased MMR vaccination coverage, with resultant reemergence of measles disease and deaths. Even the article was retracted by the journal (due to the impropriate subject recruitment and financial conflicts of interest), it has brought the doubt into the surface.7 4

224

Scientific data proved there was no evidence the association between autism and MMR vaccination The association between measles vaccination and autism has been evaluated in other studies with stronger epidemiologic designs, including case-control and cohort studies. These studies obtain individual-level data and are able to control the confounding factors which may bias the results. Case-control studies assessed the association between measles vaccination and autism by comparing the measles vaccination and autism with the means of comparison between the history of measles vaccination at children with autism, compared with the measles vaccination histories of control children without autism. Five case-control studies conducted in United Kingdom, the United States, Poland, and Japan found no evidence of increased risk of autism which follows measles vaccination with either MMR vaccine or monovalent measles vaccine.5 A meta-analysis study by Taylor, et.al,6 includes five cohort studies which involved 1,256,407 children in total, and five case-control studies involving 9,920 children. The cohort data revealed the absence of relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or autism spectrum disorder/ASD (OR: 0.91; 95% CI: 0.68 to 1.20), nor was there a relationship between autism and MMR (OR: 0.84;95% CI: 0.70 to 1.01). Correspondingly, the case-control data found no evidence for increased risk of developing autism or ASD after MMR administration (OR: 0.90, 95% CI: 0.83to 0.98; p = 0.02). In short, this meta-analysis provides no evidence of a relationship between vaccination and autism or autism spectrum disorders. A nationwide cohort study held by Hviid, et.al, conclude a consistent statement with the previously mentioned. The study claimed itself as, by far, the largest single study to date which involving 657,461 children born in Denmark from 1999 through 31 December 2010, with followup from 1 year of age and through 31 August 2013. The study compared MMR-vaccinated with MMR unvaccinated children in subgroups characterized by sex, birth cohort, other childhood vaccines received, autism risk score, or autism history in sibilings. It discovered that MMR vaccination did not increase the risk for autism in children characterized by other early childhood vaccinations, high risk for autism, or having autistic siblings. When sibling history of autism was roled as a time-varying covariate, MMR vaccination was also not associated with autism among children with autistic siblings. This study also stated criticism towards observational studies of MMR vaccination and autism. Those studies failed to take into account the existence of specific autism associated with vaccination, such as regressive autism. The great number of samples 5

225

increased the study validity and assuming unbiased result which allowing the study to conclude confidently that the study does not support that MMR vaccination increases the risk for autism, triggers autism in susceptible children, or is associated with clustering of autism cases after vaccination.8 Take Home Message Scientific data are essential in monitoring and evaluating the vaccine safety. Nonetheless, scientific evidence alone oftentimes are not sufficient in providing reassurance about vaccine safety. Although the majority of parents support immunizations, there are still many have concerns or misconceptions which could erode their confidence in vaccines.5 A sizable fraction of parents who do not have their children fully immunized and put a doubt about vaccine safety is a leading reason for under-immunization. These concerns lingers despite the scientific evidence that vaccines has been proven not causing autism. Yet, on the other hand, leaving the youngs unvaccinated means placing them at the highest risk of measles and its complications, including death.1 Vaccination has been one of the safest and effective interventions available in public health for the primary prevention of infectious diseases. Vaccination induces both direct and indirect immunity in individuals vaccinated (or often called as herd immunity). Childhood vaccinations recommended around the world are based on the scientific principle of their preventive and protective effect. Providing a complete and on-schedule vaccination, based on scientific evidence, could bring great benefit by reducing morbidity and mortality in worldwide.4 Therefore, public health agencies, medical organizations, and other influential authorities are critically responsible to give more attention on the safety of vaccines and assure public confidence by providing clear, consistent messages about vaccine safety concerns; supporting effective and transparent vaccine safety monitoring systems and research activities; providing reviews and recommendations by independent experts on vaccine controversies.5 Conclusion There are always two-side of every aspects, as well as benefits and risk. Like any other treatment or behavior, it is a must to weigh the benefits and risks in determining the course forward. At some people perspective, individual avoidance of immunization might be seen as an effort to lowering risk of possible adverse effects. The increase number of parents deciding to get this action took part of the decreased herd immunity among populations, which increases the risk of catching more 6

226

serious infectious disease that could be prevented by vaccine. Despite the fear of child developing autism due to immunization, the data consistently shows the absence of evidence for a causal relationship between autism, ASD, and vaccination. It provides no reason to avoid immunization. REFERENCE 1. World Health Organization. 2020. Measles. [online] Available at: https://www.who.int/newsroom/fact-sheets/detail/measles [Accessed 8 April 2020]. 2. Centers for Disease Controls and Prevention. 2019. Measles, Mumps, and Rubella (MMR) Vaccination:

What

Everyone

Should

Know.

[online]

Available

at:

https://www.cdc.gov/vaccines/vpd/mmr/public/index.html [Accessed 8 April 2020]. 3. Centers for Disease Controls and Prevention. 2019. Measles [online] Available at: https://www.cdc.gov/globalhealth/newsroom/topics/measles/index.html [Accessed 8 April 2020]. 4. La Torre G, Saulle R, Unim B, et al. The effectiveness of measles-mumps-rubella (MMR) vaccination in the prevention of pediatric hospitalizations for targeted and untargeted infections: A retrospective cohort study. Hum Vaccin Immunother. 2017;13(8):1879 1883. doi:10.1080/21645515.2017.1330733 5. DeStefano F, Shimabukuro TT. The MMR vaccine and autism. Annual review of virology. 2019 Sep 30. 6. Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated with autism: an evidencebased meta-analysis of case-control and cohort studies. Vaccine. 2014 Jun 17;32(29):3623-9. 7. Smith M. Vaccine safety: medical contraindications, myths, and risk communication. Pediatrics in review. 2015 Jun;36(6):227-38. 8. Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism: a nationwide cohort study. Annals of internal medicine. 2019 Apr 16;170(8):513-20.

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World Immunization Week Competition 2020

Skepticism In Fulfilling Immunization Against Immunization Coverage In Indonesia: A Literature Review Farida Aisyah1 1

Second Year Medical Student, Medical Department, Faculty of Medicine [Corresponding Email: faridaaisyah323@gmail.com] Abstract

Indonesia country with more than 40 million children thus nation have to guarantee the health of these children as the successor of the nation, one way is by immunization. Yet, immunization coverage in Indonesia show low prevalence, by 2019 immunization coverage were 57.9% for complete basic immunization, 32.9% for incomplete basic immunization, and 9.2% not immunized, the non-achievement of immunization coverage based on national and global target results in various negative impact, such as immune decline, higher costs for curative interventions, and outbreak. To increase immunization coverage, identification of problems that cause low immunization coverage is needed, such as public skepticism. The factors that might influence skepticism were maternal intelligence, maternal age, profession, internet access, health service, financial, also culture, attitude, and belief. From the analysis conducted on each factor related to skepticism and immunization coverage, solutions are obtained to overcome each solution of each factor, especially the solution in educating the public to improve immunization coverage and suppress skepticism of immunization in Indonesia. Keyword: Immunization, Coverage, Skepticism, Children, Educate ic he a i

INTRODUCTION

a e

i dec ea e he ef e

the 2020 immunization coverage must be

Indonesia, a country with 30.1% of the

optimistic rise.[1,2] Immunization defined as a

population is children consist of 40.4 million

process whereby a person is made immune or

inhabitants were male while 39.1 million

resistant to infectious disease, typically by the

inhabitants other were female this relates that

administration of a vaccine, whereas vaccine

chi d e a e a i

is a booster which helps the immune system

a e , he chi d e a e

1 228

to recognize and fight pathogens like virus or

certain situations, example for yellow fever,

bacteria.[3,4] Immunization schedule in every

rabies, or meningitis in pilgrims.[5-8]

country

different,

Indonesia,

immunization schedule ruled by the ministry of health and run by every Puskesmas, as primary health service in the area, there were two

kinds

immunization:

The

Immunization Program (Mandatory), is a compulsory immunization to someone as part of a deep society to protect the concerned and

Figure 1. Basic Immunization Schedule In

the community around it from diseases that

Indonesia For Infant (<1 year)

can be prevented, including additional,

(BCG:Bacillus Calmette-Guerin; DPT-HB-

special, and routine immunization, and; 2)

Hib:Diphtheria Pertussis Tetanus-Hepatitis

Immunization Options (Non-Mandatory) are

B-Haemophilus Influenzae type B Vaccine;

immunization that can be given to someone

IPV:Inactivate Polio Vaccine)[5,6]

according to their needs within to protect the concerned from the disease certain, for Immunization Options run by certain hospital or health clinic only, example Japanese Enchephalitis.[5]

Routine

Figure 2. Advanced Immunization Schedule

immunization

In Indonesia For Infant (<2 years)[5,6]

carried out continuously consist of basic immunization and advanced immunization, advanced

immunization

routine

immunization test for maintaining the level of immunity and for extending the period of protection of children who have already get basic immunization as an example pneumonia immunization, next additional immunization is a certain type of immunization given to certain age groups the most risk of disease according to the study epidemiologist at a certain period, lastly, special immunization is immunization implemented to protect a person and society against certain diseases in

In Indonesia, mandatory immunization is free of charge, but for non-mandatory immunization will be charged.[9] Route of administration of the vaccine in Indonesia are variant, some were intramuscular injection in hepatitis B and Hib, oral in polio and rotavirus, subcutaneous injection in measles, and intradermal injection in BCG.[10-13] The purpose of immunization is to establish a e

ecific

agai

particular disease by entering a vaccine that already contains antigens in the form of dead or

weakened,

still

intact

parts 2

229

microorganism which has been processed into

disability, injury, or premature death; 2)

toxoid as a recombinant protein.[13] The

Better health and health equity without

immunological of vaccine mechanism starts

disparities; 3) Social/physical environment

when antigen of the vaccine first entering the

that encourages better health and; 4) Better

body, the antigen will be known as an alien by

quality

a dendritic cell as an antigen-presenting cell

development/behaviors, as for SGDs 2030

in the immune system, this antigen will

immunization aimed to reduce children and

mimicking infection however rarely causes

newborn death under 5 years, and eradicate

disease yet the antigen will induce the

tropical infectious diseases.[18,19] This purpose

immune system to produce T-lymphocytes

sets must look back on immunization

and certain antibodies of a specific disease,

coverage,

subsequently, the imitation of infection gone

coverage in Indonesia is recorded for 2010,

and left with supplies to produce memory T-

2011, 2012, 2013, and 2014 were 88.9%,

lymphocytes and memory B-lymphocytes,

88.9%, 86.9%, 90%, and 86.9% respectively,

this memory cell will help to fight specific

for 2019 immunization coverage in Indonesia

antigen if second exposure happened, so if

were 57.9% for complete basic immunization,

individuals are given a vaccine during their

32.9% for incomplete basic immunization,

childhood, is expected, in the future when

and the rest 9.2% not immunized, this number

they exposed to a certain antigen their

ha e

immune

national target, global target for vaccine

system

becomes

immune.[14,15,16]

life

complete

and

basic

health

immunization

achie ed the global target nor the

coverage were 90% of all vaccine in every country moreover in The Global Action Plan (GVAP), Indonesia with other 9 countries include for a country with massive infant death because of lack immunization coverage of 3 doses DPT, however, the national average target of immunization coverage for each acci e i

90%, a

country, this value has

Figure 3. Adaptive Immune Responses In

he i eg i

f he

been achieved yet,

Vaccine (Purple:Immune With Vaccine, Pale

only reached by 5 major provinces in Java,

Green:Immune Without Vaccine)[17]

namely East Java, West Java, Central Java,

Goals of immunization based on healthy

Jakarta, and Banten for another province

people 2020 were: 1) Longer, better-quality

especially Papua, East Nusa Tenggara, and

lives

Aceh only reached a rate of 29.6%, 51.72%,

without

the

preventable

disease,

3 230

and 55.26% in sequence.[20-25] Bearing in

Indonesia also providing solutions to problem

mind

reviews through the eyes of medical students

that

delaying

skipping

out

immunization can result in individuals having herd immunity which lead to epidemic or pandemic, making it more susceptible to

and medical professionals. DISCUSSION

disease, and resulting in more cost, data show,

In this literature review, data about

approximately half of newborn in Indonesia

skepticism in fulfilling immunization against

die in the first year of life due to

immunization coverage in Indonesia, were

immunization-preventable diseases making

gathered through scientific databases such as

Indonesia the second largest country with the

ScienceDirect,

most infant death by 1.7 million infant death

Scholar, and PubMed. Articles obtain should

(5%) happen in Indonesia, with etiology such

fit into inclusion criteria, that is: 1) Articles

as pneumonia (36%), diarrhea (10%), HIV,

published from 2010-2020; 2) Articles obtain

tetanus (3.4%), diphtheria (15%), typhus

in Bahasa or English and; 3) Articles

(11.0%),

discussed

nerve

disorder

(11.8%),

and

hepatitis B followed by measles outbreak with 308

cases.[26-29]

Research

skepticism

immunization

Gate,

in to

Google

fulfilling

immunization

coverage in Indonesia. From an initial search,

This value becomes a benchmark for

559 articles were obtained, after abstract and

ongoing or already done research related to

full-text assessment, excluding overlapping

the barriers experienced to fulfill the

studies, also considering inclusion and

immunization coverage in Indonesia. Health

exclusion criteria, ultimately 12 articles were

provider have a lot obstacle on educating

qualified but only 5 cross-sectional studies

society about the importance of immunization

were used in this present review.

related to strong myth or social belief, financial

factor,

halal/haram,

Skepticism defined as an attitude of doubt

maternal this

or a disposition to incredulity either in general

enormous challenge has been running for

or toward a particular object.[30] In this review,

more than a decade in Indonesia, this has

skepticism does not mean ambiguity of all nor

caused society skeptics with the importance

means as cynical but as hesitancy results by

and effect of immunization.[30] Therefore, this

delay in acceptance or refusal of vaccines

literature review has aimed to review public

despite

skepticism

immunization,

services.[31,32] Skepticism about immunization

especially routine immunization to children,

results on immunization hesitancy, people

and its effect on immunization coverage in

who

intelligence,

and

health

fulfilling

service,

the

are

availability

skeptical

vaccination

doubtful

about 4

231

vaccinating are person who accepts but

of immunization skepticism. Those factors

unsure or accept some, delay and refuse some,

were:

or refuse but unsure.[33] Model in the hesitancy

skepticism

fulfilling

1. Maternal

immunization is realized in 3C.[34]

intelligence,

study

cross-

sectional by Wulansari et al show high educated mother immunize their child with completed immunization (96.06%) while the low educated mother immunize their child

with

completed

immunization

(98.05%) this data is significant (P<0.05) but clash with another study, same type study by Vivi shown high educated mother immunize their child by 95% yet low

Figure 4. People With Vaccine Hesitancy[34]

educated mother immunize their child by 5% however Vivi data about skepticism related to immunization coverage based on maternal intelligence is not significant (P=0.34), 2 study before followed by Agung et al study that shows 3 groups of maternal intelligence-related with the Figure 5. 3C Model[34]

tendency to immunize their child based on

Model of 3C stands for: 1) Complacency,

the level of education which is an

means a low perceived risk of vaccine-

elementary school, junior/senior high

preventable diseases and vaccination not

school, and university degree by 24%,

deemed necessary; 2) Confidence, means a

35%,

low level of trust in vaccines, in the delivery

intelligence show by their level of

system and in health authorities and; 3)

education, data from maternal intelligence

Convenience,

accessibility,

expected to show the higher level of

availability, affordability, and acceptability of

education a person has, the higher

service.[34] Thus, based on a review that has

percentage

been done on selected articles, obtain factors

because higher education should be having

that influence a parent to do or not immunize

their children in Indonesia followed by

preventable disease, vaccination deemed

analyzing these factors according to 3C model

to be necessary, better in understanding

means

high

and

41%.[24,28,35,36]

for

immunizing

perceived

risk

Maternal

children vaccine-

5 232

health and illness also high acceptability

experienced of a mother which influences

yet the data obtained show a high

the knowledge of vaccines, mother at age

percentage of immunization on low

of 20s usually a first-time mother who less

maternal intelligence, while the other two

experienced, unable to decide on her own,

data also state the percentage remains high

and often sided with internet information

with a higher level of education, however

which majority lead to misinformation.

1 of these 2 data shows an insignificant

Hence, it can be concluded the younger the

relationship, because the difference from

maternal intelligence affects

skepticism

immunization

and

tend to have a lower percentage of children with a non-working parent have a

old) show a higher percentage of complete

slightly higher percentage (97.88%) and

immunization on their child (99.26%)

this data is significant (P<0.05), another

rather than a young mother (15-34 years

study showed a child with a working

old) by 94.95% of this data is significant

parent have immunization coverage by

(P<0.05), another study showed that there

30% yet a child with non-working parent

were 3 groups of mothers by age, from the

by 70% but this data is not significant

age group of 17-25, 26-35, and 36-45 years

(P=0.66).[24,28] Children with working

old with the percentage of fulfillment of

parents tend to have a parent who is high

immunizations against their children by

convenience related to high affordability

18.75%, 68.75%, and 12.5 respectively,

however, the data show working parents

and study by Holipah et al shown 3 groups

have a low percentage because most of

he age b

complete immunization (96.93%) while

he (35-49 years

age,

a d

3. Profession, children with working parents

immunization coverage.[24,28,35,36] 2. Ma e a

e ici

the lower immunization coverage.[24,28,37]

the data obtained still can t be determined whether

age he highe he

20, 21-30, and >30

them do not have time to deliver their

years old having percentage to immunize

children to immunize and often forget

their children by 6.25%, 48.65%, and

route immunization schedules due to busy

45.10%.[24,28,37] Data obtained show a child

work result in low availability also low

with a mother in her 30s has a high

immunization coverage.[24,28]

percentage of immunization by cause of

4. Internet, children who live in accessed

the high perceived risk of vaccine-

internet areas have a percentage of

preventable disease, vaccination deemed

completed immunization by 95.63% while

to be necessary, and high acceptability as

children who live in the non-accessed

the impact of high maturity and more

internet area have a

percentage of 6

233

completed immunization by 97.83% and

44%, and 19% respectively, another study

this data is significant (P<0.05).[24] Based

c a ified

on data, there is a correlation between an

categories, Q1 (poorest quintile), Q2, Q3,

area with internet access and with not, an

Q4, and Q5 (least poor quintile) data shows

area with internet access should have high

the level of parents immunizing their

accessibility, availability, acceptability,

children based on those categories is equal

affordability, and high trust in the delivery

to 22.53%, 21.25%, 19.63%, 24.37%, and

system yet an area with internet access

12.23% in sequence and this data is

have a lower percentage, this happened

significant (P<0.01).[35,37] Factor about

because people in those areas are leaner on

higher

modern information in internet which

accessibility, affordability, and availability

contain a lot of misinformation rather than

along with data show parent with middle

from health provider result as lower

income have a good percentage in

immunization

immunizing their children nonetheless

coverage

and

higher

skepticism.[24]

financial

a a ie

high

financial should not be a factor of

5. Health service, cross-sectional study by

skepticism in fulfilling immunization

Vivi, skepticism coming from bad health

because the cost of immunization have

service said by 10% respondent but this

been covered by the government yet parent

data is not significant (P=0.47).[28] Even

with lower middle income tend to fulfill

the data from Vivi study is not significant,

their primary need first and the possibility

the reality in the field show bad health

of spending large cost due to travel from

service related to low acceptability of

home to health service which makes them

service, low trust in the delivery system

hesitant. As for parents with upper middle

and in health authorities, this is the effect

income have a strong assumption in the

of inequalities in the distribution of doctors

value of naturally acquired immunity by

wheres in a rural area there is 70% of the

exposure to the causative organism this

population however only 20% of doctors

assumption supported by the judgment of

are available, this condition leads to higher

the ability of booster immune by health

skepticism about immunization and lower

lifestyle, diet, exercise, and physical

immunization coverage.[28]

activity. It can be concluded parent with

6. Financial, based on income grouping from

lower or upper middle income have their

a parent, in 3 groups <3.5, 3.5-7, and >7

obstacle making their skepticism toward

million Indonesia rupiah, percentage those

immunization is higher and immunization

groups to immunize their children for 38%,

coverage lower rather than in parent with 7

234

middle income with lower skepticism and

support from family and society; b) Safety,

higher immunization coverage.[35,37]

some people assume that vaccines caused

7. Culture, Attitude, and Belief, a study by

severe side effects such as autism, physical

Yunitasari et al from all respondents

disabilities, destroying a healthy cell,

gather, obtain P-value equal as 0.000,

cough, and fever, this assumption is very

0.003, and 0.000 in terms of belief,

wrong, in Indonesia, vaccine safety

attitude, and culture in sequence toward

standards are higher than other drugs,

fulfilling basic immunization in Indonesia

vaccine entry permits are registered at the

this factors include trust issue about

BPOM (Badan Pengawasan Obat dan

immunization,

Makanan/Drug

p-value

obtained

and

Food

Control

significant with P<0.05.[35,38,39] Culture,

Agency), followed by monitoring post-

attitude, and belief factors are the biggest

marketing

strake in low immunization coverage

Departement under Ministry of Health, and

associated with high skepticism related to

KIPI

Imunisasi/Follow-up

low

perceived

preventable

disease,

risk

vaccine-

vaccination

not

BPOM,

(Kejadian

Immunization)

yet

The

Health

Ikutan

Pasca

Events

After

assumption

about

deemed necessary, low acceptability of the

autism appeared because of an article

service, low level of trust in vaccines, in

published by The Lancet in 1998 claiming

the delivery system, and in health

a positive intercourse between measles

authorities, based on a cultural point in

vaccine and autism, but this article has

Indonesia, there are still many folks who

been taken down in 2010 because some

have a very strict culture that is guided by

part of the paper is not true and; c)

the doctrine of the predecessor hundreds of

Misinformation, a

year ago related to local myths, one form

especially such as vaccine are useless,

fd c i ei

a hea h chi d

the immune system, misinformation that

infant was already born with innate

they also tend to trust dukun or shaman

immunity, the vaccine is a conspiracy from

more. Next point is an attitude, people will

the government to reduce the population

show

towards

by causing fertility another extreme

vaccination, attitude is influenced by: a)

conspiracy including vaccine contain pork

Motivation, 40% of people tend to unfill

their child immunization because of lack of

population, hi i

motivation (P<0.05) as a result of lack of

inclination to find information with asking

positive

he i e e i

going around

contain mercury, breast milk is enough for

complaints should not be taken to hospital ge a i ec i

lot

negative

order

reduce

global

he effec

Muslim

f e

8 235

their neighbor or co-worker, close friend,

religious leaders or traditional leaders, and

think the MUI is subordinated by the

searching the internet, this tendency

government, therefore, the MUI must be

happens because they believed health

complaint with the government regulation

provider hide the real ingredient of

thus they rely on their ustaz more.[35]

vaccine, an invalid sources of information will lead to increased skepticism about immunization.[24,35,38,39] The last point is a belief, strong belief develop in developed countries such as the strong value of immunity

acquired

exposure

causative agents and immunization disturb the natural immunization, therefore, a parent with unimmunized children discern vaccine as artificial immunity as a form of de ia

f G d

i , in Indonesia itself

with a majority Muslim population, the Islamic faith has a high role in the skeptical level of immunization coverage, such skepticism that the vaccine is haram* and mudarat** yet some Sikhs, Jews, Hindus, and Muslim also did

accept vaccine

because their belief of vaccine is an animal-derived product, in the perspective of belief it is up to everyone to believe what they believe but must be based on mature guidelines not just the words of someone prominent, many Muslim who have skepticism in immunization called vaccine is haram and mudarat because that what their leader or ustaz*** reinforce although a vaccine has received the halal label

from

MUI

Indonesia/Indonesian

(Majelis Ulema

Ulama Council)

be ie e i beca e he

Subsequently the discussion and analysis above, solutions are needed to overcome skepticism in the society therefore the immunization coverage can reach national and

international

combating

targets.

immunization

First-line

skepticism

Indonesia by conducting education done by health providers as the main escort directly or indirectly by collaborating with civil society organizations in the scope of country, regional, and community, in conducting education the main principle is being honest with

evidenced-based

information.[43-45]

Education-based on each of the factors that influence skepticism in Indonesia is described as follows. From maternal age factor, education can be started since antenatal care and first few postnatal appointments to build trust with parents, education is carried out by highlighting the benefit of immunization followed by facts in the form of testimonial stories.[45] As for profession, raise awareness of the importance of immunization thus expected that working parents can do better time management so children can immunize on time.[45] The third factor is internet access, a lot of misinformation going wild in areas with internet access thus solution can be done 9

*Haram: Something prohibited based on Islamic Law[40] **Mudarat: Something which have no benefit only bring damage [41] ***Ustaz: Preacher term in Islam[42]

236

by disseminating information as widely as possible with one valid source under the ministry

health,

centralization

information is no longer an option because as time goes by people are starting to use the internet to socialize rather than to search information, so that the target of information dissemination can be via Twitter, Youtube, Facebook, Instagram, or public transport advertising.[43,45] For health service factors, reinforce a positive attitude of a health provider to reduce skepticism and increase immunization coverage can begin with continue to provide immunization service in elementary school and primary health care, especially in previously unreached areas also

government, religion, tradition or even society.[38] Thus, education here is not carried out as a community but is carried out on face to face with traditional, religious, and society leaders, once those leaders get a conviction of how

community

services.[44,46] Next, is a financial factor, holistic education is needed to educate uppermiddle-income people to undermine their belief related to innate immunity and for lower-middle-income to reduce the cost of travel to health services, can be overcome

immunization

will

definitely

is,

the

follow,

educating with a leader must be done without offending what they believe, education is emphasized on what they doubt such as vaccine ingredient, robust vaccine safeness, honest with a vaccine side effect, address pain yet keep the focus on breaking the myth of what they believe also on protection for children and community.[35,45,46] CONCLUSION

utilize human resources, namely internship doctors to be distributed to fulfill health

important

Children are a big asset for a country, no e ce i

i I d

e ia, h

chi d e

hea h

must be a concern. In terms of immunization coverage, Indonesia has not met both national and international scales, this relates to the unfinished factor that influence immunization skepticism in parent.

with health workers who approach the nearest

In this review, factor about maternal

school or early childhood education to carried

intelligence found insignificant, for maternal

out immunizations followed by education

age, internet access, and financially found to

with a scheduled time.

[45]

The last factor is

be low skepticism and high immunization

culture, attitude, and belief, for these factors

coverage in mothers in their 30s, people with

we have to bear in mind that Indonesian is a

low or no internet access, and people with

paternalistic society whom more consider the

middle income respectively, in another hand

opinion of leaders, public figure, ancestors,

factor profession, health service, also culture,

and honor people in the eyes of the

attitude, and belief found to be high 10

237

skepticism and low immunization coverage in

working parent, bad health service, also in uptight culture, attitude, and belief in

Health Organization. 4.

sequence. It is expected that the inhibiting factors can be eradicated by the solutions

WHO. (2020a). Immunization. World WHO. (2020b). Vaccines. World Health Organization.

Ministry

Health

Republic

offered in this review, especially in the factors

Indonesia. (2017). Peraturan Menteri

culture,

therefore,

Kesehatan Republik Indonesia Nomor 12

skepticism about immunization can be

Tahun 2017 Tentang Imunisasi. Berita

suppressed and immunization coverage can

Negara Republik Indonesia Tahun 2017

fulfill the aimed target.

Nomor 559. Jakarta.

attitude,

and

belief,

SUGGESTION

Eddy Fadlyana, Soedjatmiko, Meita

Further study is needed to understand the interplay

maternal

intelligence

Dhamayanti, Rini Sekartini, Hindra I.

and

Satari, Nelly A. Risa, Dwi Prasetio,

vaccination, also other factors related to skepticism

immunization

Rodman Tarigan, Reni Garheni, Mia

against

Milanti, Sri R. Hadinegoro, Suganda

immunization coverage in Indonesia.

Tanuwidjaja, Novilia S. Bachtiar, and

In this literature review, the author

Rini M. Sari. The immunogenicity,

declares to have no intention of offending,

safety, and consistency of an Indonesia

cornering, or doing other negative things

combined

towards a certain religion, race, groups, or

2015;15:219.

Tri Windiarto, Al Huda Yusuf, Setio

Vaccination Services of Umrah Pilgrims

Fera Hermawati. (2019). Profil Anak Jakarta:

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Kerjasama

Kementerian Pemberdayaan Perempuan Dan Perlindungan Anak Dengan Badan

Kesehatan. 2018;21(1):60-70. 8.

Hoax Imunisasi Masih Beredar. Ministry

Nabila

Elchirri.

Mengenai

Pusat Statistik. Ministry of Health Indonesia. (2019).

Rustika, Herti W. Puspasari, and Asep Kusnali. Policy Analysis of Meningitis

Nugroho, Siti Latifah, Riyadi Solih, and

vaccine

schedule. BioMed Central Pediatrics.

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Involvement and Impact of Religious Leader to Eradicate Halal/Haram Myth of MR Vaccine and Promote Immunization in Indonesia Intan Qanita1, Ghina Mardhatillah2

ABSTRACT Background: Indonesia commits to maintain MR immunization above 90%. Indonesia is one of the countries that struggled with many measles cases. From 2015-2017 it showed an increase incidence of measles. From 2012-2017 measles vaccine coverage rates drop from 99,3% to 89,8%. Studies show that this phenomenon happens as vaccination hesitancy and refusal emerge due to myth, inaccurate information about MR Vaccine. As a country with the most Muslim population, Indonesia also affected the halal and haram issue of MR Vaccine as it contains pig derivates, prohibited for Muslims. MUI has released its statement by Fatwa MUI No 33 Tahun 2018 about the usage of the MR vaccine and it is now permissible. Ho ever, through this ear there hasn t been any significant improvement of the MR vaccine coverage rate since the label of haram is still sticking to the society. A religious leader is a great figure that influences many groups of people in Indonesia including on the health side. This paper discusses the involvement and impact of religious leaders to eradicate myths and promoting vaccination. Method: This review is made by finding relevant journals and articles through database research specifically PubMed, Medline, GoogleScholar and Elsevier. Further analysis is conducted based on the references and related journals. Result: Research confirms parental knowledge correlates with immunization rate and improving parent s kno ledge level ill increase the chance of vaccine completion. Several studies show the important impact of the religious leader in social, political and health in the community. Several studies also show a positive impact on vaccination rates if religious leaders also take part in efforts to deal with myths and misconceptions in MR vaccination. Conclusion: MR Vaccination rate target will be accomplished by improving vaccine-related knowledge so it will increase awareness in the society to do immunization with also. Religious leaders can bring better understanding, break the myth that disseminated in society and increase society's immunization knowledge thus immunization refusal will be decreased.

diseases that can cause 2-3million deaths per year [1]. Vaccination usually will be done to children from 0-15 years old. Approximately 37 million children will be born in the Southeast Asian region, and almost 90% if the children are born in 3 countries: India, Indonesia, and Bangladesh. One of the most important vaccines that need to be done by

INTRODUCTION Immunization is a way to make a person will be immune or resistant to the infectious disease usually by doing vaccination. The vaccine will work by stimulating the body immune to protect themselves from disease and infectious substances. By doing vaccination, it will reduce the number of life-threatening

242

children in South East Asia is the Measles vaccine [2].

people do not need to vaccination [4]. Another research about social perception about measles vaccine and other vaccine showed that there are still a lot of people lack knowledge about the vaccine. The response that showed by the society for instance vaccine is haram, children who did measles vaccination do not have any advantage, the vaccine will make children sick, people just need to drink herbal medicine, etc [5] [6]. Indonesia, as the biggest Muslim majority country in the world, is struggled to eradicate the halal/haram myth among society because this belief in myth will lead to vaccinehesitant and refusal.

In Indonesia, measles vaccine is combined with rubella vaccine and called as MR/MMR vaccine. It will be done when the child at 9-month-old, 18-month-old, and 6 years old. As an ASEAN country and part of SEARO, Indonesia commits to maintain MR immunization above 90%. In fact, Indonesia is one of the countries that struggled with many measles cases. Indonesian Ministry of Health reports measles cases by comparing each region with the incident rate. It will show how many cases per 100,000 people. From 2011-2017 shown a decrease from 9.2 to 5.6 incident rate per 100,000 people. But, from 2015-2017 it showed an increase in number from 3.2-5.6. There are 18 from 34 provinces that showed an increasing number of measles cases from 2015-2017. In 2008, measles vaccine coverage was 90.2% and reached the number of 99.3% in 2012. Unfortunately, it was decreasing to 89.8% in 2017 [3].

MR vaccination a vaccine in which there are pigs which made as haram substance. But, both of the measles and rubella are included as a dangerous infectious disease that can cause permanent disability even death. From 2014-2018 reported cases for both are 57,056 cases with 8,964 positives for measles and 5,737 positives for rubella. Due to the dangerous impact, MUI responded and released Fatwa MUI Number 33 Year 2018 about the usage of the MR vaccine and Serum Institute of India (SII) for immunization. The fatwa (decision or opinion from Islamic expert after doing some study and consideration) said that the usage of vaccination that use pigs and their derivative is haram, but due to compulsion because there is no other halal substance that can replace it, so the law will be mubah (permissible) until the halal vaccine is founded [7]. Ali his journal mentioned that the legality of vaccination in Islam is approved by the Maqasid Al-Sha i ah; the protection of human life, it is still permissible to do vaccination with prohibited ingredients

Some causes can make new measles and rubella cases that can be prevented by vaccination appear. One of them is vaccine hesitancy and refusal. The most important reason due to vaccine refusal is lack of knowledge that leads to ignorance. This phenomenon will create a belief in a myth that disseminated among society and make people will not do vaccination. Ahmed in his review showed that the increase of vaccinepreventable diseases in Muslim majority countries is due to the spread of inaccurate information about vaccines such as vaccines do more harm than good to Muslims, the vaccine is haram (prohibited in Islam), and

243

in the vaccine due to dharurah (dire necessity) [8].

From experience and research, it is proved that behavior with a knowledge base will last longer than a behavior without knowledge base. Some factors will affect knowledge of a person such as education, job, age, experience, culture, and information. In her research, it is showed that there is a relation between mother knowledge about immunization and immunization completion. It is also supported by Muchtar's (2010) research with the result from 250 respondents showed the respondent with good knowledge that done vaccination completion is 94.2% compared to people with less knowledge only reach the number 27.4% for immunization completion [9]. Other research from Wadud (2013) with 53 samples showed that respondents with good knowledge that completed immunization reach the number of 84.38% and respondents with less knowledge that completed immunization only 47.62% [10].

One of the ways to make people will do vaccination is by educated and eradicate false information and myth. As a religious country, religion is holding an important part in people life. A lot of things will be associated with the law that applied in a religion, including Muslims. The religious leader will hold an important role to decide to solve any kind of problem including vaccination. This paper discusses the involvement and impact to eradicate myths and promoting vaccination.

METHOD This literature review was conducted by finding related articles and journals through a database search. Database resources were PubMed, MedLine, GoogleScholar, and Elsevier. The following keywords and MESH terms are used: Vaccine; MMR Vaccine; Vaccine Hesitancy; Knowledge and Vaccine Relation; Halal; Vaccine Acceptance in Muslim Countries; Religious Leader Role in Health. Indonesian and English language publications are included. Further relevant articles are identified from reviewing the references.

Dewi (2014) in her research using questioner that given to mothers in the Parupuk Tabing region in Padang showed that more than 50% of the respondents are having good knowledge about immunization and done immunization completion to their children [11]. Research from Sari (2017) in Public Health Center Bendo Magetan District with using cluster sampling showed that mother knowledge about immunization has a significant relation with immunization status of the infant where the infant with mother that have a good knowledge will have a complete immunization [12]. Gahara (2015), in her research about mother knowledge and immunization completion that held in Public Health Center Kampung Sawah Lampung with proportional random sampling in 10

RESULT The Relationship of Knowledge about Immunization and Immunization Rate Research from Hijani in 2014, mentioned that knowledge or cognitive is an important domain in order to create an over behavior.

244

integrated healthcare center showed there are a notable relation between parents knowledge about immunization and immunization completion [13].

Aya (2018) in her research about the importance of a religious leader in social politic said that religious leaders held an important role among the society at the political election. The role of the religious leader plays a very important role to eradicate negative rumors among the society about politics and other matters. The result that a lot of people believe that religious leaders are role models and have responsibilities to lead society into the right path [18].

Another research was done by Simanjuntak and Nursina in a resident with the least immunization target in West Java. The research was about increasing mother knowledge about immunization using promotion. The result is the reason why a lot of infants not yet getting complete immunization is due to a lack of information, situation, and motivation [14]. A person that knows a certain matter will apply the knowledge that they got in their daily routine. It is included in immunization matters. Parents that have adequate knowledge about immunization will give basic vaccination completion to their children and will consider the right time to give vaccination [15].

Religious leaders have a strategic plan as an agent of change. 3 important roles can be played by religious leaders, those are (1) Education role that embraces all dimensions, (2) The role of providing enlightenment to society in uncertain situations, and (3) The role of building system, a tradition, culture that reflect wisdom. That is why there are a lot of problems that needed a religious leader to be solved including economy, law, education, society, politics, culture, and morality [19]. Mustafidah in her research about the role of the religious leader in society Lajo Lor Village Tuban District showed how a Kyai (religious leader) has a big play in society. Kyai will be an advisor in society in all aspects of the problem including economic, social, politics, and culture. It also showed that most people will follow what Kyai suggests to them [20].

The Importance of Religious Leader in Society UNICEF (2004) said that religious leader holds a really important play in the society because people assume that religious leader is a reliable source of information, and can be a role model to agree or disagree about something that spread in society. People believe that religious leaders can be trusted for all of the problems [16]. Ibu Sakdan said a religious leader is a person without any formal election as a leader, but because the person has better religious knowledge, the religious leader will influence the society with a suggestion, prohibition, and other knowledge support to solve any kind of problems [17].

The Role of Religious Leader to Eradicate Myth and Increase Immunization Rahman et al, in their journal bout, peer spiritual leader s role to improve lo vaccination in Akre District, Iraq with study sample, and intervention method, and

245

comparison showed a significantly greater number in vaccination after the intervention done. The vaccination coverage from DPT1, DPT2, DPT3, and measles vaccines preintervention (January-June 2006) are 55.9%, 42.7%, 21.5%, and 27.6%) and postintervention (July 2006), the rates increase drastically to be 95.5%, 90.0%, 84.4%, and 80.3%. It is showed that Sorchi tribe with the spiritual leader advocating for vaccination have a significantly greater improvement on vaccination than villages without spiritual leader advocating for vaccination [21].

Cijedil, Cianjur showed one of the effective strategies that can be applied to is to do crosssector corporation with the religious leader to encourage the mother to bring their children to Public health center to do vaccination [24].

DISCUSSION Improving Knowledge Increases Immunization Rate To reach immunization coverage rate in a country, analysis of the factors behind it must be conducted. Several studies in Indonesia showed that the higher knowledge of parents the higher chance of children getting complete immunization. All parents should know the beneficial side of the vaccine, the side effects, and the steps that have to be followed to accomplish vaccine completion. Besides that, parents also have to know about the danger that the children might face without having a vaccine. Recent studies have shown that a lack of knowledge of the seriousness of the vaccine-preventable disease leads to the reduction of vaccine acceptance [25]. Lacking that information will lead people to have skepticism about immunization. Parents tend to believe that vaccine is not important in maintaining the health of their children. While vaccine itself works as prevention to a lot of serious diseases. Knowledge about the role of the vaccine as preventive measurement should be given to all parents. Knowledge about a vaccine has to be thorough and deep. Including information about side effects and vaccine safety. Public fear of adverse effects from vaccine and

Nasir et al, with a research about Muslim Clerics, were engaged to eradicate polio cases in Nigeria, the engagement of the religious leader and traditional leaders including polio survivors, Quranic school teachers, and entertainers was vital to the success of the countr s PEI and primar health programs. They were trying to eradicate myth and inaccurate information that spread among society and encourage people to do vaccination. After the campaign, the occurrence of new polio cases has been drastically dropped to the lowest level. The prevalence of polio cases in 2009 was 154 and decreased drastically in 2013 to be only 1 case [22]. Obi-Jeff et al (2019), in their report about improving vaccination initiation and completion via vaccine indicator and reminder bands: a formative stud in Nigeria has found that community leaders (religious and traditional leaders) are strong and lasting influence among the society to do or to not do vaccination [23]. Juhamad and Krianto on their research about communication strategy to increase immunization practice in public health center

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vaccine safety concerns are the prime obstacles of vaccine acceptance [25]. Misconception about side effects and adverse effects of being vaccinated spread in many groups of people. People with less knowledge believe that vaccinated children will get other diseases. A study about myth and misconception about vaccine shows that the Wakefield paper hypothesized that the MMR vaccine caused a reaction in the gut (ileocecal lymphoid nodular hyperplasia), that led to a release of brain-damaging peptides that increased ASD rial [26]. A later study in Canada found ASD rate increase while the MMR vaccine rate decrease, disproving the claim that the MMR vaccine was the cause of ASD. Other misconceptions that are spread among people are DTP vaccine can cause encephalitis, multiple vaccinations will make the immune system to be overwhelming, and many substances in the vaccine that are not safe [26].

In Malaysia, the number of parents who refused to get their children vaccinated has almost increased three-fold, from 470 cases in 2013 to 1054 cases as of May 2015. The reason behind this is believed to be many misconceptions regarding the vaccine. A lot of speculations are spreading from vaccine aim to weaken Muslim, and even vaccine program was a plot to transmit the disease to non-western Countries [29]. Another aspect that should be in consideration is the halal issue. A questionnaire-based study was conducted to a wide range of religious participants. The study found that several branches of religion have restrictions on using medical products that contain animal-derived substances. Some of them specifically restrict porcine containing products namely Muslims, Hindus, and Sikhs [30]. People in Muslim countries like Malaysia and Indonesia still assume that numerous vaccines contain derivates of pig and consider them as haram or prohibit for them7. This will interfere with the government's aim to improve immunization coverage in the community. Besides all the countries mentioned above accept the use of the animal-derived product if there is no other alternative or if in an emergency and have to comply with patient informed consent [30]. This emergency policy has been implemented in many situations. Several patient conditions require medical treatment using porcine drugs. To treat the patient, the hospital has the policy to get consent from either the patient or family by signing the consent letter. However, regarding the vaccine, since many people perceive that

Immunization Problem in Educated Community While performing immunization programs, all parents must take a role in observing vaccine progress that has been given to their child. Low parental literacy regarding immunization and vaccine schedules shown to be a factor of immunization completion Ade [27]. Educational interventions promoting vaccine use have also proven cost-effective in improving immunization coverage rates in this setting [28]. However, in contradiction from all the statement above, parent s refusal hesitancy to accept childhood vaccination also increase even in more educated parents.

247

vaccine is not an emergency matter, then this issue lead to vaccine hesitancy. Even after Indonesia Ulama Council (MUI) stated their fatwa in 2018 saying that MR vaccine is permissible considering its emergency and no replacement exists condition, the MR vaccination rate drop in 2018 from 95% during the first period of the campaign to 68% in the second-period campaign [31]. The act of vaccine hesitancy appears since parents still confused about determining their decision regarding this halal issue.

play a fundamental role in healthcare decision-making for Muslims within hospital and mosque settings This reveals how the leader can function as interpreters and cultural brokers. Healthcare partnerships with religious leaders and their mosques may be an important way to strengthen the communit s health. Religious leaders may also encourage cultural competency efforts for the healthcare system [34]. Religious leaders have a particularly strong influence on the behavior of members of their religious institution and in the community, in general. Their willingness to preach the good point of a healthy lifestyle, especially if grounded in sermons, can be a source of promoting healthy habits and reducing health care costs [35].

Religio

Leader Role in Socie Heal h Many groups of people especially religious groups of people tend to make their leader as a role model and influence them in deciding things in their daily life that can be doubtful or concerning for them. This makes religious leaders play a great role in society whether in social, politic, economic even health. Community-based research has done in America about how Muslim religious leaders play a role in the community health, and the main roles are including (1) encouraging healthy behaviors through scripture-based messages in sermons; (2) performing religious rituals around life events and illnesses; (3) advocating for Muslim patients and delivering cultural sensitivity training in hospitals; and (4) assisting in healthcare decisions for Muslims [32]. Various reasons also become known on why religious leaders can influence people's health-related practice, including scriptural influences, religious leaders as role models, social influences, social support and fear of stigmatization [33]. Another study also shows how Muslim religious leaders

Religious Leader Role in Promoting Immunization Several studies have shown that with measures from religious leaders in promoting and advocating people in doing vaccination, immunization rates increase. This gives us information that religious leaders play a great role in diminishing factors behind vaccine hesitancy or vaccine ignorance event antivaccine movement. Their role in this could be in promoting healthy behavior, involving vaccine information in sermons, and making a decision in vaccine regarding the halal haram issue. A systematic review about addressing vaccine hesitancy shows that religious leader involvement in intervention aims at one of the more difficult factors of vaccine hesitancy, which is misconceptions and community distrust and it is significant. This type of intervention believed to be more

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targeted to the audience, enable open dialogue and integrating activities with familiar processes and Systems [36]. Collaboration with Islamic religious leaders has been suggested to help increase living donor kidney transplantation within ethnic minority groups [37]. In a recent development, several countries with majority Muslim populations have seen a sharp increase in the number of vaccinepreventable disease cases such as polio, diphtheria, measles, tetanus, and pertussis [29]. Thus making the target of vaccination coverage is also those Muslim population. The religious leader mainly Islamic imams could promote the vaccine program by explaining the duty of parents to secure the well-being of their children and preach about vaccination. Another report of a successful intervention comes from the USA, where the involvement of religious leaders in the campaign to increase influenza vaccination coverage indeed increased coverage among adults [37]. Regarding the halal issue, Malaysia and European Fatwa Council internationally have ruled about the permission of the vaccine as long as it used as treatment and prevention, also mention that porcine containing in the vaccine is insignificant and makes no difference [29]. As religious leaders have a great impact on influencing the general community specifically the corresponding religious community than their involvement should also have an impact on advocating people to get their children vaccinated with the MR vaccine.

CONCLUSION RECOMMENDATION

AND

Based on the result it is showed that knowledge about immunization is very important to increase awareness among society to do immunization for their family or children. In order to do that, the involvement of religious leaders will able to bridging better understanding and break myth that disseminated in society. The result already approved that religious leader can clarified false rumor and myth, so it will also work for halal/haram myth of MR vaccine. Moreover, the religious leader can increase society's knowledge about immunization in so the immunization refusal will be decreased and increase immunization rate. There are some recommendations that the government and health worker could do to make this happen: 1. Enhance religious leader knowledge about vaccination to create better understanding to the society 2. Spread more fatwa MUI about halal and haram vaccination. 3. Enforce integrated measures by Government, Health Care Providers, and religious leader to fight against myth, misconception, and lack of knowledge in vaccine.

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20. Mustadifah A. Peran tokoh agama dalam kehidupan social keagamaan. Surabaya: Fakultas Ilmu Sosial dan Ilmu Politik UIN Sunan Ampel [Internet]. Digilib.uinsby.ac.id. 2018 [cited 5 April 2020]. Available from: http://digilib.uinsby.ac.id/23279/3/Arina%2 0Mustafidah_I73214013.pdf

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21. Abdul Rahman M, Al Dabbagh S, Al Habeeb Q. Health education and peer leaders'role in improving low vaccination coverage in Akre district, Kurdistan region, Iraq. Eastern Mediterranean Health Journal. 2013;19(02):125-129.

16. UNICEF. Building Trust In Immunization Partnering With Religious Leaders And Groups. 2004. https://www.unicef.org/publications/index_2 0944.html

22. Nasir S, Aliyu G, Ya'u I, Gadanya M, Mohammad M, Zubair M et al. From Intense Rejection to Advocacy: How Muslim Clerics Were Engaged in a Polio Eradication Initiative in Northern Nigeria. PLoS Medicine. 2014;11(8):e1001687.

17. Sakdan I. Optimalisasi Peran Tokoh Agama Dalam Meningkatkan Kesadaran Beragama Masyarakat di Kecamatan Kuala Kabupaten Nagan Raya [Internet]. Repository.ar-raniry.ac.id. 2020 [cited 7 April 2020]. Available from: https://repository.arraniry.ac.id/id/eprint/329/1/Ibnu%20Sakdan. pdf

23. Chisom Obi-Jeff, Ebubechi Nwaononiwu, Nahum Nuhu, Kelechi Irechukwu, Suleiman Mahmud, Tobi Bamiduro, et al. Improving Vaccination Initiation and Completion Via Vaccine Indicator and Reminder Bands: A Formative Study in Nigeria. 3ie. 2019. https://www.3ieimpact.org/sites/default/files /2019-05/FE06-TW10.1113-VIR-bandNigeria_0.pdf

18. Demianus Aya. Peranan tokoh agama dalam meningkatkan partisipasi politik masayarakat pada pilkada bupati 2010 di kabupaten Halmahera selatan. 2013. EJournal Unsrat. [Internet] [cited 3 April 2020] https://ejournal.unsrat.ac.id/index.php/politic o/article/view/3409

24. Juhamad J, Krianto T. STRATEGI KOMUNIKASI PENINGKATAN PRAKTEK IMUNISASI DIFTERI PADA IBU BALITA DI PUBLIC HEALTH CENTER CIJEDIL, DINAS KESEHATAN KABUPATEN CIANJUR. Jurnal Ilmiah Kesehatan. 2019;11(2):115-123.

19. Fauziyah S. peran toko agama dalam masyarakat modern menurut anthony giddens [Internet]. Digilib.uin-suka.ac.id. 2020 [cited 1 April 2020]. Available from:

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26. Ott MA, Alexander AB, Lally M, Steever JB, Zimet GD, Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions. Preventive misconception and adolescents kno ledge about HIV vaccine trials. Journal of Medical Ethics. 2013 Dec 1;39(12):765-71.

33. Heward-Mills NL, Atuhaire C, Spoors C, Pemunta NV, Priebe G, Cumber SN. The role of faith leaders in influencing health behaviour: a qualitative exploration on the views of Black African Christians in Leeds, United Kingdom. Pan Afr Med J. 2018;30:199. Published 2018 Jul 6.

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AMINO | AMSA INTERNATIONAL COMPETITION 19/20

Immuni ation For Your SPECIAL One F ll co erage of imm ni a ion, a orld i h minimal infec ion A er Gilber h I ano Kalaij, Ade Ga ama, Rani Perma a

Background Imm ni a ion i a cr cial hing o achie e in he S Vaccina ion pre en

ickne

and dea h a ocia ed

ainable De elopmen Goal (SDG ).

i h infec io

di ea e

ch a diarrhea,

mea le , pne monia, polio and hooping co gh. The al o hold p broader gain in ed ca ion and economic de elopmen . Thro gh imm ni a ion, dea h from mea le , he major child killer, ha declined b 80 percen

orld ide pre en ing an e ima ed 21.1 million dea h . In 2019, almo all

co n rie ha e elimina ed ma ernal and neona al e an , a di ea e i h a fa ali percen among ne born . Moreo er, appro ima el 2 o 3 million dea h

ra e of 70 o 100

ere pre en ed hro gh

imm ni a ion. Ne er hele , he World Heal h Organi a ion e ima e ha 19.4 million children are n or nder- accina ed. The p ard rend in co erage ha increa ed b onl 5% in he pa decade and ha pla ea ed.1,2 Thi phenomenon happen d e o rea on incl ding he belief ha na ral di ea e ill make child imm ne

em ronger in erm of gro ing in o ad l hood, he

belief of minimal ri k of heir children con rac ing he e di ea e , he belief o no p

e ra

chemical in o heir children bodie , he po ible nega i e ide effec of accine admini ra ion hich o be ea il

eighed he benefi of he accine , and he belief ha he pre en able-di ea e

o ld

rea able. On he con rar , he m h i no a he percei ed, he imm ni , in fac , bo h

are imilar ei her b na ral infec ion or childhood accina ion. In Addi ion, he co in he long erm i far cheaper b doing accina ion ra her han ha ing na ral infec ion; ho e er, people ill hink hor -mindedl . We belie e ha here i a h ge mi concep ion among paren

hich ind ce

he rejec ion of imm ni a ion i elf.3 If mo of he famil doe no kno abo

he impor ance of imm ni a ion, i

ill promo e

or e ca e la er. Moreo er, he impac of no ha ing imm ni a ion i no a joke. For e ample, if a per on a no

accina ed, he eaker imm ne

em o ld danger he children in o more life-

hrea ening condi ion and e en dea h. Therefore, he promo ion of imm ni a ion i de pera el needed d e o of en rejec ion and igma from ocie , kno ing he or e impac hi phenomenon co ld bring. We

gge

he heal h promo ion p blic po er for in rod cing accina ion benefi

among common people and in i e heir children o be accina ed. We crea e hi p blic po er o

255

rai e a arene , ed ca e ocie , and figh he igma among people. We pro dl in rod ce o r idea for imm ni a ion, remember ha imm ni a ion i SPECIAL. SPECIAL

and for Safe,

Pre en a i e care, Effec i e imm ni , Co -effec i e, and Long- erm pro ec ion. 4-7 Safe, a Imm ni a ion are comple el re ie ed and e ed b i can ca e mild ide effec , he effec of he real di ea e i b he imm ni a ion hich make i afe for hich can pro ec

o in he f

ill or e han he ide effec ca ed

e. Pre en a i e care, like imm ni a ion, can pre en

o from ge ing deadl di ea e beca e o r imm ne he di ea e

he cien i . E en ho gh

em alread kno

he di ea e. So, i

ill prod ce he ame imm ni

Effec i e, rela i el , imm ni a ion i

o deal

a ing more mone

i ho

a if o are infec ed

o ge ing he di ea e. Co -

han ha ing real di ea e. The real

di ea e can gi e o e pen i e bill for medicine and long- erm care. So, i i be er for o imm ni a ion o pre en he e pen i e bill ha

o do

o can ge from he di ea e, and al o can gi e

o Long- erm pro ec ion, rela i el , imm ni a ion can gi e o di ea e . Some of hem ma pro ec

re from ge ing he di ea e. Effec i e Imm ni , a

imm ni a ion i pre en a i e care ha i effec i e o b ild o r imm ni j b

ear of pro ec ion o ard

o for 4-5 ear mean hile, ome can gi e o life ime

pro ec ion.4-7

Objectives To increa e kno ledge and a arene To figh he igma among people abo

among ocie

abo

he impor ance of imm ni a ion

imm ni a ion hich of en in rod ce rejec ion

To increa e imm ni a ion co erage in children

Conclusion Imm ni a ion co ld be promo ed hro gh rai ing a arene hope hi kind of heal h promo ion ill impac he ocie

ha imm ni a ion i SPECIAL. We hro gh kno ledge impro emen and

increa e he n mber of imm ni a ion co erage, herefore figh ing he igma and m h in ocie .

256

References 1. WHO. Progre

and challenge

i h achie ing ni er al imm ni a ion co erage

[In erne ]. WHO; 2019 [ci ed 2020 April 5]. A ailable from: h p ://

. ho.in /imm ni a ion/moni oring_ r eillance/ ho-imm ni .pdf? a=1

2. UNICEF. Vaccina ion and imm ni a ion

a i ic [In erne ]. UNICEF; 2019 J l [ci ed

2020 April 5]. A ailable from: h p ://da a. nicef.org/ opic/child-heal h/imm ni a ion/ 3. McKee C, Bohannon K. E ploring he rea on behind paren al ref al of accine . J Pedia r Pharmacol Ther. 2016;21(2):104 109. DOI:10.5863/1551-6776-21.2.104 4. Imm ni a ion Ad i or Cen re. Vaccine efficac and effec i ene

[In erne ]. A ckland.

Imm ni a ion Ad i or Cen re; 2017 [ pda ed 2020 Jan; ci ed 2020 April 5]. A ailable from: h p ://

.imm ne.org.n / accine /efficienc -effec i ene

5. U.S. Na ional Librar of Medicine. Imm ni a ion: MedlinePl

Medical Enc clopedia

[In erne ]. Uni ed S a e : Medlinepl .go ; 2019 [ci ed 2020 April 1]. A ailable from: h p ://medlinepl .go /imm ni a ion.h ml 6. Cen er for Di ea e Con rol and Pre en ion. Fi e impor an rea on o accina e o r child [In erne ]. Cen er for Di ea e Con rol and Pre en ion; 2015 Feb [ci ed 2020 April 5]. A ailable from: h p :// 7. WHO. Se en ke rea on

.cdc.go /mea le /do nload /ma e-rea on - accina e.pdf h imm ni a ion m

remain a priori

in he WHO

E ropean region [In erne ]. WHO; 2017 [ci ed 2020 April 5]. A ailable from: h p://

.e ro. ho.in /__da a/a e /pdf_file/0017/84302/Se en_Ke _Rea on .pdf

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258

The Adventure of Captain Vaccine: Banishing Vaccine Hesitancy Abstract When facts are not enough, people will tend to belittle the benefits of vaccines and believe in those myths circulating in the society.1 Vaccines, come from the word vaccinia, are antigenic substances used to produce immunity to a disease.1 Giving vaccines (vaccination) is one of the most effective ways to prevent or reduce the influence of infections that cause disease by stimulating the body to release antibodies against certain diseases.1 Vaccines usually contain agents that mimic disease-causing microorganisms and are often made from weakened or dead microbes that will later stimulate the immune system to recognize the vaccine as a threat, destroy it, and create defenses that may be encountered in the future. Vaccines can be prophylactic (prevention) or therapeutic.1,6 The effectiveness of vaccinations has been widely studied and verified, for example vaccines have proven to be effective including influenza vaccines, HPV vaccines, and chickenpox vaccines.6 According to WHO, immunization currently prevents 2-3 million deaths every year.13 Despite the overwhelming volume of evidence on the benefits of immunization, widespread misconceptions and mistrust of information about vaccine efficacy and safety remain.2 Vaccine hesitancy is threatening the global achievements made in defeating infectious diseases, which have plagued humanity for centuries.2 In fact, there are still thousands of people out there who believe that vaccines have several unfavorable side effects, such as autism, allergies, sudden infant death syndrome and many others.2 Whereas, vaccines are extremely helpful to prevent transmission and contract of infectious disease.6 At times like this, it is our duty as medical students who are part of the society to dispel myths about vaccines by providing information and educating people who are still lacking information about vaccination.6 It is important for people to know that, for someone to be immune against infectious agents, everyone must reached the target vaccination in order to create herd immunity. If the herd immunity was not reach, there is still a possibility for someone to be infected. In the other hand, if people reached their herd immunity, they will be safe from infectious agents.14 Captain Vaccine here can be described as a superhero who is loved by her parents and grew up healthily because she was given vaccination to protect her from infectious agents. Later when she grew up to be an adult, she wanted to spread and educate the society about vaccines by becoming a doctor. Her first mission is to banish vaccine hesitancy in the society by the LOVED methods, which provide awareness related to myths and facts about vaccines. 1 259

Every type of vaccine can help children to create a defense mechanism against infectious agents and fight them.4,5 It is extremely important to know that these vaccines are completely safe as long as they are used as directed by doctors.4 However, due to the myths floating around, it is quite hard to convince some parents to approve vaccinating their children.3 The most famous myth is that vaccines can cause autism in children.3,4 It started in 1998 when a study written by Andre Wakefield about a possible connection between measles-mumpsrubella (MMR) or any other vaccines and autism was published.7,8 It is proven that the study was seriously flawed and the paper has been retracted by the journal.7,8 Then, in 2002, a Danish study was proven that there are no link between MMR vaccines and autism.7,8 Then, there are other myths saying that giving a child more than one vaccine at a time could increase the risk of harmful side effects and could o erload the child s immune s stem, which is absolutely wrong, since evidence shows that giving several vaccines at the same time has no negative effect on a child s immune s stem.11 Combining vaccines can save more time, save money and will also increase the probability for the child to get all of the vaccines required by the government on time.11 Vaccines also do not contain any harmful mercury like information circulating in the society.10 However, some vaccines do contain thimerosal, which is an organic ethylmercurycontaining compound acting as a preservative.10 There is no evidence that suggests this mercury poses a health risk.10 It is also impossible to stop the transmission of infectious agents only by ensuring proper hygiene and sanitation since many infections can spread regardless of how clean we are.10 Moreover, vaccines teach our immune system to react to certain antigens instead of overwhelming the body and there is no evidence of a link between vaccination and the development of allergic, autoimmune and respiratory diseases later in life.6 In order to eradicate the myths and bad stigma about vaccines, the most effective interventions are multi-component.11 In most cases, interventions should be dialogue, based and directly targeted to a specific under-vaccinated population group.11 By engaging collaboratively with health workers, parents and their families as well as communities, national authorities can generate the insights to develop better quality health services, systems, policies, and communication strategies that support and enable recommended vaccination behaviors. WHO has also developed a complete guideline Adjusting the Immunization Program (TIP) to manage the Immunization Program.11 Vaccines hesitancy problems cannot be resolved only by doctors and pediatricians alone, the governments and civil society also play an important role in educating and promoting vaccines so people can understand and realize how important immunization is.11 Given the 2 260

potential for vaccine hesitancy in the society, it is important that all countries take steps to understand both the extent and nature of hesitancy.11 Accordingly, each country should develop a strategy to increase acceptance and demand for vaccination, which should include ongoing community engagement and trust-building, active hesitancy prevention, regular national assessments of concerns, crisis response planning or even deducting the price of vaccines for the community.11 Besides that, as a community we can also provide education about the benefits and effects of vaccines on the human body to the public. This can be done by implementing a health campaign about vaccines, conducting counseling, and testimonials. Therefore, only the collaboration between every aspect of the society will allow the myths and misinformation to be dispelled.11 Keywords: World Immunization Day, vaccines hesitancy, myths, infectious agents, immune system

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References 1. Alvira X. Vaccine hesitancy is a global public health threat. Are we doing enough about it? [Internet]. Elsevier Connect. 2020 [cited 4 April 2020]. Available from: https://www.elsevier.com/connect/vaccine-hesitancy-is-a-global-public-healththreat-are-we-doing-enough-about-it 2. Elflein J. Topic: Vaccine hesitancy in the U.S. [Internet]. www.statista.com. 2020 [cited 4 April 2020]. Available from: https://www.statista.com/topics/5166/vaccinehesitancy-in-the-us/ 3. Loney S. When facts aren't enough: Why some parents are scared of vaccines [Internet]. Today's

Parent.

2020

[cited

April

2020].

Available

from:

https://www.todaysparent.com/family/family-health/when-facts-arent-enough-whysome-parents-are-scared-of-vaccines/ 4. Natbony J, Genies M. Vaccine Hesitancy and Refusal. Pediatrics in Review. 2019;40(Supplement 1):22-23. 5. The Lancet Child & Adolescent Health. Vaccine hesitancy: a generation at risk. The Lancet Child & Adolescent Health. 2019;3(5):281. 6. MODUL 1

Tipe Vaksin - DASAR KEAMANAN VAKSIN WHO [Internet].

In.vaccine-safety-training.org. 2020 [cited 4 April 2020]. Available from: https://in.vaccine-safety-training.org/types-of-vaccine-overview.html 7. MMR vaccine does not cause autism. Journal of Paediatrics and Child Health. 2019;55(8):996-996. 8. SULLIVAN M. IOM: No Link Between Autism, MMR Vaccine. Pediatric News. 2011;45(9):4-5. 9.

[Internet].

Euro.who.int.

2020

[cited

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2020].

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http://www.euro.who.int/__data/assets/pdf_file/0005/339620/Myths-andfacts.pdf?ua 10. Vaccine Ingredients: Frequently Asked Questions [Internet]. HealthyChildren.org. 2020

[cited

April

2020].

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https://www.healthychildren.org/English/safetyprevention/immunizations/Pages/Vaccine-Ingredients-Frequently-AskedQuestions.aspx

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11. Multiple Vaccines and the Immune System | Concerns | Vaccine Safety | CDC [Internet].

Cdc.gov.

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https://www.cdc.gov/vaccinesafety/concerns/multiple-vaccines-immunity.html 12. Improving vaccination demand and addressing hesitancy [Internet]. World Health Organization.

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Available

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https://www.who.int/immunization/programmes_systems/vaccine_hesitancy/en/ 13. Immunization coverage [Internet]. Who.int. 2020 [cited 5 April 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/immunization-coverage 14. Mallory M, Lindesmith L, Baric R. Vaccination-induced herd immunity: Successes and challenges. Journal of Allergy and Clinical Immunology. 2018;142(1):64-66.

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Combatting Vaccine Myths by 5 CENTS Immunization or vaccination has become the most important prevention strategy in fighting vaccine-preventable diseases in the world. Almost 30% of deaths of children under 5 years of age are caused by vaccine-preventable diseases (e.g. Measles, rubella, diphtheria, pertussis, tetanus, hepatitis B, polio, etc).1 This high number of deaths has been proven to be significantly decreased by the use of vaccines. Currently, immunization or vaccination prevents approximately 2 until 3 million deaths, especially due to vaccine-preventable diseases, every year worldwide.2 However, people in the society are still unaware of this situation. People are more focused on and afraid of the negative sides of vaccines, and this false idea on vaccines carries a detrimental major problem for themselves, that is the emergence of myths and misconceptions about vaccines.3,4 These myths and misconceptions about vaccine are the only pioneers of the anti-vaccine movement formation, which further will increase the concerns on vaccines safety. Such concerns may blur the understanding about how vaccines actually work. This will eventually lead to society refusal on vaccinating themselves and even their children.3,5 Public attention is now becoming more inclined to vaccine’s side effects, myths, and misconceptions due to the decreasing evidence of devastating effects of vaccine-preventable diseases, whereas this decreasing evidence was mainly caused by the important contribution of vaccine protection in the past time and will also make people unaware and “blind” to the importance of vaccination.6 According to the facts and the increasing problems about immunization or vaccination as stated above, creators proposed an intervention to help health authorities in eliminating the myths and misconceptions about vaccination. This intervention is shown in the public poster as an idea to help society to understand more about the right facts of vaccination and to help WHO in reducing the misperception gap between public and health authorities.7 Creators want to convey a simple algorithm that hopefully can be easily remembered called “5 CENTS”. Number 5 in the front means that there are 5 important facts for society, in order to straighten up some common myths and/or misconceptions.3–5 First, C is for Contain safe materials and clinically harmless. The first fact is meant to fix perception about vaccine’s components. People tend to worry about the safety of its components that are considered to be unsafe and “toxic”, such as mercury and ether. Both materials are just adjuvants in a very small amount and proven to be clinically harmless. Both materials also will not affect the effectivity of vaccines. No evidence suggests that their amounts poses a health risk.3–5 Second, E is

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for Effectively teach body how to fight infections. The second fact is meant to fix perception about how vaccines actually work. Vaccines (e.g. Polio, MMR, and DTP) are 80-99% effective in protecting children from vaccine-preventable diseases in their later lives. Vaccines do not cause suppression on the immune system. On the contrary, vaccines work by mimicking an infection to let the body learn how to fight off a future infection.3 Third, N is for No disease transmission from vaccinated people. The third fact is meant to fix perception about the concern of vaccine-preventable diseases transmission. There are two kinds of vaccines; vaccines prepared from only part of the pathogen or a pathogen that has been inactivated and vaccines prepared from weakened (“live attenuated”) form of a pathogen. The former vaccines are therefore not living, while the latter vaccines may still replicate in the host in order to create an immune response. Hence, vaccines cannot cause any diseases, except on very rare occasions, such as people with HIV and other people with immunocompromised conditions, and cannot be spread from vaccinated people to others surround them.3,6 Fourth, T is for Toughen immune system in the child’s body. The fourth fact is meant to fix perception about the concern of overloaded or overwhelmed child’s immune system due to vaccines administrations. Scientific evidence shows that vaccination does not have any negative effects on child’s immune system. It boosts and strengthens child’s immune system. Vaccines contain fewer antigens than children’s environment in their every day lives and do not overwhelm or “use up or consume” the immune system.4,6 Fifth, S is for Seek doctor’s advices about vaccination. The fifth and the last fact is meant to fix perception about the vaccine’s misunderstanding from society and anti-vaccine movement. Doctors as a part of health professionals are the most important information source about vaccination, not society or even anti-vaccine movement. Society needs to explain their concerns to the doctors so that doctors may give the best advice and explanation about vaccination. In this situation, there will be a less barrier between doctors and society, and the rightest information will slowly be spread around the society.3,5,6 By understanding and giving attention to 5 CENTS, creators hope that each people will internalize the right facts about vaccination and also contribute in helping UNICEF in achieving vaccine-preventable disease elimination and eradication goals, as stated in UNICEF Immunization Roadmap 2018-20301, by starting to vaccinate again, especially their children. Creators also hope that people will start to stay away from the myths and misconceptions about vaccine. In the end, this intervention is expected to regain people’s trust on vaccination. Let’s save 5 CENTS as a small step to save our world!

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Bibliography 1.

UNICEF. UNICEF Immunization Roadmap: 2018–2030 [Internet]. New York: UNICEF; 2018. 7–9 p. Available from: https://www.unicef.org/immunization/unicefaction

WHO. Immunization Coverage [Internet]. World Health Organization. 2019. Available from: https://www.who.int/en/news-room/fact-sheets/detail/immunization-coverage

Tan MT, Matthews KRW. Scientific Misconceptions and Myths Perpetuated in the 2017 Texas Legislative Session. Rice Univ Bak Inst Public Policy. 2018;(10.23.18):2003–6.

WHO Europe. Myths and facts about immunization [Internet]. Copenhagen: WHO Regional

Office

for

Europe;

2015.

1–3.

Available

from:

http://www.euro.who.int/en/health-topics/disease-prevention/vaccines-andimmunization/publications/2017/myths-and-facts-about-immunization-2017 5.

Smith TC. Vaccine rejection and hesitancy: A review and call to action. Open Forum Infect Dis. 2017;4(3):1–7.

WHO Europe. Training manual: Vaccine safety and false contraindications to vaccination [Internet]. WHO Europe. Copenhagen: WHO Regional Office for Europe; 2017.

28–37

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http://www.euro.who.int/__data/assets/pdf_file/0009/351927/WHO-VaccineManual.pdf 7.

WHO Europe. Vaccination and trust [Internet]. WHO Europe. Copenhagen: WHO Regional

Office

for

Europe;

2017.

23–32

Available

http://www.euro.who.int/en/health-topics/disease-prevention/vaccines-andimmunization/publications/2017/vaccination-and-trust-2017

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from:

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THE USE OF ABORTED FETAL TISSUE IN VACCINES FACT OR MYTH? Abstract

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. The immune system recognizes vaccine agents as foreign, destroys them, and remembers them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the virus, and thus is prepared to respond. There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The World Health Organization (WHO) suggests that vaccination prevents 2-3 million deaths each year. One of the most common infectious diseases is rubella (German measles). The disease is caused by rubella virus, a togavirus that is enveloped and has a single-stranded RNA genome. Rubella can be prevented with MMR (Measles, Mumps, and Rubella) vaccine. The rubella vaccine was introduced in 1969. There were 57,686 cases and 29 deaths from the virus that year. The MMR combination vaccine was introduces in 1971. There were 45,086 cases of rubella that year and 20 deaths from the rubella virus that year. The significant changes of the rubella cases and deaths can be seen bellow.

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Vaccination coverage has improved greatly over the past decades, but globally 13.5 million children were not vaccinated in 2018. The WHO has listed vaccine hesitancy as one of the top ten threats to global health in 2019. There are many reasons on why people refuse vaccines. One of the reasons are people have expressed concern that the first MMR vaccine has been produced in fetal tissue. Some parents are concerned about this issue because of misinformation they have encountered on the Internet. Two such untrue statements are that ongoing abortions are needed to manufacture vaccines and vaccines are contaminated with fetal tissue. The truth is about to be dismantled. Articles through Internet about the origin of the rubella vaccine told that there was a pregnant woman who was deliberately infected by the rubella virus and after the virus attacked the fetus, the fetus was aborted as material to make the rubella vaccine. The fact is, in 1960 several cases of rubella were detected during pregnancy. It had to be terminated to avoid the serious risk of rubella infection and severe CRS (Congenital Rubella Syndrome) conditions in the unborn child. In Sweden, a pregnant woman was infected by Rubella and her fetus was infected by CRS, a condition that would cause many

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health issues including deafness, congenital heart diseases, mental disorder, pneumonia, brain inflammation, and many more. Therefore, the woman has rights to abort her fetus. Only two fetuses were involved in research into vaccine production, both originating from medical terminations or abortions carried out with the mother's consent for consideration of the risk of severe fetal defects. There is no deliberate abortion to look for human cell lines in making vaccines. The results of abortion of medical indication are further studied in the laboratory and managed to isolate the rubella virus from fetal kidney cells. Other researchers developed cell lines from the fetal lungs that was named WI-38 and found many viruses, included rubella, grow well in WI-38 cells .The virus were proven to be free from contamination and were safe to use as a vaccine for humans. Here are the risks of avoiding vaccination: 1. B a iding accina i n,

ing

famil in dange . A accine

e en able

disease that might make you sick for a week or two could prove deadly for your family if it spreads to them. Adults are in the most common source of whooping cough infection in infants. 2. Millions of adults get sick from vaccine-preventable diseases, causing them to miss work and leaving them unable to care for those who depend on them.

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MMR Vaccs Myth Busters Authors: Bella Renata, Adara Kirana Putri, Eigieneo Elmattana Nosatiya Abstract Thanks to vaccines, smallpox has been eradicated and we rarely see children and adolescences suffering from diphtheria complications, poliomyelitis, or measles complication. Vaccination has drastically reduced measles deaths up to 73% between 2000-2018 (1). Thus, vaccine is the most important weapon in reducing global morbidity and mortality related to infectious diseases. However, measles is still one of the leading causes of death with more than 140,000 people died in 2018 (1). Most deaths occur among children under 5 years of age. These children have the greatest risk of developing serious complications, as well as further longe m heal h im ac ,

i h he i

damagi g he imm e

mem

af e i fec i

(2). Consequently, previously-infected children will become more vulnerable to other potentially deadly disease. There are multiple factors for an individual to be unvaccinated, such as healthcare access, individual or parental choice, and contraindication to vaccination (3, 4). Studies found that the major issue which mostly influences parental decision is publicity of false findings about MMR vaccine (measles, mumps, rubella). This key factor may have been precipitated since a publication in 1998 in the United Kingdom, claiming an association between MMR vaccine with autism and bowel disease. Fear of autism resulted in the decline of measles vaccination coverage in the UK from 92% in 1996 to 84% in 2002 (5). Later then, this article was strongly retracted and discredited by WHO, and the author was found guilty and can no longer practice as a medical doctor. In addition, studies in the past 9 years have found no link between MMR vaccine and autism or bowel disease. Unfortunately, this controversy remains a concern for parents and carers regarding MMR vaccine. Further reasons of hestitancy include mistrust in experts, religious convictions, particular beliefs

the risks of vaccination were greater than the severity of measles, and many

more (6). Some of European countries continue to have suboptimal coverage below 95%. This is even more problematic regarding the second dose vaccination coverage, which only reached 90% in 2017 (7). That is why, it is necessary to promote awareness about measles, mumps, and rubella, and its dangers via media campaigns e le

ledge ab

such as public posters. This poster is aimed to raise

MMR acci a i , i be efi , a d

b ia e h a

ha ma

e de

fear among parents and caretakers. This poster also states important contraindications of MMR

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vaccination, that may be beneficial as prevention of emerging misconception regarding the safety of the vaccine. References 1. WHO. Measles - Fact Sheets: World Health Organization; 2019 [cited 2020 April 4th]. Available from: https://www.who.int/news-room/fact-sheets/detail/measles. 2. Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science. 2019;366(6465):599. 3. McHale P, Keenan A, Ghebrehewet S. Reasons for measles cases not being vaccinated with MMR: investigation into parents' and carers' views following a large measles outbreak. Epidemiology & Infection. 2016;144(4):870-5. 4. Pearce A, Law C, Elliman D, Cole TJ, Bedford H. Factors associated with uptake of measles, mumps, and rubella vaccine (MMR) and use of single antigen vaccines in a contemporary UK cohort: prospective cohort study. bmj. 2008;336(7647):754-7. 5. Brown KF, Kroll JS, Hudson MJ, Ramsay M, Green J, Long SJ, et al. Factors underlying parental decisions about combination childhood vaccinations including MMR: a systematic review. Vaccine. 2010;28(26):4235-48. 6. Wilder-Smith AB, Qureshi K. Resurgence of Measles in Europe: A Systematic Review on Parental Attitudes and Beliefs of Measles Vaccine. Journal of Epidemiology and Global Health. 2019. 7. Measles, 1st dose (MCV1): Immunization coverage estimates by WHO region [Internet]. Global Health Observatory data repository. 2019 [cited April 3rd, 2020]. Available from: https://apps.who.int/gho/data/view.main.MCV2vREG?lang=en.

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AMINO | AMSA INTERNATIONAL COMPETITION 19/20

INJECT TO PROTECT: ENDING VACCINE HESITANCY

BACKGROUND Vaccine is one of the most cost-effective interventions to improve health outcomes. Vaccination currently prevents 2-3 million deaths a year, and a further 1.5 million could be avoided if global coverage improved. Since significant decrease in morbidity and mortality is strongly associated with high uptake rates – which are essential for herd immunity to be sustained – vaccine hesitancy must be better understood and addressed. In 2019, WHO has listed vaccine hesitancy as one of the ten global health threats. It refers to delay in acceptance or refusal of vaccines despite availability of vaccination services. At its core, vaccine hesitancy is the behavior that results from the decisionmaking process and reflects a constellation of factors that may influence the decision to accept some or all vaccines in accordance with the recommended schedule. Table 1: Determinants of Vaccine Hesitancy – The 3C’s Model Determinants Complacency Confidence Convenience

Definition Perceived risks of vaccine-preventable diseases are low, making vaccination not viewed as necessary preventive action Distrust in vaccines, in the system that delivers them, and in the policy-makers who decide which vaccines are needed and when Extent to which physical availability, affordability, willingnessto-pay for, geographical ability, capacity to understand, and appeal of immunization services affect uptake

Globally, the top reasons for vaccine hesitancy were: 1) beliefs, attitudes, and motivation about health and prevention, 2) risk/benefit of vaccines and 3) communication and media environment. Major issues were fear of side effects and distrust in the vaccine, lack of perceived risk of vaccine-preventable diseases and the influence of anti-vaccination reports in the media. Below are general recommendations in tackling the current problem: 1) Vaccine hesitancy is a complex and rapidly changing global problem, 2) It is caused by many determinants, making single intervention strategy impossible and 3) Addressing vaccine hesitancy requires an understanding of its magnitude and setting, root cause(s) diagnosis, tailored evidence-based strategies followed by monitoring and evaluation to determine its impact along with possible recurrence of the problem.

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Strategies may include: •Target specific populations; •Engagement of influential leaders •Mandating vaccinations/sanctions for non-vaccination •Social mobilization •Mass media •Improving vaccination convenience and access •Employing reminder and follow-up •Communications training for HCW •Non-financial incentives Since AMSA’s social campaign aim to reverse the growing sense of disbelief towards vaccination by raising awareness, we must first acknowledge why communication is crucial. Scarce communication resources limit the capacity to counter negative information and achieve community support. In conclusion, communication can not only improve knowledge but also influence policy and realize behavioral changes. Mass communication campaigns may be more useful in building the pro-vaccination social norms, while targeted interventions might be more effective in addressing vaccine hesitancy problems. Active and meaningful dialogue-based intervention, particularly those focusing on community engagement and the improvement of healthcare workers communication, were most effective for improved uptake. We should remember that many vaccine-hesitant people are not opposed to vaccination but rather seeking guidance about the issues involved, beginning with the complexity of the schedule and the number of vaccines proposed. They question vaccine’s necessity because most have never seen nor experienced the diseases vaccines are designed to prevent, and they have concerns about its possible adverse effects. Lastly, we decide to take benefits of immunization and drawing on the emotional values around child health as or main focus, since they are messages that particularly resonated in people’s mind. Through this campaign, together we can take part in battling vaccine hesitancy, helping parents to provide the best care for their children while shaping youths’ future vaccine acceptance for a better, healthier, and happier world.

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II.

SCOPE OF CAMPAIGN

Project Title: Inject To Protect Details of Project: §

Project Aim and Purposes Increase community awareness and knowledge regarding the importance of vaccination to counter misconceptions and achieve community support.

Project Objectives Social media publication materials for 7 days (at least one post/day) which are authentic, scientific-based, and feasible to perform in a week.

Benefits Identification For AMSA: Leveraging AMSA’s local and international reputation for its concern towards SDG 3 mainly in communicable disease prevention through vaccination. For the Community: Addressing major issues for vaccine hesitancy and providing credible guidance through meaningful and actively engaging approach.

Limits and Exclusions - This campaign heavily relies on story-based social media (e.g. Facebook, Instagram, Snapchat) which might result in reach and participation limitation - Topic’s broadness and diversity along with short campaign time making in-depth explanation a hard thing to do, since our main focus is must-know information - Mass communication, although proven useful in building the pro-vaccination social norms, might be less effective than targeted population interventions in solving vaccine hesitancy problems

Targets: - Primary: Parents or prospective parents and adolescent - Secondary: Health care workers and school staffs - Tertiary: Influential leaders and stakeholders

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III.

BASIC THEORY

1. 1st Day Material: Vaccines FAQs – Myths and Facts FAQs about vaccine answered in the form of myths and facts followed by explanation, including but not limited to: vaccine safety and side effects, vaccination schedules, protection from diseases, and lastly vaccine types, doses, and ingredients. Material was inspired by Infant Immunization FAQs made by CDC. The Journey of Vaccine: Extensive lab testing followed by rigorous clinical trials was done, it can take several years for the vaccine to be Safety

licensed > If the FDA licenses a vaccine, experts may consider adding it to the recommended immunization schedule > Health experts continue to monitor the vaccine’s safety and effectiveness

Side Effects

Well designed and conducted studies stated that the evidence favors rejection of a causal relationship between MMR vaccine and autism. It is best to stay on schedule, non-standard schedule offer no added

Schedules

benefit and put your children at risk. Remember that children are susceptible to disease, particularly young ones who have the highest risk of complication that could lead to hospitalization or death.

Protection from Disease

Although it is true that babies may get some temporary immunity from mom during pregnancy, but these antibodies wane over a period of 6 – 12 month, making your baby vulnerable to infection. -

Vaccine cannot overload our body’s immune system since it only contain a tiny fraction of antigens that is necessary to induce an

Types, Doses, and

immune response but without the symptoms of the disease

Ingredients -

Getting every needed dose is crucial for giving best protection, sometimes multiple doses are needed to build adequate immunity

2. 2nd Day Material: Immunization Coverage Fact Sheet Vaccine is one of the most successful and cost-effective interventions to improve health outcomes. On this day, we will present global and local data about the significant decrease in mortality and morbidity after vaccine administration. Material was inspired by WHO (globally) and the Ministry of Health of the Republic of Indonesia (locally).

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3. 3rd Day Material: A Brief History of Vaccination One of the most phenomenal chapter in the history of science is the impact of vaccines on human longevity and health. Hundreds of years have elapsed since Edward Jenner invited a method to protect against smallpox, which involved taking material from a blister of cowpox-infected person and inoculating it into another personâ&#x20AC;&#x2122;s skin in 1796. Up until now, successful vaccines have been rationally developed by protection studies in animals, departing from immune responses shown to protect against repeated natural infection and from the use of passive administration of antibodies against specific antigens to show that those antigens should be included in vaccines. 4. 4th Day Material: Common Side Effects of Vaccines The most common side effects after vaccination are minor, such as: pain, swelling or redness on where the shot was given; mild fever; chills; feeling tired; headache; and muscles or joint aches. No need to worry since they will likely go away within a few days. Severe, long lasting side effects are extremely rare â&#x20AC;&#x201C; moreover, health care workers are trained to deal with allergic reactions and treat them immediately. Vaccine Adverse Event Reporting Systems is also available, with purpose to collect and analyzes reports of adverse effect that happen after vaccination. Anyone can submit a report, including parents, patients, and health care professionals. Close monitoring helps to ensure that possible vaccine-associated risks are identified. 5. 5th Day Material: Bon Voyage â&#x20AC;&#x201C; A Guide To Travel Vaccine There is no one size fits all.

Different countries have different vaccination

requirements. The recommended vaccines for travelling depend on a number of factors, including: your age, pregnancy or planning pregnancy, underlying medical conditions, vaccination history, location, itinerary, and season of travel. You should consult your doctor or visit a travel health clinic 6 to 12 weeks before you travel. Reasons are as follow: building up immunity takes time; getting all the doses of the vaccine might require several weeks; your primary doctor may not stock travel vaccine and if your destination requires a yellow fever vaccine, only a limited numbers of clinics have the vaccine and will probably be some distance from where you live.

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Diseases like cholera, hepatitis A, and typhoid are common in developing countries with poor sanitation and limited access to clean water, therefore you should be careful of the food and beverages that you consume. Rabies spreads through a bite, scratch, or lick from infected animals through an open wound. Japanese encephalitis is a serious disease spread by mosquitoes throughout Asia an in the Torres Strait regions of Australia while Meningococcal is spread by close contact with an infected person and more common in sub-Saharan Africa. Lastly, yellow fever – which causes fever, jaundice, along with liver and kidney impairment – is spread by mosquitoes and commonly found in Africa, the Caribbean, Central and South America. Another tips that you might find useful are: CDC’s travel website is useful for finding your vaccination needs, TravWell app enable you to get a personalized packing list, reading current travel notices can inform you about new diseases outbreaks or vaccine recommendation, and lastly visiting your country’s official health website might help to learn about vaccination, insurance, and medical emergency while travelling. 6. 6th and 7th day materials: Instagram Filter & Twibbon We previously have stated several times that our focus is on building active and meaningful engagement within communities, where everyone is included and no one is left behind. For the last two days, we want everyone to take part in battling vaccine hesitancy in order to achieve a better, healthier, and happier world. IG’s bewitching features are the perfect channel to show AMSA’s sense of unity. Furthermore, you’ll also get the chance to express yourself and expand your network by making new friends from all around the world. Please do share your most wonderful moments with us in the spirit of AMSA’s vision: Knowledge, Action, and Friendship. IV.

CAMPAIGN PLANS: 7 DAYS CHALLENGE No. 1. 2. 3. 4. 5. 6. 7.

Date 24/04/20 25/04/20 26/04/20 27/04/20 28/04/20 29/04/20 30/04/20

Materials Vaccines FAQs – Myths and Facts Immunization Coverage Fact Sheet A Brief History of Vaccination Common Side Effects of Vaccines Bon Voyage – A Guide To Travel Vaccine Twibbon Instagram Filter

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Upon completing each day task, participant will get a clue to fill our daily crossword. If the participant successfully complete all tasks and manages to solve each given daily crossword, the horizontal parts of the crossword will form a meaningful sentence. Interesting prize is provided for those who are lucky to find the hidden message.

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ATTACHMENTS 1.1 Campaign example: Day 1 1.1.1 Story

1.1.2 Post

1.1.3 Answers to Story The answers can be accessed by swiping on the middle post.

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1.2 Campaign Example: Twibbon 1.2.1 PNG

1.2.2 Caption “Getting a disease or getting a vaccine can both give you future protection from that disease. The difference is that with the disease you have to get sick to get that protection. With the vaccine you don’t.” (CDC, 2019) Vaccine is one of the most cost-effective health interventions. Vaccination currently prevents 2-3 million deaths a year, and a further 1.5 million could be avoided if global coverage improved. Unfortunately, vaccines have quickly become a victim of their own success. In 2019, WHO has listed vaccine hesitancy as one of the ten global health threats.

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Hesitancy refers to delay in acceptance or refusal of vaccines despite availability of vaccination services. Some question vaccineâ&#x20AC;&#x2122;s necessity because most have never seen nor experienced the diseases vaccines are designed to prevent. Through this campaign, I, (your name), believe that together we can take part in battling vaccine hesitancy, helping parents to provide the best care for their children while shaping youthsâ&#x20AC;&#x2122; future vaccine acceptance for a healthier and happier world! #InjectToProtect #AMSAInternational 1.3 Prize for Crossword Solvers: Wallpaper

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REFERENCES: 1. World Health Organization. Reports of the SAGE working group on Vaccine Hesitancy. Geneva: WHO; 2014. Available on: <https://www.who.int/immunization/sage/meetings/2014/october/SAGE_working_group _revised_report_vaccine_hesitancy.pdf?ua=1> 2. Jarrett C, Wilson R, O’Leary M, Eckersberger E, Larson HJ. Strategies for addressing Vaccine Hesitancy – A systematic review. Vaccine. 2015; 33(34):4180-90 Available on: <https://www.who.int/immunization/sage/meetings/2014/october/3_SAGE_WG_Strategi es_addressing_vaccine_hesitancy_2014.pdf?ua=1> 3. Edwards KM, Hackell JM, Committee on Infectious Diseases, Committee on Practice and Ambulatory Medicine. Countering Vaccine Hesitancy. Pediatrics. 2016; 138(3) Available on: <https://pediatrics.aappublications.org/content/pediatrics/early/2016/08/25/peds.20162146.full.pdf> 4. Centers for Disease Control and Prevention. Infants’ immunization FAQs. Atlanta: CDC; 2019. Available on: <https://www.cdc.gov/vaccines/events/niiw/ed-resources/downloads/f_provider-qacolor.pdf> 5. World Health Organization. WHO and UNICEF Immunization Coverage Estimates: 2018 revision. Geneva: WHO; 2019. Available on: <https://www.who.int/immunization/monitoring_surveillance/routine/coverage/WUENIC _notes.pdf?ua=1> 6. Kementerian Kesehatan Republik Indonesia. Kebijakan Penyelenggaraan Imunisasi. Jakarta: Kemenkes RI; 2019. Available on: <https://www.kemkes.go.id/resources/download/info-terkini/rakerkesnas2019/SESI%20I/Kelompok%205/4-Kebijakan-Penyelenggaraan-Imunisasi.pdf> 7. Kementerian Kesehatan Republik Indonesia. Profil Kesehatan Indonesia 2018. Jakarta: Kemenkes RI; 2019. Available on: <https://pusdatin.kemkes.go.id/resources/download/pusdatin/profil-kesehatanindonesia/PROFIL_KESEHATAN_2018_1.pdf>

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8. Childrenâ&#x20AC;&#x2122;s Hospital of Philadelphia. Vaccine History: Developments by Years. Philadelphia: CHOP; 2019. Available on: < https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-history> 9. U.S. Department of Health and Human Services. Vaccine side effects. Washington D.C.: U.S. Department of Health and Human Services; 2020. Available on: <https://www.vaccines.gov/basics/safety/side_effects> 10. Centers for Disease Control and Prevention. Making the Vaccine Decision: Addressing Common Concerns. Atlanta: CDC; 2019. Available on: <https://www.cdc.gov/vaccines/parents/why-vaccinate/vaccine-decision.html> 11. U.S. Department of Health and Human Services. Vaccines for Travelers. Washington D.C.: U.S. Department of Health and Human Services; 2020. Available on: < https://www.vaccines.gov/who_and_when/travel> 12. Australian Government Department of Health. Immunization for Travel. Canberra: Australian Government Department of Health; 2019. Available on: <https://www.health.gov.au/health-topics/immunisation/immunisation-throughoutlife/immunisation-for-travel> 13. Centers for Disease Control and Prevention. Need Travel Vaccines? Plan Ahead. Atlanta: CDC; 2018. Available on: <https://wwwnc.cdc.gov/travel/page/travel-vaccines>

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THE PROPOSAL OF ONLINE SOCIAL CAMPAIGN WORLD IMMUNIZATION WEEK 2020 AMSA International

STRIVING TOWARDS 100% IMMUNIZATION COVERAGE AND ZERO VACCINATION MISCONCEPTION

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1. BACKGROUND Immunization is one of the most successful public health intervention. It prevents an estimated 2 to 3 million death every year. Immunization almost eradicates polio, with only 3 remaining endemic countries, Pakistan, Nigeria, and Afghanistan. Between 2000 and 2017, deaths due to measles declined up to 80%, saving 21.1 million lives. And up until March 2019, maternal and neonatal tetanus, a disease with case fatality rate range from 70 to 100 % among neonates, have been eliminated worldwide except in 13 countries. 1 Despite the fact that the number of vaccinated children is constantly increasing, there are still a great amount of unvaccinated children. One of the vaccine that is commonly used as an indicator on how well a country can provide routine immunization is the diptheria, tetanus, and pertussis vaccine (DTP). According to World Health Organization, 86% of children worldwide vaccinated with 3 DTP vaccine in 2018, accounting up to 116.3 million infants. 2 The percentage of vaccine coverage showed an increase compared to the year 2000 and 1980, 72% and 20% respectively. The 86% of vaccinated children is definitely not sufficient. It is due to the fact that the Global Vaccine Action Plan target is 90% or greater coverage, is have yet to achieved. Practically the percentage coverage in 2018 remains unchanged from 2016, leaving 19.4 million children under the age of 1 year vulnerable to vaccine preventable diseases, and an estimated 13.5 million children in the same age group did not benefit from any vaccination. The upward trend in coverage has increased by only 5% in the past decade and has plateaued. 3 There are several factors that inhibit the effort to achieve the Global Vaccine Action Plan target, one of them is the anti-vaccination or anti-vax movement. A growing number of parents refused to vaccinate their kids due to several reasons, including irrational fears. This rising movement will threatens the safety of general public and immunodeficiency people who rely on herd immunity. Anti-vax-movement caused multiple breakouts of measles, a previously considered eliminated disease, throughout different parts of the world, especially in the global northern countries infecting dozens of patients and even causing deaths. These outbreak was reported to have occurred as a direct result of a drop in vaccination rates following the dismissal in anti-vax community.4 The obvious consequence can be seen in the vaccination coverage percentage that are essentially stagnant in recent years.

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World Health Organization held World Immunization Week each year celebrated in the last week of April.5 The objective of World Immunization Week is to advocate vaccine usage as a protection of all ages against disease, blabla. Thereby, the authors propose innovative campaign project to increase public awareness about the importance of vaccinations in the community as a comprehensive approach in striving towards a world with 100% Immunization coverage and zero misconception on vaccination. 2. SCOPE OF CAMPAIGN a. Participant of Campaign: General

: All social media users

Particular

: AMSA I

b. Target of Campaign : General

: All social media users, general public, and health students

Particular

: Parents with unvaccinated kids and people that has not been

vaccinated c. Media of Campaign : Instagram

: Announcement, campaign material, and story challenge

Twitter

: Announcement and campaign material

Website

: Announcement and campaign material

Facebook

: Announcement and campaign material

3. BASIC THEORY Definition of Immunization Immunization is the process which individuals are protected against illness caused by infection with microorganisms (pathogens). Vaccine is the biological preparation given for immunization. Vaccination is the administration of a vaccine

immune system develop protective

mechanism from a disease. Most vaccines are given by injection as they are not absorbed reliably through intestines. Vaccines contain a relatively small dose of microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. By stimulating adaptive immunity, vaccines help prevent sickness and death from an infectious disease.

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Mechanism of Immunization I

to protect itself by combating or eliminating potentially harmful

foreign invaders.6 The immune system consists of a specialized cells, known as white blood cells, and their products, such as antibodies. These cells are spread throughout the body, not only in the bloodstream, but also in lymph glands, the spleen, and other mucosal tissues. When white blood cells detect the presence of pathogens, lymphocytes will be activated.7 Lymphocytes are categorised into two types: B-cells and T-cells. Both types of lymphocytes, like all blood cells, are derived from common stem cells in the bone marrow.6 T-cells respond to infections by releasing chemicals signalling substances called cytokines, which trigger inflammation. Later, T-cells help combat pathogens by killing cells that harbour a pathogen inside them.8 B-cells make antibodies, which are complex proteins that attach to specific pathogens or to the toxins. When antibodies attach to a pathogen, they flag it for destruction, and when they attach to a toxin, they neutralize its ability to cause damage to cells. 9 In most cases, the result of these immune responses is termination of infection followed by repair a

a a

stimulated lymphocytes, do survive for long periods in the absence of antigen and rapidly stimulate immune response when re-exposed to the antigen10. Nevertheless, some infections exceed immune ca ac

, ca

a .

Vaccines are a way of artificially activating the immune system to protect against infectious disease. Vaccination exposes the person to a pathogen that has been stripped of its disease-inducing capability (the pathogen is attenuated) but can still induce antibody formation. 6 Importance of Immunization Immunization creates herd immunity. Herd immunity may be defined as the resistance of a group of people to a disease to which a large proportion of the members of the group are immune. 9 When lots of people in an area are vaccinated, fewer people get sick and reduce the probability of transmission. Herd immunity protects not only people who are immune, but also people who can't get vaccinated because their immune system is weak and vaccines might make them sick. This includes babies, people with vaccine allergies, and anyone with an immune-suppressing disease

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like HIV, cancer, or Diabetes Mellitus Type I. By immunizing a large part of the population, the rest will also be protected because of herd immunity, that way everyone is protected.9 Immunization prevents death and control a large number of infectious disease in all age groups every year. Some diseases that can be prevented through immunization are 10 :

Tuberculosis Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, an acid-fast bacillus that usually affects the lungs, but may spread and invade other body systems. TB is highly contagious and is transmitted from person-to-person in airborne droplets and becomes the leading cause of death from infectious disease throughout the world 11. Globally, an estimated 10.0 million (range, 9.0 11.1 million) people fell ill with TB in 2018.12 Bacillus Calmette GuĂŠrin (BCG) vaccine is a vaccine used against TB. One dose is recommended in healthy babies as close to the time of birth as possible. 13 Measles Measles is an airborne disease, caused by measles morbillivirus, which spreads easily through the coughs and sneezes of infected people. It may also be spread through direct contact with mouth or nasal secretions. The first sign is usually a high fever. A runny nose, a cough, red and watery eyes, and small white spots inside the cheeks can develop in the initial stage. After several days, a rash erupts, usually on the face and upper neck. 14 Measles is still common in many developing countries particularly in parts of Africa and

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Asia. Unvaccinated young children and pregnant woman are at highest risk of measles and its complications, including death.15 Diphteriae Diphtheria is an acute, toxin-mediated upper respiratory tract disease caused by the bacterium Corynebacterium diphtheriae. This disease generally attacks children, body parts that usually are invaded are the nose, tonsils, pharynx, and larynx, but clinical manifestations can also be seen on the skin. Complications due to toxins from the bacteria include myocarditis and neuritis may lead to death. 16 Pertussis Pertussis also known as whooping cough, is a highly contagious respiratory disease, caused by the bacterium Bordetella pertussis. It usually starts with cold-like symptoms and maybe a mild cough or fever. Pertussis is known for uncontrollable, violent coughing which often makes it hard to breathe. Pertussis can affect people of all ages, but can be very serious, even deadly, for babies less than a year old. The best way to protect against pertussis is by getting DPT vaccine.17 Tetanus Tetanus is an acute, often fatal, disease caused by an exotoxin produced by the grampositive bacterium Clostridium tetani. It is characterized by generalized rigidity and convulsive spasms of skeletal muscles. The muscle stiffness usually involves the jaw (lockjaw) and neck and then becomes generalized. 18 Polio Polio, or poliomyelitis, is a disabling and life-threatening disease caused by the poliovirus. People with poliovirus infection will have flu-like symptoms that may include sore throat, fever, tiredness, nausea, headache, and stomach pain. A smaller proportion of people with poliovirus infection will develop more serious symptoms that affect the brain and spinal cord. Paralysis is the most severe symptom and can lead to permanent disability and death19. Hepatitis B

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Hepatitis B virus (HBV) infection is a worldwide problem and may cause hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC) 20. Infection with HBV in infancy or early childhood may lead to a high rate of persistent infection (25-90%), while the rates are lower if infection occurs during adulthood (5-10%)21. In most endemic areas, infection occurs mainly during early childhood and mother-to-infant transmission accounts for approximately 50% cases21. Infants should get their first dose of hepatitis B vaccine at birth and will usually complete the series at 6 months of age. Children, adolescents younger than 19 years of age who have not yet gotten the vaccine, and immunocompromised patients should also be vaccinated22. HPV Human Papilloma Virus (HPV) is the most common sexually transmitted infection. There are many different types of HPV. Some types cause mild problems including genital warts. Other can cause cervical and other cancer including cancer of the vulva, vagina, penis, and in the back of the throat, including the base of the tongue and tonsils (oropharyngeal cancer)23.

4. CAMPAIGN PLAN a. Timeline on Instagram Day

Story & Highlights

Post

Explanation

Announcement

Opening

Basic information about Vaccination

Explanation 1

Myths or facts Challenge

Announcement to join the challenge and link to download the IG story template

Challenge 1

Importance of Vaccine Explanation 2

Find The Words Challenge

Announcement to join Challenge 2 the challenge

Explanation about Myth or Fact

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Explanation 3

1. Closing Announcement 2. Winner Announcement

Closing statement

B. Material Overview 1. Day 1 [Three Different Feeds and Instastory]

2. Day 2 [Single Feed with Multiple Post]

3. Day 3 [Single Feed and Instastory Challenge]

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Closing

4. Day 4 [Single Feed with Multiple Post]

5. Day 5 [Single Feed and Instastory Challenge]

6. Day 6 [Single Feed with Multiple Post]

7. Day 7 [Four Different Feeds]

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8. Overall Feeds

C. Caption Post 1. Day 1 : [World Immunization Week 2020] Hello People of Tomorrow!

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Starting from this day, World Immunization Week officially begins. Join our campaign to help spread the facts and educate others about immunization. #VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 2. Day 2 : [What is Vaccine?] Hello People of Tomorrow! B

learn about the basic information about immunization!

#VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 3. Day 3 : [Challenge: Myths or Facts?] Hello People of Tomorrow! C a our

b a a H

Fac

!F a

hashtags #VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts and tag @amsa_intl! #VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 4. Day 4 : [Myths and Facts about Immunization] Hello People of Tomorrow! L

immunization.

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#VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 5. Day 5 [Challenge : Find the Words!] Hello People of Tomorrow! We dare you to participate World Immunization Week online campaign by joining c a

a a

The template can be found on our instagram Highlight. Post your answer on your snapgram, use the hashtags #VaccineWorks #Vacc

B a T U

#C c T Fac a

a @a

#VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 6. Day 6 : [Importance of Immunization] Hello People of Tomorrow! Do you know why we need to get vaccinated? Do you know what is herd immunity? Swipe to know more! #VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts 7. Day 7 : [Closing] Hello People of Tomorrow!

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Today is the last day of World Immunization Week 2020. Thank you for your participations in the challenges and congratulations to all the winners. Keep educating yourself and others and build a healthy community, together. #VaccineWorks #VaccineBeatsTheUnseen #CheckTheFacts

REFERENCES 1. Global Vaccine Action Plan [Internet]. World Health Organization. 2020 [cited 8 April 2020]. Available from: https://www.who.int/immunization/global_vaccine_action_plan/en/ 2. Vaccination and Immunization Statistics - UNICEF DATA [Internet]. UNICEF DATA. 2020 [cited 8 April 2020]. Available from: https://data.unicef.org/topic/childhealth/immunization/ 3. Immunization coverage [Internet]. World Health Organization. 2020 [cited 8 April 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/immunizationcoverage 4. Hussain A, Ali S, Ahmed M, Hussain S. The Anti-vaccination Movement: A Regression in Modern Medicine. Cureus [Internet]. 2018 [cited 8 April 2020];. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122668/ 5. World Immunization Week 2020 #VaccinesWork for All [Internet]. World Health Organization. 2020 [cited 8 April 2020]. Available from: https://www.who.int/newsroom/campaigns/world-immunization-week/world-immunization-week-2020 6. Sherwood L. Human physiology from cells to systems Ninth Edition. Appetite. 2016. 7. Gowans JL, McGregor DD, Cowen DM, Ford CE. Initiation of immune responses by small lymphocytes. Nature. 1962; 8. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974; 9. M

K. Ja

. Ja

. 2016.

10. Abbas, Abul K, Lichtman, Andrew H. and Pillai S. Basic Immunology: Functions and Disorders of the Immune System, Fifth Edition. Elsevier Health Sciences. 2015. 11. Gordis L. Epidemiology Gordis. Epidemiology. 2008. 12. J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo JL. Ha P c I a M c . JAMA J A M A c. 2018;

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13. McCance KL, Huether SE. Pathophysiology The Biologic Basis for Disease in Adults and Childeren Sixth Edition. MOSBY ELSEVIER. 2014. 14. World Health Organization. Global Tuberculosis Report. Blood. 2015. 15. BCG vaccines: WHO position paper

February 2018. Relev Epidemiol Hebd. 2018;

16. World Health Organization. Measles Fact Sheet 2015. WHO. 2015. 17. Hamboursky J. Immunology and Vaccine-Preventable Diseases Epidemiol Prev Vaccine-Preventable Dis. 2015;

Pink Book - Varicella.

18. Centers for Disease Control. Pertussis | Whooping Cough | Causes and Transmission | CDC. Centers Dis Control Prev. 2017; 19. CDC. CDC Global Health - Polio - What Is Polio? Centers from Disease Control and Prevention. 2017. 20. Ganem D, Prince AM. Hepatitis B Virus Infection - Natural History and Clinical Consequences. New England Journal of Medicine. 2004. 21. Chang MH. Hepatitis b virus infection. In: Liver Disease in Children, Fourth Edition. 2011. 22. Vaccine information statement. J Pediatr Heal Care. 1999; 23. Centers for Disease Control and Prevention (CDC). Genital HPV Infection Sheet. CDC Fact Sheets. 2014;

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World Immunization Week Competition 2020 by AMSA International Asian Medical Studentsâ&#x20AC;&#x2122; Association (AMSA) International

Online Social Media Campaign Proposal Get Children Vaccinated, Let the Immunity Encouraged to Keep Them Protected #ImmunizationMatters Arranged By: Chatrine Angelica Dwi Christy Angela Lady Kezia Joyna Getruida Sopaheluwakan AMSA-UKI Batch 2018 Faculty of Medicine Universitas Kristen Indonesia 2020

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Background World Immunization Week is a health campaign activity carried out by people

globally to raise awareness about the importance of using vaccines as a preventative measure against diseases that can occur in various ages. The immunization week was first observed globally in 2012 where more than 180 countries around the world participated in this activity.1 The World Immunization Week is then held on the weekends in April, on April 24-30 every year. Vaccines can be said to be the most cost-effective disease prevention after washing hands, where vaccination obtained through immunization has an important contribution in reducing the incidence of disease as well as the mortality rate due to the disease.2 Every year it is estimated that the vaccine prevents 5 million deaths caused by smallpox, 2.7 million cases of measles, 2 million cases of neonatal tetanus, 1 million cases of pertussis, 600,000 cases of paralyzed polio, and 300,000 cases of diphtheria worldwide.2 Although this vaccine is effective in reducing mortality, it can be estimated that up to 400,000 people die from vaccine-preventable diseases. In 2013, there were about 22 million infants who had not been immunized completely with routine vaccines and more than 1.5 million children under five died of preventable diseases with existing vaccines.1 This is because children who are not vaccinated do not have antibodies to germ antigens, so the body is not strong enough to fight the disease.1,3 Besides being related to economic conditions, rejection from parents is one of the causes of a child's being late or not even vaccinated. Based on a literature study conducted in 2016, 4 main reasons cause parental concerns about immunization. These reasons are religion, personal beliefs or philosophical reasons, security issues, and the desire to get more information from health care providers.4 It is even said that some parents consider vaccination dangerous for their children, they also say that children who are not vaccinated are healthier than children who are vaccinated.4,5 Rising for our background, we have the desire to plan an online campaign focused on increasing knowledge and awareness of the importance of immunization and dispelling myths that exist in the community that results in doubts about vaccination. The campaign we are doing is â&#x20AC;&#x153;Get Children Vaccinated, Let the Immunity Encouraged to Keep Them Protected #ImmunizationMattersâ&#x20AC;?.

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II.

Scope of Campaign

Participant of Campaign -

General

: All Social Media Users

Particular

: AMSA Internationalâ&#x20AC;&#x2122;s Members

Target of Campaign -

General

: All Social Media Users

Particular

: Parents, Health-Care Workers, and Policy Makers.

Media of Campaign

: Instagram (post and story), Facebook (post) Line/WhatsApp (announcement and invitation), and YouTube (animation video).

III.

Basic Theory

A. What is Immunization In general, immunization cannot be confused with vaccination. Immunization is a process in which a person forms his immune system or becomes resistant to diseases where the body will form an immune system itself.6 Vaccination is a therapy with a vaccine (usually by injection, oral, or intranasal) to enhance immune system against infection in the future.7 B. Types of Vaccine The vaccine contains microorganisms as an entire or its components that can cause disease. Vaccines can be classified based on their construction.7,8 1. Live-attenuated: vaccine-derived from living organisms that are weakened so that their ability to cause disease is decreased (Measles, Mumps, Rubella, Varicella zoster). 2. Inactivated: vaccine-derived from organisms that are no longer active either due to chemical influences, the influence of heat, or other conditions (Hepatitis A, Influenza, Pneumococcal polysaccharide).

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3. Recombinant sub-unit: vaccine-derived from components of disease-causing organisms (Hepatitis B). 4. Toxoid: vaccine-derived from bacterial toxins that are no longer active (Tetanus, Diphtheria). 5. Conjugate polysaccharide-protein: vaccine-derived from the conjugation of polysaccharides to protein (Haemophilus influenza type b) C. How do Vaccine Work When germ invades the body, the immune system will release red blood cells to carry oxygen and white blood cells to fight against the germ. In the first invasion, the body will need time to put up a fight, but after the second infection, the body has remembered the defense mechanism from the first invasion. Antigens will be remembered via T-lymphocytes (memory cells) and B-lymphocytes will produce antibodies to attack the germ after exposure of the identified antigen. The vaccine develops immunity by mimicking infection. Vaccines do not usually produce infections but cause the immune system to produce T-lymphocytes and antibodies. After the effects of the vaccine are exhausted, the memory cells will remember the antigen given and the B-lymphocytes will remember how to fight the disease in the future.8 D. Why Vaccine is Important There are various purposes for why vaccines demand to be given to everyone, including:9 1. Vaccination saves children's lives. 2. Immunization is the primary right and strategic component of poverty-reduction programs. 3. With the vaccination, the disease is easier to control and even be eliminated. 4. Immunization is cost-effective but will provide great benefits for the community. 5. There is still a risk of diseases that can be prevented by vaccines. 6. Immunization is used as an indicator to assess the capacity of the health system and access to primary health care.

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E. Why Parents Refuse to Vaccinate Their Children Based on the literature study in 2016, there are 4 main reasons why parents refused to vaccinate their children:4 1. Religious reasons: this reason relates to the core belief of parents which is a deliberate decision in which a full rejection of all vaccines is made 2. Personal beliefs or philosophical reasons: Many parents believe that the best immunity is natural immunity produced by the body directly. In addition, there is an opinion that allowing children to be affected by the disease makes their immune systems stronger when they are adults. 3. Safety concern: when parents get information from various sources, many things make them doubt the safety and success of vaccination. 4. Wish for Extra Education: they want to be able to make decisions based on information about their child's health by knowing both the benefits and risks associated with each vaccine F. Effect if Children Unvaccinated If a child does not get vaccinated, then he is at risk of contracting vaccine-preventable diseases. However, not only about himself, unvaccinated children can infect other people around the public.10 G. How to Increase Awareness of Parents to Vaccinate Their Children The first thing to do to increase parents' awareness of the importance of immunization is to find out why they are hesitant or not to vaccinate their children. But the main and necessary step is health education about the importance of vaccines for children and what risks will occur if a person is not vaccinated.

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IV.

Campaign Plan

TITLE : Get Children Vaccinated, Let the Immunity Encouraged to Keep Them Protected HASHTAG : #ImmunizationMatters #WIW2020 TIMELINE D A Y

Instagram (@amsa_intl and

Line and

@getvaccinechildren)

Post

6 Common Announcement Misconceptions

Misconceptions

of WIW 2020

about Immunization*

YouTube

Story

6 Common 1

Facebook

about Immunization*

This or That

Twibbon

Parental Tips

Invitation to

during

Join Campaign

Child’s

by Posting

Immunization

Twibbon

GIF

Challenge Question

about Immunization Share Animation

Video about Immunization

@amsa_intl’s post Answer Key of Day 5’s

Invitation to check and

Animation

Video about

@amsa_intl’s

Immunization

post

Question 7

BINGO

*8 slides compile into ONE post (for Instagram and Facebook post Day 1)

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Overview of Design Day 1 Instagram and Facebook Post (8 slides compile into ONE post)

Caption: [6 Common Misconceptions about Immunization] Greetings People of Tomorrow! With this post, AMSA International proudly announces the World Immunization Week online social campaign with the title “Get Children Vaccinated, Let The Immunity Encouraged to Keep Them Protected“ that focuses on raising people’s awareness and knowledge regarding the importance of vaccinations and other forms of immunization. This campaign will be held in a week, starting from today, and is mediated by Facebook, Instagram posts, and stories. You can follow their campaign on instagram @getvaccinechildren and this account itself. We are looking forward to your participants by following our instagram and facebook account for joining challenges, games, quizzes, and posting a twibbon. Follow our progress for more info! #ImmunizationMatters [space] #WIW2020 Day 2 Instagram Story (This or That Template)

Day 3 Instagram Story (Steps Getting Immunization)

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Day 3 Instagram and Facebook Post (Twibbon) Caption*: Greetings People of Tomorrow! We are inviting all AMSA International to join World Immunization Week online social campaign with the title Encouraged to Keep Them Protected“ by posting our twibbon in individual instagram account. These are steps to join our twibbon campaign: 1. Download the twibbon from https://bit.ly/GetVaccineChildren 2. Choose your photo and upload it through instagram and facebook with the caption included in the link 3. Don’t forget to follow and tag @amsa_intl @getvaccinechildren Don’t wait any longer, post your twibbon now! #ImmunizationMatters [space] #WIW2020 * The caption is then used as a broadcast message on Line and WhatsApp Day 4 IgStory (GIF)

Day 5 IgStory (Question)

Day 6 IgStory (Answer)

Day 7 IgStory (BINGO)

Messages for Line and WhatsApp Day 1 Greetings People of Tomorrow! AMSA International proudly announces the World Immunization Week online social campaign with the title “Get Children Vaccinated, Let The Immunity Encouraged to Keep Them Protected“ that focuses on raising people’s awareness and knowledge regarding the importance of vaccinations and other forms of immunization.

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This campaign will be held in a week, starting from today, and is mediated by facebook, instagram posts and stories. You can follow their campaign on instagram @getvaccinechildren, @amsa_intl, and AMSA International facebook account. We are looking forward to your participants by following our instagram account for joining challenges, games, quizzes, and posting a twibbon. Follow our progress for more info! Thankyou, AMSA International! Day 3 (Just like the Instagram caption for conducting campaigns using twibbon) Day 6 Greetings People of Tomorrow! We are inviting all AMSA International to join World Immunization Week online social campaign with the title “Get Children Vaccinated, Let The Immunity Encouraged to Keep Them Protected“ by checking out our short animation video on instagram (@amsa_intl), youtube channel (link), and AMSA International facebook account. Also, please share the video to other people through individual social media accounts. Thankyou, AMSA International! YouTube, Facebook, and Instagram Video Caption (Animated Video) https://drive.google.com/open?id=1i-_bijHEt-xF3DIpD2h0bwnuZHEHArJ6 Facebook and Instagram Video Caption [Get Children Vaccinated, Let The Immunity Encouraged to Keep Them Protected] Greetings People of Tomorrow! With this post, AMSA International proudly presents a short animation which illustrates how vaccine works and what challenge the world is facing right now regarding immunization. We hope this short animation can achieve our aim on raising people’s awareness and knowledge regarding the importance of vaccinations and other forms of immunization. As we encourage you who is willing to join this online social campaign, please share this post to other people through individual social media account. #ImmunizationMatters #WIW2020

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YouTube Caption Title: [SHORT ANIMATION] World Immunization Week 2020 Description: “Get Your Children Vaccinated, Let The Immunity Encouraged to Keep Them Protected” AMSA International proudly presents a short animation which illustrates how vaccine works and what challenge the world is facing right now regarding immunization. We hope this short animation can achieve our aim on raising people’s awareness and knowledge regarding the importance of vaccinations and other forms of immunization. As we encourage you who is willing to join this online social campaign, please share this post to other people through individual social media accounts.

Reference: 1. World Health Organization. Campaign Essentials: World Immunization Week 2013 [Internet].

[Cited

2020

Apr

7].

Available

from:

https://www.who.int/campaigns/immunizationweek/2013/WIW_campaign_essentials.pdf?ua=1 2. RĂŠmy V, ZĂśllner Y, Heckmann U. Vaccination: the cornerstone of an efficient healthcare system. J Mark Access Health Policy. 2015; 3:10. 3. Center for Disease Control and Prevention. Vaccine & Immunizations. USA: CDC. 2018 May 16 [Cited 2020 Apr 7]. Available from: https://www.cdc.gov/vaccines/vacgen/howvpd.htm 4. McKee C, Bohannon K. Exploring the Reasons Behind Parental Refusal of Vaccines. J Pediatr Pharmacol Ther. 2016 Mar-Apr; 21 (2): 104-109. 5. Kajetanowicz A. Why parents refuse immunization? [Abstract]. Wiad Lek. 2016; 69 (3 Pt 1): 346-51. 6. World Health Organization. Immunization [Internet]. [Cited 2020 Apr 8]. Available from: https://www.who.int/topics/immunization/en/ 7. Plotkin SA. Vaccine Fact Book 2012. Pennsylvania: PhRMA; 2012. 8. Center for Disease Control and Prevention. Understanding How Vaccine Work [Internet]. USA: CDC. 2018 Jul [Cited 2020 Apr 8]. Available from: https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-understandcolor-office.pdf 9. World Health Organization. Seven Key Reason Why immunization must remain a priority in the WHO European Region [Internet]. [Cited 2020 Apr 8]. Available from: http://www.euro.who.int/__data/assets/pdf_file/0017/84302/Seven_Key_Reasons.pdf 10. Immunization Action Coalition. What If You Don't Vaccinate Your Child? [Internet]. Minnesota: IAC. Date Unknown [Cited 2020 Apr 8]. Available from: https://www.immunize.org/catg.d/p4017.pdf

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Hepatitis B Vaccination for Health Workers

Abstract

Background : Among other infectious diseases, Hepatitis B and C Virus (HBV and HCV) are the most frequently occupational exposure related disease in health workers and responsible for 96% of all hepatitis mortality. Hepatitis B Vaccine (Hep B vaccine) is recommended by WHO as one of ten immunizations for health workers. Number of HBV infections decreased among vaccinated health workers. Purpose : To educate medical students about WHO recommendation of 10 immunizations for health workers and invite them to get Hep B vaccine before clinical year. Scope : Participants are all social media users, especially AMSA International. Targets are medical students and health workers (general) and pre-clinical medical students, clinical medical students, doctors, nurses (specific). The media used in campaign are Instagram and LINE. Basic theory : WHO suggests 10 vaccines for health workers, including Hep B vaccine. It is able to prevent HBV infection which contaminates 67,7% sharp instruments injured health workers. WHO recommends Hep B vaccine for self-protection against occupational related disease. Campaign plan : Beat Hepatitis B campaign will be held in a week through two social media. Instagram is used for publishing facts of World Immunization Week, AMSA International, 10 Vaccines Recommendation from WHO, and Hep B vaccine related to campaign. On day 2, there will be an invitation to twibbon-campaign. On day 5, another invitation is going to be posted to repost campaign s quizzes through Story Instagram, followed by answers on the next day. LINE is used for sending announcement and invitation of the campaign through representatives.

Keywords : Hepatitis B vaccine, health workers, occupational related disease

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WORLD IMMUNIZATION WEEK 2020 BY AMSA INTERNATIONAL ASIAN MEDICAL STUDENTS’ ASSOCIATION – INDONESIA

Online Social Media Campaign Proposal

Hepatitis B Vaccination for Health Workers by: Febby Gunawan Siswanto

AMSA-UNS Batch 2018

Chalista Putri Tessalonika Ambarita

AMSA-UNS Batch 2018

Lyviana Patrishia Purnata

AMSA-UNS Batch 2018

FACULTY OF MEDICINE SEBELAS MARET UNIVERSITY SURAKARTA

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Background World Immunization Week (WIW) is an annual awareness week supported by World Health Organization (WHO) and partners on April 24th to 30th. Since 2012, the celebration has been running every year to support immunization worldwide (1). Accordance to WHO recommendation, there are 22 immunizations globally (2). Ten of them are selected vaccinations for health care workers. Hepatitis B vaccine (Hep B vaccine) is included as a suggested thing for health workersâ&#x20AC;&#x2122; self-protective action (3). Hepatitis B Virus (HBV) are reported as deathly viruses. Together with Hepatitis C Virus (HCV), they are responsible for 96% of all hepatitis mortality. Thus, World Health Assembly through Global Health Sector Strategy on viral hepatitis 2016-2021 endorses actions to reduce new viral hepatitis infections by 90% as a public health threat by 2030 (4). Among other infectious diseases, HBV and HCV are the most frequently occupational exposure related disease in health workers. The risk is three times higher in percutaneous transmission than mucosal-cutaneous exposure. According to WHO, HBV contaminates 67,7% health care workers who get injured by a sharp instrument, while HCV affects the rest (5). The data showed that HBV infection remains an urgency problem in occupational related disease. Fortunately, infection of HBV can be prevented by Hep B vaccine since 30 years ago (6). It is highly recommended by WHO in the health workerâ&#x20AC;&#x2122;s immunization schedule (3). The incidence of acute and chronic HBV infection becomes rare among health workers who respond well to Hep B vaccine (7). Rising from the background, we have concern in planning an online campaign which is focused on supporting Hep B vaccine for health workers. This campaign educates medical students about WHO recommendation of 10 immunizations for health workers and invite them to get Hep B vaccine before clinical year.

II.

Scope of Campaign 1. Participants of Campaign -

General : All social media users

Particular : AMSA International

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2. Targets of Campaign : -

General : Medical students and health workers

Particular : Pre-clinical medical students, clinical medical students, doctors, nurses

3. Media of Campaign : Instagram (facts, quizzes and twibbon) and LINE (announcement and invitation) III.

Basic Theory 1. Ten immunizations recommendation from WHO WHO recommends ten vaccinations for health workers as a selfprotective action for occupational-related diseases. There are BCG, Polio, Diphtheria, Measles, Rubella, Meningococcal, Influenza, Varicella, and Pertussis, and Hepatitis B (3). The schedule, composition, and administration route are written in appendix 1. 2. Hepatitis B Virus (HBV) as occupational disease of health worker HBV causes acute and chronic liver diseases. It leads the patients to liver cancer and death (8). Yet, HBV contributes occupational disease burden among health care workers. There are two HBV infections every three sharp instrument injury cases. The highest transmission route remains percutaneous procedure by health workers (5). Unvaccinated health workers are susceptible to HBV infection (7). 3. Hepatitis B vaccine (Hep B vaccine) Hep B vaccine is able to protect people from HBV infection. There are at least 3 doses of Hep B vaccine for each person. The first dose is given within 24 hours after birth and followed by 2-3 additional doses that are usually given at the same time as the first and third doses of DTP-containing vaccine (DTPCV) (3). Hep B vaccine contains HBsAg protein (9). They are administered by intramuscular injection (3). Information related to Hep B vaccine are written in appendix 2.

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Campaign Plan TITLE

: Beat Hepatitis B

GENERAL CAPTION

: Beat Hepatitis B, Be A Fit Health Worker

HASHTAGS

#BeatHepatitisB

#Vaccineforhealthworkers

#VaccineWorksforAll #WIW2020 #VIVAAMSA TIMELINE

: Instagram (made in day 1)

Day

IV.

Story

Post

Uploading

12 Posts

welcoming story and video

LINE

Sending online

1. Introduction about World

announcement of

Immunization Week and

the campaign to

AMSA International in

regional

general (1 post)

chairpersons of all

2. A fact about immunization in chapters AMSA general (1 post)

International

3. A question about health workerâ&#x20AC;&#x2122;s vaccinations (1 post) 4. Title of the campaign and its purpose (1 post) 5. WHO recommendation for health workerâ&#x20AC;&#x2122;s immunization (8 posts) : BCG, Polio, Influenza, Measle and Rubella, Pertussis and Diphtheria, Meningococcal, Varicella, and Hepatitis B 2

Uploading twibbon example

12 posts

Sending online

1. Highlight of Hepatitis B (3 posts)

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invitation to all representatives to

2. Facts about Hepatitis B disease (3 posts) 3. Invitation for joining the campaign (4 posts)

post the twibbon and forward the invitation to their universities

4. Tutorial for joining the campaign (1 post) 5. Example of twibbon (1 post) 3

Reposting

Facts about Hepatitis B vaccination

twibbon

(6 posts)

Reposting

Quiz time (3 posts)

twibbon 5

Reposting

Answers of quizzes day 4 (3 posts)

Sending online

twibbon and

invitation to all

uploading story

representatives to

quizzes

join the story quizzes and forward the invitation to their universities

Uploading

Facts about Hepatitis B vaccination

answers for

(3 posts)

Story Quizzes 7

Uploading story of gratitude

6 posts 1. Facts about Hepatitis B vaccination (1 post) 2. Reminder for get hepatitis B vaccination (1 post) 3. Invitation to keep sharing the information to others (1 post) 4. Gratitude (3 posts)

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The full materials will be listed in appendix 1-3. Materials can be downloaded in bit.ly/BeatHepatitisB (Email: beathepatitisb@gmail.com Instagram: @BeatHepatitisB ) The story photos for Instagram are attached below :

Overview photos for Instagram posts

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Line messages for the campaign Day 1 [Beat Hepatitis B, Be A Fit Health Worker] Greetings People of Tomorrow! With this post, we are announcing to AMSA International about World Immunization Week online campaign entitled â&#x20AC;&#x153;Beat Hepatitis Bâ&#x20AC;? that is focused on supporting Hepatitis B vaccination for health workers. This campaign will be held in a week, starting from today, and mediated by instagram account : @BeatHepatitisB. We are looking forward to your participants by following our social media account and sharing interactive stories on instagram. All the campaign materials can be downloaded in bit.ly/BeatHepatitisB Thank you, AMSA International! Viva-AMSA! #BeatHepatitisB #Vaccineforhealthworkers #VaccineWorksForAll #WIW2020 #VivaAMSA

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Day 2

Day 5

[Beat Hepatitis B, Be A Fit Health Worker]

Greetings People of Tomorrow!

With this post, we are inviting you to support World Immunization Week online campaign entitled “Beat Hepatitis B” by posting a twibbon in Instagram Story. The twibbon can be downloaded in bit.ly/BeatHepatitisB

With this post, we are inviting you to join a quiz “Beat Hepatitis B” campaign in Instagram Story. The quiz sheet can be downloaded in bit.ly/BeatHepatitisB.

Our campaign focuses on Hepatitis B vaccination for health workers. Kindly follow our instagram account : @BeatHepatitisB. Thank you, AMSA International! VivaAMSA! #BeatHepatitisB #Vaccineforhealthworkers #VaccineWorksForAll #WIW2020 #VivaAMSA

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Bibliography 1. World Health Organization, World Immunization Week 2014. Accessed 6 April 2020. 2. World Health Organization. Summary of WHO Position Papers - Recommendations for Routine Immunization. WHO web page [Internet]. 2019;(April):1–11. Available from: https://www.who.int/immunization/policy/Immunization_routine_table1.pdf?ua=1 3. World Health Organization. (2019). Summary of WHO Position Papers Recommendations for Routine Immunization. WHO Web Page, (April), 1–11. Retrieved

from

https://www.who.int/immunization/policy/Immunization_routine_table1.pdf?ua=1 4. World Health Organization. Global hepatitis report, 2017 [Internet]. 2017. Available from: https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ 5. Coppola N, De Pascalis S, Onorato L, Calò F, Sagnelli C, Sagnelli E. Hepatitis B virus and hepatitis C virus infection in healthcare workers. World J Hepatol. 2016;8(5):273–81. 6. Meireles LC, Marinho RT, Van Damme P. Three decades of hepatitis B control with vaccination. World J Hepatol. 2015;7(18):2127–32. 7. Centers for Disease Control and Prevention. CDC Guidance for Evaluating HealthCare Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management. MMWR 2013;62(No. RR 10):12. 8. Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health Professionals. Cdc. Retrieved from https://www.cdc.gov/hepatitis/hbv/hbvfaq.html 9. Le, T. et al. (2019). First Aid For The USMLE Step 1. USA : Mc Graw Hill.

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Appendix 1 FACTS SHEET OF NON-HEPATITIS B

1. BCG Schedule

: 1 dose for neonates at birth, usually with first Hepatitis B dose

Note : neonates = newborn baby from birth

1 month old

Composition : attenuated strain of Mycobacterium bovis Bacillus of Calmette and Guerin, known as BCG Administration: Intradermal Injection 2. Polio There are two types: OPV (oral polio vaccine) and IPV (inactivated polio vaccine) Schedule for OPV plus IPV 3-4 doses at least 1 dose IPV with the first dose is administered immediately at birth. Next doses can be started from the age of 6 weeks. The interval for the following doses of OPV is 4 weeks. If IPV is used, it is given at 14 weeks of age or later. Composition : attenuated polio viruses, residual amounts (less than 25 Âľg) of antibiotics including streptomycin and neomycin. Administration: orally (OPV) or intramuscular injection (IPV)

3. Diphtheria, Tetanus, Pertussis Schedule

: 1 - 6 weeks

The interval is minimum 4 weeks. The 3rd dose should be given up to 6 months of age. Three booster doses of diphtheria toxoid should be given in childhood and teenage years, as a combination with tetanus for 12-23 months, 4-7 years, 9-15 years Composition : Tetanus and Diphtheria Toxoid . Note

: Toxoid is a chemically modified toxin from a pathogenic microorganism,

which is no longer toxic but is still antigenic and can be used as a vaccine Administration: Intramuscular injection

4. Measles, Mumps, Rubella Schedule

: 2 doses (MCV 1 and MCV 2

for children, country with high

transmission MCV1 should be given at age 9 months and then continued by MCV 2 between 15-18 months. Composition : attenuated viral material from measles, mumps, and rubella viruses

359

Administration: Subcutaneous injection

5. Meningococcal Schedule

meningococcal A, C, W135, and Y-D is also

licensed for children 9-23 months of age. It is given as 2-dose series, 3 months apart beginning at age 9 months. Composition : 4 micrograms (Âľg) each of meningococcal A, C, W, and Y polysaccharides conjugated to approximately 48 Âľg of diphtheria toxoid protein carrier. Administration: Intramuscular injection

6. Influenza Schedule

: 2-3 doses for a child with the interval 4-8 week. 1 dose is given starts

from age of 6 weeks

59 months

Booster is administered at least 6 months after the last dose. It s not recommended for children above 5 ages. Composition : joins a protein to an antigen in order to improve the protection the vaccine provides (live and inactivated (whole-virion, split, subunit) vaccine types) Administration: Intramuscular injection

7. Varicella Schedule

: 1 -2 dose administered at 12-18 months of age, ranging 3-4 week in

between. Composition : Attenuated live strain of the Varicella-zoster virus Administration: Subcutaneous injection

Source : -

World

Health

Organization.

(2019).

Summary of

WHO

Position

Papers

Recommendations for Routine Immunization. WHO Web Page, (April), 1 11. Retrieved from https://www.who.int/immunization/policy/Immunization_routine_table1.pdf?ua=1 -

Setiati S, et al. (2014). Buku ajar ilmu penyakit dalam jilid I. edisi VI. Jakarta: InternaPublishing.

360

Appendix 2.

FACTS SHEET OF MATERIAL HEPATITIS B

(1) How serious is hepatitis B infection? Hepatitis B infection leads the patient to cirrhosis, liver failure, and liver cancer. Approximately 25% of people who become chronically infected during childhood and 15% of those who become chronically infected after childhood die prematurely from cirrhosis or liver cancer. On the other hand, acute infection of HBV has no cure, except supportive care. Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

Retrieved

Cdc.

from

https://www.cdc.gov/hepatitis/hbv/hbvfaq.html

(2) How does HBV transmitted? Blood and body fluids (e.g. semen, saliva) can spread the virus. Activities that involve percutaneous or mucous membranes can transmit the virus. sex with an infected partner; injection-drug use that involves sharing needles, syringes, or drug-preparation equipment; birth to an infected mother; contact with blood from or open sores on an infected person; exposures to needle sticks or sharp instruments; and sharing certain items with an infected person that can break the skin or mucous membranes (e.g., razors, toothbrushes, and

glucose monitoring equipment),

potentially resulting in exposure to blood Note : percutaneous is any medical procedure where access to inner organs or other tissue is done via needle-puncture of the skin Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health Professionals. Cdc. Retrieved from https://www.cdc.gov/hepatitis/hbv/hbvfaq.html

(3) When do people get Hepatitis B vaccination? There are at least 3 doses of hepatitis B vaccine for each person.

361

The first dose is given within 24 hours after birth and followed by 2-3 additional doses that are usually given at the same time as the first and third doses of DTP-containing vaccine (DTPCV). The additional dose does not cause any harm. The interval between doses should be at least 4 weeks.* Source : *World Health Organization. (2019). Summary of WHO Position Papers Recommendations for Routine Immunization. WHO Web Page, (April), 1 11. Retrieved from https://www.who.int/immunization/policy/Immunization_routine_table1.pdf?ua=1 Interruption between doses? The vaccine series does not need to be restarted whenever there is interruption . However, the following should be considered. Interrupted after the 1st dose : the 2nd dose should be administered as soon as possible and the 3rd dose should be separated by an interval of at least 8 weeks. Interrupted after the 2nd dose : the 3rd dose should be administered as soon as possible. In case of delayed / late immunization, 3 doses are recommended following 0,1, and 6 months rule. It means that the 2nd dose administered at least 1 month after the 1st dose and the 3rd dose 6 months after the 1st dose Source : -

World Health Organization. (2019). Summary of WHO Position Papers Recommendations for Routine Immunization. WHO Web Page, (April), 1 11. Retrieved

from

https://www.who.int/immunization/policy/Immunization_routine_table1.pdf?ua=1 -

Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health Professionals. Cdc. Retrieved from https://www.cdc.gov/hepatitis/hbv/hbvfaq.html

(4) How does Hepatitis B vaccine work? Hep B vaccine contains a surface protein of virus membrane, called HBsAg proteins, as part of virus body. 3 important proteins of HBV : -

HBsAg : indicate Hep B infection, found in the surface part of virus

HBcAg : found in the core part of virus

HBeAg : indicate active replication, rate of transmissibility, and poor prognosis

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Immunity pathway : HBsAg protein becomes the antigen that is presented by APC to T helper cell. Then, T helper cell continues the signal to B cell which becomes activated and transforms into plasma cell and B cell memory. The B cell memory keeps the memory of this infection to enhance and fasten immune response for next Hep B infection (with the whole body of virus, not only the protein of vaccine). Hepatitis B Immunoglobulin (HBIg) is different from Hep B vaccine. It contains antiHBs, not HBsAg. Hence, this is a type of passive immunization. Administration of HBIg is indicated for a person who needs anti-HBs immediately such as postexposure prophylaxis, and given 0.06 mL/kg intramuscular in deltoid/gluteal muscle. The anti-HBs is temporary for about 3-6 months. Source : -

Le, T. et al. (2019). First Aid For The USMLE Step 1. USA : Mc Graw Hill

Das, S., Ramakrishnan, K., Behera, S. K., Ganesapandian, M., Xavier, A. S., & Selvarajan,

Concepts. Journal

(2019). of

Hepatitis

clinical

and

Vaccine

and

translational

Immunoglobulin:

hepatology, 7(2),

Key

165 171.

https://doi.org/10.14218/JCTH.2018.00037 -

Centers for Disease Control and Prevention. CDC Guidance for Evaluating HealthCare Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management. MMWR 2013;62(No. RR 10):11.

(5) How is the administration of Hep B vaccine? Hep B vaccine is administrated intramuscularly in deltoid muscle. A needle 22-25 gauge 1-1Â˝ inch are used, but longer needle is used for obese people. The recommendation doses are available in CDC Source : -

CDC. (1991). Which workers in the health care setting need hepatitis B vaccine? Occupational

Health,

43(10),

1 2.

Retrieved

from

http://www.who.int/occupational_health/activities/3hepatiti.pdf -

Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health Professionals. 2017(1). Retrieved from https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

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(6) Who should get Hep B vaccine? -

Health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood- contaminated body fluids

All infants and unvaccinated children aged <19 years

People with hepatitis C virus infection

People with HIV infection

People at risk for infection by sexual exposure (see CDC*)

People at risk for infection by percutaneous or mucosal exposure to blood (see CDC*)

International travelers to countries with high or intermediate levels of endemic

And others (see CDC)

Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

2017(1).

Retrieved

from

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

(7) Who shouldn t get Hep B vaccine? Anyone who has had a serious allergic reaction to -

a prior dose of hepatitis B vaccine,

a component of the hepatitis B vaccine, or

yeast should not receive hepatitis B vaccine

When hepatitis B vaccine is administered as part of a combination vaccine, contraindications to other vaccines should be checked. Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

2017(1).

Retrieved

from

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

(8) Is Hep B vaccine safe for pregnancy? Hepatitis B vaccine CAN BE GIVEN to during pregnancy or lactation. The hepatitis B vaccine contains no live virus, so it is safe for them. Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

2017(1).

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

364

Retrieved

from

(9) Can anti-HBs levels decline over time? Yes. Following vaccination, anti-HBs levels decline over time. Anticonsidered a correlate of vaccine-induced protection for people who have completed an approved vaccination series. Immunocompetent people who achieve an anti-HBs level U/mL 1 2 months after completing the hepatitis B vaccine series remain protected, even if anti-HBs levels decline to <10 mIU/mL beyond that time (presumably because of persistent cellular immunity). Source : Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

2017(1).

Retrieved

from

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

(10) Are boosters recommended? Booster doses are not recommended for people with normal immune status who have been vaccinated (16,22). Only certain people should receive a booster dose in specific situations. For hemodialysis patients, if annual testing for antibody to hepatitis B surface antigen (anti-HBs) shows a decline to <10 mlU/mL, a booster dose should be administered. For other immunocompromised people (including those with HIV, hematopoietic stem-cell transplant recipients, and people receiving chemotherapy), the need for booster doses has not been determined. When anti-HBs levels decline to <10 mIU/mL, annual anti-HBs testing and booster doses should be considered for those with an ongoing risk for exposure Source: Centers for Disease Control. (2020). Hepatitis C Questions and Answers for Health

Professionals.

2017(1).

Retrieved

from

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

(11) What is the interpretation of Anti-HBs? -

-response, less protected, need to get vaccination series (0,1,6

months rule) -10Source :Sahana, H. V., Sarala, N., & Prasad, S. R. (2017). Decrease in Anti-HBs Antibodies over Time in Medical Students and Healthcare Workers after Hepatitis B Vaccination.

BioMed

Research

https://doi.org/10.1155/2017/1327492

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International,

2017.

(12) Is Hep B vaccination effective for Health Workers? After a properly administered 2 or 3 dose series, at least 9 of 10 healthy young adults and more than 9 of 10 infants, children, and adolescents develop protective antibodies and subsequent immunity to hepatitis B virus infection. Source : Immunization Action Coalition. (2006). 4205(651), 1 7. Available from www.immunize.org/catg.d/p4205.pdf

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Appendix 3. QUIZ TIME

RIGHT An Asian medical student, member of AMSA, come to physician to consult about Hepatitis B vaccination. Medical student : Hi, doctor! I am a fourth year medical student. Right now, I am preparing for my clinical year. People ask me to get Hepatitis B vaccination. Do I really need to get it? Doctor : What should the doctor reply? Choose the best response below : A. Ask the medical student about his Hepatitis B immunization history to know whether he had received full doses of Hepatitis B immunization or not B. Ask the medical student to make a schedule for Hepatitis B vaccination immediately before his clinical year C. Ask the medical student to get HBsAg and HBcAg testing and come afterwards D. Ask the medical student to get anti-HBs or anti-HBc and also HBsAg testing and come afterwards

Answer : D Based on CDC guideline*, pre-vaccination serologic testing i.e. HbsAg and anti-Hbs or antiHbc testing is indicated for persons born in geographic regions with HBsAg prevalence of

of vaccination history. *Centers for Disease Control and Prevention. CDC Guidance for Evaluating Health-Care Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management. MMWR 2013;62(No. RR 10):11. SWIPE HBsAg indicates Hepatitis B infection which is detected high in either acute or chronic infection. -

If it is negative, no further action required

If it is positive, the person should be referred to specialist for management of Hepatitis B infection

Anti-HBs indicates immunity of Hepatitis B infection, due to vaccination or recovery from infection.

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further doses or testing are indicated -

practically, the person need to receive 3 consecutive additional doses of HepB vaccine (usually 6 doses total), followed by anti-HBs testing 1 2 months after the last dose.*

Anti-HBc can indicate 2 cases : IgM positive means acute / recent infection ; IgG positive means chronic or prior exposure of infection. If it is negative, no further action required. Note : IU = international unit **Centers for Disease Control and Prevention. CDC Guidance for Evaluating Health-Care Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management. MMWR 2013;62(No. RR 10):12.

LEFT A co-assistant (a clinical year medical student) has just been exposed to blood from HBsAg (+) patient. He had received vaccine series in pre-clinical year but forgotten to check his postvaccination-anti-HBs. What should he do? HBIg or Hep B vaccine series? ANSWER : Due to his unknown anti-HBs, he should check anti-HBs immediately. -

e should receive :

Option 1 : a single dose of HBIG and a first dose of Hepatitis B vaccine series within 24 hours after exposure in different site of injection. Then, the second and third hepatitis B vaccine are given following 0,1, and 6 months after first dose. Option 2 : two doses of HBIG. One dose within 24 hours after exposure and the second dose 1 month later* *Centers for Disease Control and Prevention. Updated U.S. Public Health Service. Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR 2001;50(No. RR-11);22.

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AMINO | AMSA INTERNATIONAL COMPETITION 19/20