107/05/11疫苗注射新進展

小港醫院家庭醫學科主任 林晴筠

• 在中國文明，這項技術於公元前200年可能 也出現過。清代醫書認為，11世紀起，中國 人於北宋時期即開始種天花痘，而另一本醫 書則記載「江南趙氏始傳鼻苗種痘之法」， 且「種痘者八九千人，其莫救者，二三十耳 。」顯示該技術對天花的預防頗有成效 • 隨後這項技術沿絲路傳播開來

細菌學之父 • 確立細菌與疾病之間的關係 • 狂犬病炭疽病疫苗

JE: Most common worldwide cause of encephalitis

Flaviviridae RNA virus

Prognosis 50%: severe disability 20-30% die

JE 70-80% survive

30%: motor deficits 20%: convulsions 20%: severe cognitive or language problems

50%: no / mild disability Learning difficulties Behavioral problems Others

Solomon T. J Neurol Neurosurg Psychiatry .2000;68:405–415

In common with other flaviviruses, many JE infections are asymptomatic* For every symptomatic case…

…there are 4.4 asymptomatic infections

Zika1 (on Yap island)

Every single JE case = Outbreak …1 – 8 asymptomatic infections

Dengue2 …200 – 1,000 asymptomatic infections

Japanese encephalitis3 *Averages determined from serological/active study comparisons 1. Duffy MR, Chen T-H, Hancock WT, et al. N Engl J Med 2009; 360: 2536–43.

2. Endy TP, Yoon I, Mammen MP. Curr Top Microbiol Immunol 2010; 338: 1–13.

3. Mackenzie JS, Williams DT, Smith DW. Emerging Viruses in Human Populations. 2007: 201–68.

Human-tohuman transmission

Fly Distance

Mean (m) Max (m)

Aedes aegypti 40 – 86 363

Culex mosquitoes 1300 1980

Ciota AT. J Med Entomol. 2012; 49(1): 35.

Maciel-de-Freitas R. Am J Trop Med Hyg 2007;76(4):659.

JE in Taiwan 1938: first documented JE cases 1955: JE included in the notifiable disease 1967: biggest outbreak, 273 confirmed cases, 206 deaths 1968: 2 doses of MBDV for toddler (2y/o) 1974: a booster dosage added (one year later) 1983: another booster dosage for school children (now 4-6 years of age)

Hsu LC 2014 PLOS Negl Trop Dis

Confirmed JE cases Taiwan 1998 - 2016

Seroprevalence in Taiwan 2002 (n= 6594)

43

1981 37

1968 50 Hsu LC 2014 PLOS Negl Trop Dis

Jj2

JE Confirmed cases & Vaccination History Taiwan 2000 - 2014 Total: 379

4 doses 45%

No 12%

2 doses 22%

3 doses 21% Chang YK 2016 Am J Trop Med Hyg

Various JE Vaccines Virus strain Nakayama or Beijing-1

SA 14-14-2

Live or inactivated Replication substrate Mouse brain

Primary Hamster Kidney

1st Generation

Vero cell

2nd Generation

Mouse brain-derived inactivated vaccines (MBDV) Inactivation Purification

+ Disadvantages: Increased reactogenicity

ADEM (acute disseminated encephalomyelitis)

Higher number of doses; need for boosters Should be replaced by the newer generation JE vaccines WHO position paper on JE 2006 & 2015

Around 1 mouse for 1 dose of MBDV

台灣百年公立疫苗 製造史 CDC 2014

Recombinant Vaccine Technology*

Attenuated vaccine strain 17D yellow fever

Attenuated vaccine strain SA14-14-2 JEV

> 25 yr use > 90M dose/yr

> 75 yr use > 500M dose considered as an ideal live vector for development of new vaccines

Recombinant chimeric JE vaccine virus *Recombinant vaccine technology in the past use to produce Engerix-B®, HB Vax II, Euvax-B, Infanrix ® -Hexa, Rotateq ®, Cervarix ®, Gardasil ® (HPV)

Chambers TJ et al. J Virol 1999 23

Vaccine Design Virus Construction

Yellow fever 17D genome

C

E

prM

C

NS1

NS2

NS3

NS4

NS5

NS1

NS2

NS3

NS4

NS5

NS4

NS5

Cut out E and PrM genes of Yellow Fever 17D vaccine, resulting in YF17D backbone

YF 17D backbone E

C

E C

E

prM

NS1

NS2

NS3

Cut our E and prM genes of flavivirus of interest to paste them into YF17D backbone

prM prM

YF 17D based recombinant construct

NS1

NS2

NS3

NS4

NS5

Flavivirus of interest genome 24

JE vaccine sine 2017 • IMOJEV: new live-attenuated vaccine Long-term immunity Good safety profiles Dose: children (2); adults (1) Can switch from other JE vaccines

Recommendedation

登革熱 Dengavaxia

• Dengue hemorrhagic fever • 四種血清型 • 活性減毒 • FDA approved in 2016 • Scandal in Philippine in 2017 , 733 thousands children, • Antibody enhancement reactions

Recombinant Vaccine Technology*

Attenuated vaccine strain 17D yellow fever

Attenuated vaccine strain SA14-14-2 JEV

> 25 yr use > 90M dose/yr

> 75 yr use > 500M dose considered as an ideal live vector for development of new vaccines

Recombinant chimeric JE vaccine virus *Recombinant vaccine technology in the past use to produce Engerix-B®, HB Vax II, Euvax-B, Infanrix ® -Hexa, Rotateq ®, Cervarix ®, Gardasil ® (HPV)

Chambers TJ et al. J Virol 1999 34

• Dengvaxia 2014, Sanofi Pasteur • WHO recommend epidemic area use only • If use on seronegative person : antibodydependent enhancement -> 增加重病風險 • Dengue vaccine scandal :Philipine : 0.73 million children in 2016

子宮頸癌疫苗

HPV VACCINE

死亡人數

子宮頸癌 vs. 重大傳染病 1000 900 800 700 600 500 400 300 200 100 0

830

180

174

SARS (2002)

登革熱(2015)

78 EV71 (1998)

CC (yearly)

HPV（人類乳突病毒） 導致子宮頸癌的沉默殺手

HPV is a necessary cause of cervical cancer – 99.7%4 Cancer causing Types High risk group-16,18, 31,33,45,52,58

HPV

Non-cancer causing types Low risk group- 6,11.

HPV 16

HPV 6

HPV 18

HPV 11

• >70% of Cervical Cancer5,6 • >50% of Vaginal & Vulvar Cancer5

90% of Anogenital warts5

1.Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 2. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 3. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285. Reprinted from J Virol. 1994;68:4503–4505 with permission from the American Society for Microbiology Journals Department. 4. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19. 5. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne,F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre6. Bhatla N et al.Vaccine (2008;26; 2811-17

HPV感染 感染人類乳突病毒並不等於得到癌症

超過80%的 感染會改善

若持續感染約 1/3會形成CIN

41

至2015年12月。53國公費採用四價。 北美地區 (3國)

歐洲地區 (26國)

加拿大 美國 墨西哥 加勒比海 & 中美洲地區 (7國)

四價疫苗 87%

巴拿馬 巴貝多 百慕達 千里達及托貝哥 英屬開曼群島 法屬聖馬丁 波多黎各

2億1,000萬劑

南美洲 (9國) 阿根廷 祕魯 蓋亞納 哥倫比亞 烏拉圭 巴拉圭 蘇利南 巴西 智利

Cayman Is.

中東 & 非洲地區 (9國) 科威特 阿拉伯聯合大公國 賴索托 塞席爾 盧安達 哈薩克 利比亞 以色列 南非

公費狀況 使用四價疫苗(Gardasil) 使用二價疫苗(Cervarix) 同時使用二價及四價疫苗

二價疫苗 13% 3100萬

1.

2.

亞太平洋地區(7國) 澳洲 紐西蘭 馬來西亞 汶萊 澳門 台灣 日本

英國 (2012年9月起指 定採購四價疫苗) 奧地利 愛爾蘭 丹麥 挪威 羅馬尼亞 斯洛維尼亞 瑞典 馬其頓共和國 瑞士 保加利亞 法國 比利時 德國 希臘 盧森堡 西班牙 葡萄牙 義大利 捷克共和國 列支敦斯登公國 冰島 荷蘭 拉脫維亞 芬蘭 匈牙利

http://www.spmsd.com/category/news/ http://www.gsk.com/media/press-releases/2013/gsk-cervarix--two-dose-schedule-receiveseuropean-marketing-auth.html

105年12月更新

™ GARDASIL 9

[Human Papillomavirus 9-valent Vaccine (Recombinant, adsorbed)]

Protection Against Certain Diseases Caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, 58

• HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 是造成男性與女性HPV 相關癌症與疾病的前九大最常見的HPV型別1–6

Estimated Type Contribution for Certain HPV-Related Cancer and Disease Cases 4 HPV types cause:

9 HPV types cause a total of:

(6, 11, 16, and 18)

(6, 11, 16, 18, 31, 33, 45, 52, and 58)

子宮頸癌

70%1

90%1

外陰癌

75%2

90%2

陰道癌

65%3

85%3

肛門癌

85%4

90%–95%4

高惡性度子宮頸前期癌

50%5

80%5

低惡性度子宮頸前病變

25%5

50%5

生殖器疣

90%6

90%6

aNot

all cervical precancers and lesions, and vulvar, vaginal, and anal cancer cases are caused by HPV. Approximately 90% of high-grade cervical precancers,7 75% of low-grade cervical lesions,7 30% of vulvar cancer cases,2 70% to 75% of vaginal cancer cases,3 and 85% to 90% of anal cancer cases4 are HPV related. bHigh-grade cervical precancers defined as cervical intraepithelial neoplasia (CIN) 2/3.

1. de Sanjosé S et al. Lancet Oncol. 2010;11:1048–1056. 2. de Sanjosé S et al. Eur J Cancer. 2013;49:3450–3461. 3. Alemany L et al. Eur J Cancer.

2014;50:2846-2854. 4. Alemany L et al. Int J Cancer. 2015;136:98–107. 5. Joura EA et al. Cancer Epidemiol Biomarkers Prev. 2014;23:1997−2008.

6. Garland SM et al. J Infect Dis. 2009;199:805–814. 7. Guan P et al. Int J Cancer. 2012;131:2349–2359.

43

Nine HPV Types in Cervical Cancer: Consistency Across World Regions1 造成子宮頸癌的前九大HPV型別，在全球相當一致 Relative Contribution (%) of 9 HPV Types

HPV 6/11/16/18/31/33/45/52/58a 100

96 90

88

89

87

92

89

Latin America

Europe

Africa

Asia

Oceania

(n=2,058)

(n=544)

75

50

25

0 Worldwide

(n=8,977)

North America

(n=160)

(n=3,404)

(n=2,641)

(n=170)

aChart

represents the relative contribution of the 9 HPV types in HPV-positive cervical cancer cases in an international study of 8,977 HPV-positive cases; the dashed-line highlights the worldwide relative contribution of ~90%.

1. Serrano B et al. Infect Agent Cancer. 2012;7:38.

44

Composition of MSD HPV Vaccinesa GARDASIL™ Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)1

AAHS 225 µg

6

11

16

18

20 µg

40 µg

40 µg

20 µg

AAHS

GARDASIL™9 Human Papillomavirus 9-valent Vaccine (Recombinant, adsorbed)2

45

500 µg

6

11

16

18

31

33

45

52

58

30 µg

40 µg

60 µg

40 µg

20 µg

20 µg

20 µg

20 µg

20 µg

aFor

the remainder of the presentation, GARDASIL will be referred to as 4vHPV vaccine and GARDASIL 9 will be referred to as 9vHPV vaccine.

AAHS=amorphous aluminum hydroxyphosphate sulfate; HPV=human papillomavirus; MSD=Merck Sharp & Dohme Corp.

1. GARDASIL [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2014. 2. GARDASIL 9 [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2015.

台灣市售HPV疫苗

嘉喜: 唯一為提供更多保護而設計的HPV疫苗 (二價HPV疫苗)

Gardasil (四價HPV疫苗)

Gardasil 9 (九價HPV 疫苗) 16 18 31 33 致癌型別: 45 52 58

致癌型別: 16 18 致癌型別: 16 18 (造成全球約70%的子宮頸癌 (造成全球約70%的子宮頸癌及 (造成全球約90%的子宮頸癌 可預防人類乳突病毒 及50%的高度癌前病變)1,2 50%的高度癌前病變) 1,2 及80%的高度癌前病變) 1,2 的型別 非致癌型別: 6 11 (造成全球約90%的生殖器疣)3 1.子宮頸癌 適應症 (可預防的癌症與疾病 )

全球累計銷售劑數 施打時程

4,100萬4 (統計至2013年底)

非致癌型別: 6 11 (造成全球約90%的生殖器疣)3

1.子宮頸癌

1.子宮頸癌

2.原位腺癌AIS

2.原位腺癌AIS

3.外陰癌前病變

3.外陰癌前病變

4.陰道癌前病變

4.陰道癌前病變

5.男性與女性生殖器疣(菜花)

5.女性生殖器疣(菜花)

2億500萬5 (統計至2015年底)

700萬5 (統計至2015年底)

0 / 1 / 6 個月，共三劑 0 / 2 / 6 個月，共三劑(男女皆可接種) 9-14歲女孩亦可選擇接種兩劑 (0/6個月) 9-13歲女孩可選擇接種兩劑 or三劑(0/6個月)

0 / 2 / 6 個月，共三劑

製造廠/國家

GSK

MSD

MSD

台灣核可上市時間

2008

2006

2016

Q4. 9價疫苗保護時間多久?

ANS : 1. 根據最新研究報告指出，4價疫苗目前保護力達10年、2 價疫苗達9.4年，且保護力研究持續追蹤當中。 2. 9價疫苗保護時間目前追蹤至54個月(持續追蹤當中)，經 實驗證實保護時間不亞於4價疫苗，且經電腦數學模式計 算達30年以上(電腦運算僅供參考)。

四價HPV疫苗 (嘉喜)

九價HPV疫苗 (嘉喜9)

疫苗照片

致癌型別: 16, 18, 31, 33, 45, 52, 58

致癌型別: 16、 18 預防 人類乳突病毒 的型別

70%的子宮頸癌 50%的高度癌前病變 非致癌型別: 6 、11 90%的生殖器疣(菜花)

90%的子宮頸癌 80%的高度癌前病變 非致癌型別: 6 、11 90%的生殖器疣(菜花)

適應症 (可預防的癌症與疾 病)

子宮頸癌 原位腺癌AIS 外陰癌前病變 陰道癌前病變 男性與女性生殖器疣(菜花)

子宮頸癌 原位腺癌AIS 外陰癌前病變 陰道癌前病變 女性生殖器疣(菜花)

施打時程

0 / 2 / 6 個月，共三劑

0 / 2 / 6 個月，共三劑

製造廠國家

Merck & Co., Inc. 美國默克藥廠/ USA

Merck & Co., Inc. 美國默克藥廠/ USA

TFDA核可上市時間

2006

2016 June

水痘疫苗 VARICELLA (CHICKENPOX) VACCINE

• 水痘病毒是一種疱疹病毒(herpesvirus) • 在人體初次感染會造成水痘,之後潛伏於神經節內, 等人體免疫力降低時則會引起 帶狀疱疹 • 約有的人一生中 疹

?

會得到一次帶狀疱

• 帶狀疱疹引起的症狀以疱疹後神經痛(postherpetic neuralgia)最為擾人 (1/6 shingle)

• 1995 VARIVAX, Merck • -childhood schedule , 2 dose sine 2004 at 1y/o ( 民國92年出生) 1st: 12-15 months 2nd: 4-6 years -Adults and adolescence>13 y/o w/o evidence of immunity 2 dose, 4-8 wks apart

1. aspirin or other salicylates 2. 3months 內不可懷孕

ZOSTAVAX® [zoster virus vaccine live (Oka/Merck), MSD]

伏帶疹® 活性帶狀疱疹疫苗

臨床症狀：皮蛇纏身，痛不欲生

年紀越大，疼痛會較嚴重且持續時間也會越久4,5。 水泡紅疹開始出現 通常出現在臉部或身體單側

疹子開始結痂

持續數月或數年 前驅期： 發癢、疼痛

急性期： 劇烈疼痛 Day 0

疼痛強度慢慢減弱 2–4 Weeks

急性期1,2

1. Johnson RW. Herpes. 2007;14(suppl 2):30A–34A. 2. Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1–30.

3. Drolet M et al. Hum Vaccin Immunother. 2013;9:1177–1184 4. Nagasako EM et al. J Am Acad Dermatol. 2002;46(6):834–839.

慢性期：帶狀疱疹後神經痛 (PHN)

3 Months 慢性期3

Months/Years

帶狀疱疹會隨神經分布生長1,2 三叉神經 ~13%

V1 V2 V3

頸部 ~14% 腰部~50%

© Dr. P. Marazzi / Science Source

L1~5~13% © Dr. Allan Harris / Phototake.

© Bart’s Medical Library / Phototake.

Copyright 2008 Elsevier Inc. All rights reserved. www.netterimages.com

C=cervical; L=lumbar; S=sacral; T=thoracic; V (roman numeral 5)=trigeminal (5th) cranial nerve.

1. Cohen JI. N Engl J Med. 2013;369:255–263. 2. Seward J et al. In: Arvin A et al, eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge, UK: Cambridge University Press; 2007. Chapter 40. ncbi.nlm.nih.gov/books/NBK47367/. Accessed March 10, 2014.

帶狀疱疹治療困難 • 帶狀疱疹以及帶狀疱疹後神經痛通常需要全方位的治療1-3 。 Non-narcotic analgesics

Antivirals

Herpes

Topical agents

PHN

Zoster

Corticosteroids

Narcotic analgesics

Anticonvulsants for pain management

• 帶狀疱疹的抗病毒治療應在紅疹出現後72小時內開始，但病患通常 會拖過72小時後才就醫1-3。 – 抗病毒藥物可以減緩皮疹但無法降低帶狀疱疹後神經痛發生的風險1,4。

• 帶狀疱疹後神經痛通常很難處理，且治療滿意度低4,6。 1.

Cochrane JI. N Engl J Med. 2013;369:255–263.

2.

Johnson RW. J Infect Dis. 2002;186(Suppl 1):S83–S90.

3.

Harpaz R et al. MMWR. 2008;57(RR-5):1–30.

4.

Chen N et al. Cochrane Database Syst Rev. 2014 Feb 6;2:CD006866. doi: 10.1002/14651858.CD006866.pub3.

5.

Sacks GM. Am J Manag Care. 2013;19(1 Suppl):S3–S9.

HZ=herpes zoster; PHN=postherpetic neuralgia.

全球帶狀疱疹的年齡分布：50歲 以上風險遽增 Worldwide HZ Incidence by Age 1–12

Annual Incidence (per 1,000 person-years)

15

10

Australia1 Australia1

Canada2 Canada2

France3 France3

Israel4 Israel4

Italy5 Italy5

Japan6 Japan6

Germany7 Germany7

Netherlands8 Netherlands8

Spain9 Spain9

Taiwan10 Taiwan10

UK11 UK11

US12 US12

5

0 0

10

20

30

40

50

60

Age (years) 1. MacIntyre CR et al. PLoS One. 2015;10:e0125025. 2. Tanuseputro P et al. Vaccine. 2011;29:8580–8584. 3. Gonzalez Chiappe S et al. Vaccine. 2010;28:7933–7938. 4. Weitzman D et al. J Infect. 2013;67:463–469. 5. Gialloreti LE et al. BMC Infect Dis. 2010;10:230. 6.

Toyama N et al. J Med Virol. 2009;81:2053–2058. 7. Ultsch B et al. Eur J Health Econ. 2013;14:1015–1026. 8. de Melker H et al.

Vaccine. 2006;24:3946–3952. 9. Esteban-Vasallo MD et al. J Infect. 2014;68:378–386. 10. Lin YH et al. Vaccine. 2010;28:1217–1220.

11. Gauthier A et al. Epidemiol Infect. 2009;137:38–47. 12. Johnson BH et al. BMC Infect Dis. 2015;15:502. 13. Kim YJ et al. J Korean Med Sci. 2014;29:1706–1710.

70

80

年齡為帶狀疱疹發生的重要因素 因為全球人口老化，罹患帶狀疱疹的人應會越來越多1。 50歲之後，罹患帶狀疱疹的風險及嚴重性會大幅增加，這是由於免疫力會隨著年齡增長而降低的緣故(immunosenescence)2 到了85歲，約有50%的人會出現至少一次的帶狀疱疹3

預估全世界50歲以上的人口1 人(口 十)億

成長

1.

World Bank. Health Nutrition and Population Statistics: Population estimates and projections. databank.worldbank.org. Accessed March 4, 2014.

2.

Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill;

3.

Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2008;57(RR-5):1–30..

年紀越大會經歷較嚴重的帶狀疱 加拿大 南韓 美國 疹疼痛 1

2

3

帶狀疱疹 嚴重程(度 -

0 10 0

)天

年齡

冰島

英國

1. Drolet M et al. Clin J Pain. 2010;26:656–666.

2. Song H et al. Int J Infect Dis. 2014;20:23–30.

3. Oxman MN et al. N Engl J Med.2005;352:2271–2284.

年齡

帶狀皰疹的高危險群 • 例如肝癌患者較一般人增加帶狀皰疹發病 20%的風險 -愛滋病、糖尿病患增加52%的風險 -乳癌增加56%、血癌增加90% -紅斑性狼瘡病患更相較一般人增加110%的 發病風險。 -已得過帶狀皰疹者，復發機率約為6% 這些病患可與醫師討論本身年齡、免疫狀態、用藥狀況等條件， 評估施打的優缺點後，再考慮施打。

ZOSTAVAX (Zoster Vaccine Live) Product Profile • Live, attenuated VZV vaccine 1 • No preservative1 • Lyophilized product1 • Each 0.65-mL dose contains a minimum of 19,400 PFU (plaqueforming units) of Oka/Merck VZV when reconstituted and stored at room temperature for up to 30 minutes.1

• 14 times dose of VARIVAX® • Cannot be used to treat existing shingles or the pain associated with existing shingles

PFU = plaque-forming units.

1. Data on file. MSD. 2. Oxman MN et al. N Engl J Med. 2005;352:2271–2284.

NEW TYPE OF SHINGLE VACCINAION Subunit vaccine

Zostavax 2006 • The efficacy against : 60-69 :51% 70-79:41% >80: <20%

• the efficacy against postherpetic neuralgia was about 67%, and the duration ⋯ • After about 6 years, the protective effect <35% 10years later, protection gone

Shingrix Oct 2017 by ACIP â&#x20AC;˘ a biologically different manner. one protein - glycoprotein E + two adjuvants Very new adjuvant (first used) :QS-21 Stimulon very reactogenic , studied in Vaccine against HIV, malaria , cancer

Soap bark trees, Chile

Shingrix • efficacy against shingle, it's not 51% (as was the case with Zostavax); it’s >95% , for all age groups—even for those over 70 years of age.[1,2] • efficacy against postherpetic neuralgia : 85% to 95% • the duration—4 years later, the protective efficacy is still about 85%.

Shingrix • starting at 50 years of age; • a two-dose vaccine, with the second dose being given 2-6 months after the first; • It is the preferred vaccine • Even if you've already had Zostavax, it is still recommended that you receive two doses of the Shingrix vaccine.

侵襲性肺炎鏈球菌 感染症流行病學

目前市面疫苗上有那些肺炎鏈球菌疫苗 預防保護效果如何

先PCV 13 後PPV 23 效益最高

先接種PCV13再接種PPV23後 可產生最高的抗體濃度

PCV13 PPSV 23 (50-50歲) PCV13 PPSV 23 (60-64歲) PCV13 PCV 13 (50-59歲)

PPS23 PPSV 23 (60-64歲)

Pfizer data

高危險群 • 嬰幼兒及老人 • 免疫低下患者 無脾症、脾臟切除、HIV 感染、特殊的免疫功 能缺失、器官移植和癌症患者等 • 其他慢性病患者 糖尿病、肝硬化、慢性腎衰竭或慢性腎病等

Intervals for PCV13–PPSV23 sequence

>=8 weeks

Intervals for PPSV23–PCV13 sequence

>=1 year

ACIP recommendation, USA Sep. 2015

Immunocompetent: Cerebrospinal fluid leak Cochlear implant

Persons with functional or anatomic asplenia Sickle cell disease/other hemaglobinopathy Immunocompetent persons Immunocompromised p.

Chronic heart disease Chronic lung disease Diabetes mellitus Alcoholism* Chronic liver disease, cirrhosis* Cigarette smoking*

Human immunodeficiency virus infection Chronic renal failure Nephrotic syndrome Leukemia/Lymphoma Generalized malignancy Iatrogenic immunosuppression Solid organ transplant Multiple myeloma*

傳染力 1. Basic production rate. R0 2. Secondary attack rate

Transmission • Transmitted person-to-person through aerosolized droplets from cough or sneeze or by direct contact with secretions from the respiratory tract of infectious persons.

• Highly contagious; 80% secondary attack rates among susceptible persons. Measles is one of the most contagious viruses, with a secondary attack rate among susceptible individuals higher than 90%.

• high basic reproduction number (R0): 12 to 17 • Incubation period: 7–10 days (range 5–21 days)

http://immunisation.book.health.govt.nz/1+General+immunisation+principles/1.1+Immunity+and+immunisation

Bordetella pertussis • • • •

Small, gram negative, fastidious, aerobic coccobacillus only in humans Strong tropism for ciliated cells of respiratory mucosa virulence factors： − Pertussis toxin (PT): cell toxicity, favors bacterial colonization − Filamentous hemagglutinin (FHA) − Pertactin − Fimbriae (agglutinogens) − Adenylate cyclase: inhibits phagocytosis − Endotoxin: induces fever − Tracheal cytotoxin: causes paralysis of cilia

http://www.cdc.gov/pertussis/clinical/features.html

百日咳傳播

Transmission • Transmitted person-to-person through aerosolized droplets from cough or sneeze or by direct contact with secretions from the respiratory tract of infectious persons.

• Highly contagious; 80% secondary attack rates among susceptible persons. Measles is one of the most contagious viruses, with a secondary attack rate among susceptible individuals higher than 90%.

• high basic reproduction number (R0): 12 to 17 • Incubation period: 7–10 days (range 5–21 days)

http://immunisation.book.health.govt.nz/1+General+immunisation+principles/1.1+Immunity+and+immunisation

百日咳流病變化-國外

Before generalized use of pertussis vaccine

After generalized use of pertussis vaccine in children Hewlett EL, Edwards KM. Pertussis â&#x20AC;&#x201D; Not Just for Kids. N Engl J Med 2005; 352: 1215-22.

Whooping cough can cause life-threatening complication in babies.

• 1 out of 4 will get pneumonia • 1 or 2 out of 100 will die • Other complications include violent, uncontrolled shaking, life-threatening pauses in breathing, 嬰兒猝 死and brain disease.

台灣流行病學

Pertussis, confirmed cases By year, 2001 â&#x20AC;&#x201C; 2016 100 90

90

70

70

61

60

54

50

43 38

40

51

41

26

30 18

20 10

78

77

80

21 14

17

6

0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Pertussis, confirmed cases By age, 2001 â&#x20AC;&#x201C; 2016 40 y 8% 20-39 y 13%

<1 y 46%

10-19 y 21% 1-9 y 12%

Pertussis Incidence, Taiwan 2001 – 2014, by age Incidence per

Incidence per 100,000 (< 1 y/o)

< 1 y/o

100,000 (≧ 1 y/o) ≧ 21

y/o

Conclusions Approximately 5% of adult patients presenting to hospitals with chronic cough for at least 2 weeks showed serological evidence of pertussis infection, while over two thirds had no evidence of existing immunity.

Pertussis should be considered in patients with prolonged or paroxysmal cough

Possible causes for pertussis resurgence 1.Short-lived immunity following immunization 2.

3.

4.

Lack of vaccine protection against bacterial transmission Suboptimal vaccination schedule or population coverage Increased awareness, better diagnostic tests, and more complete reporting needed

Waning Immunity After Source of Immunity Duration Reference Infection/Vaccination Natural infection Whole-cell vaccine

15 years

Wirsing Von Kรถnig, 1995

UK

6 years

Jenkinson, 1988

Finland Germany

6 years >6 years

He, 1994 Lugauer, 2002

France

8 years

Grimprel, 1996

Acellular vaccine Italy

6 years

Salmaso, 2001

Germany

>6 years

Lugauer, 2002

France

>4 years

Guiso, 2000 |

100

Wirsing Von Kรถnig CH, et al. Lancet Infect Dis. 2002:2(12):774-750.

ACIP recommendation • Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks’ gestation, regardless of previous receipt of Tdap • 坐月子中心 ⋯

MMR

•

流行病學（Epidemiology）

麻疹具有高傳染力，在疫苗尚未使用前，麻疹被視為是 孩童期例常性不可倖免的，超過99％的人都會被感染，可以 說幾乎每個人一生中難逃過麻疹。大部分麻疹發生於嬰幼兒 期（5歲以前），臺灣從1978年起全面實施活性疫苗接種， 自疫苗廣泛使用後，麻疹病例大大減低，多發生於未接種疫 苗的人。1980年代末最後一次比較有規模的流行中，病者大 部分為學齡前孩童或國小學生，同年代美國也有麻疹流行（ outbreaks），多發生於學校，感染者多見於從未接種疫苗 者，或是因太早接種疫苗而無疫苗抗體保護者。國內1990年 代，尤其是1995年以後，報告的麻疹病人數都很少，並且不 少病例是由中國或東南亞境外移入者。

流行病學（Epidemiology） •

傳染窩（Reservoir）

•

人為唯一之宿主及傳染窩。 傳染方式（Mode of transmission）

•

經由空氣、飛沫傳播或是直接與病人的鼻腔或咽喉分泌物接觸而 感染。 潛伏期（Incubation period）

•

7～18天，通常為14天（自暴露至紅疹出現）。 可傳染期（Period of communicability） 發疹之前、後各4天內。

• 八、感受性及抵抗力（Susceptibility and resistance） 所有不曾得過麻疹或者不曾接種麻疹疫苗的 人，都可能感染麻疹。嬰兒自母體得來的抗體只 持續6～9個月左右（視母親之抗體效價高低而異 ）；在沒有接種人口中，每隔幾年，只要當易感 性人口累積到一定數目，就會爆發流行；而得過 麻疹的人有終身免疫力。

CDC Recommendation

原則

疫苗接種實務 • 活性減毒疫苗 BCG. MMR. OPV. varicella. Yellow fever • 不活化疫苗 DTP. Japanese encephalitis. Hib Hepatitis A, B, rabies, Cholera • + :除了日本腦炎和百日咳需間隔 隔一個月，其他可同時/分開任何時間打 • + :可同時接種，若分開要相隔一個 月 • + :除了霍亂與黃熱病疫苗需間隔三 周以上，其他可同時或間隔任何時間接種

禁忌症 1. 懷孕婦女:活化疫苗除OPV，A肝，日腦，霍 亂疫苗安全性尚未確定 2. 免疫力不全: 接受化療之癌症患者， HIV 不可接種活性疫苗

疫苗和公共衛生 • 在印度針對36萬6625人的研究發現卡介苗甚 至對肺結核毫無預防功效Fifteen year follow up trial of BCG vaccines in south India for tuberculosis prevention Tuberculosis research center, Indian J. Med Res (1999): 110, 56-69 .

• 印尼地區抽取6萬人做樣本，亦發現霍亂疫 苗沒有顯著的預防效果