Public Health Journal 26 (2015)

Public Health Journal No. 26

October 2015

INNOVATIVE RESISTANCE-BREAKING MODES OF ACTION

Combating increasing insecticide resistance will be essential to achieve the goal of RBM’s new strategy: Action and Investment to defeat Malaria 2016-2030 – for a malaria free world. The recent rapid development of resistance also endangers the vital role played by vector control to realize this goal. Only new ­compounds, which are tested in practice, and their correct application in resistance management can assure this essential element of disease prevention.

CONTENT

KEY FACTS

Malaria eradication

MALARIA: FACT & FIGURES

Innovative vector control is vital

31

by Dan Strickman REGIONAL NETWORKS

MALARIA: THE DEADLIEST VECTOR-BORNE DISEASE

Asia Pacific Malaria Elimination Network (APMEN)

Working towards malaria elimination Mosquito

Person infected

by Malaria

Infected mosquito

Healthy people

Infected people

PROGRESS SINCE 2000

ON ALERT SINCE 2010

Pan African Mosquito Control Association (PAMCA)

30%

3,2 BILLION PEOPLE AT RISK

45% OF THE GLOBAL POPULATION

584 000 DEATHS A YEAR MALARIA REPRESENTS 80,55%

OF 725 000 DEATHS CAUSED BY MOSQUITOES

50 CHILD DEATHS

198 MILLION CASES A YEAR

EVERY HOUR

NGO

Break Dengue & Dengue Lab

47%

EVOLUTION OF MOSQUITOES

MORTALITY RATE DECREASE

DECLINING EFFICIENCY OF VECTOR CONTROL SOLUTIONS

100 MILLION LIVES PROTECTED

Book review

EXISTING SOLUTIONS TO FIGHT MALARIA INSECTICIDES

MEDICAL TREATMENT

IN OUR INVESTMENT INTO NEW VECTOR CONTROL PRODUCT DEVELOPMENT OVER THE LAST 10 YEARS. INVESTMENT INTO PRODUCTION

INDOOR RESIDUAL SPRAY

120 000 NEW VICTIMS PER YEAR*.

TREATED BEDNETS

123 MILLION people protected BY INDOOR RESIDUAL SPRAY. 1 BILLION TREATED BEDNETS distributed since 2004 globally.

44% of the population at risk sleep under BEDNETS.

PREVENTIVE OR CURATIVE

CAPACITY OF VECTOR CONTROL PRODUCTS IN SOUTH AFRICA, FOR AFRICA.

50

PEOPLE A GLOBAL TEAM OF INVOLVED IN VECTOR CONTROL.

TO COMBAT RESISTANCE

+

NOTES

INTRODUCING A NEW MODE OF ACTION FOR VECTOR CONTROL. 1ST MIXTURE PRODUCT FOR INDOOR RESIDUAL SPRAY. CONTINUED INVESTMENT TO BRING RESISTANCE MANAGEMENT TOOL TO MARKET.

48

Putting the last mile first

BAYER SOLUTIONS

+

45

Malaria Consortium

* Source WHO

FIVE-FOLD INCREASE

Dengue Global Status: The A to Z of a (re)emerging disease

DANGER : RISK OF MALARIA RESURGENCE WITH ABOUT

THANKS TO BAYER SOLUTIONS.

HIGH RISK FOR 1,2 BILLION PEOPLE.

41

Building a global community

INSECTICIDE RESISTANCE

REGIONS AT RISK

103 COUNTRIES AND TERRITORIES

Malaria: First vaccine worldwide to be approved Antibiotics: Increase vector efficiency Dengue: Vaccine is more than 80% effective Malaria: Rapid non-invasive laser diagnosis History Elephantiasis CD-ROM Cover photo: Mosquito trap used in Awassa, Ethiopia (With permission of Malaria Consortium).

BAYER-infographie Malaria-GB-A4paysage_(2A5)-.indd Toutes les pages PUBLIC HEALTH JOURNAL 26/2015

36

Malaria – Africa’s modern scourge

DECREASE IN THE NUMBER OF CASES

32

Available as poster on the enclosed Public Health CD-ROM

07/08/15 14:35

PUBLIC HEALTH JOURNAL 26/2015

54 54 55 55 56

59

CONTENT

Editorial

4

by Jacqueline Applegate

Editor’s note Vector control

Need for innovation

5

by Gerhard Hesse COVER STORY

The importance of vector control in malaria elimination

The right tools for the job

6

by Jo Lines I N N O VAT I O N S F O R V E C T O R C O N T R O L

Towards eliminating vector-borne diseases

The need for insecticide resistance management

by Janet Hemingway

13

Vector control

The challenges of developing new vector control solutions

by Justin McBeath and Frédéric Schmitt

18

Pyrethroids

Metabolic resistance of insects

by Sebastian Horstmann

24

arctec

Evaluation of arthropod control products 2

28 PUBLIC HEALTH JOURNAL 26/2015

CONTENT

Malaria eradication

Innovative vector control is vital

31

by Dan Strickman REGIONAL NETWORKS

Asia Pacific Malaria Elimination Network (APMEN)

Working towards malaria elimination Pan African Mosquito Control Association (PAMCA)

32

36

Malaria – Africa’s modern scourge NGO

Break Dengue & Dengue Lab

41

Building a global community Book review Dengue Global Status: The A to Z of a (re)emerging disease

45

Malaria Consortium

48

Putting the last mile first NOTES

Malaria: First vaccine worldwide to be approved Antibiotics: Increase vector efficiency Dengue: Vaccine is more than 80% effective Malaria: Rapid non-invasive laser diagnosis History Elephantiasis CD-ROM Cover photo: Mosquito trap used in Awassa, Ethiopia (With permission of Malaria Consortium).

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54 54 55 55 56

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EDITORIAL

Insecticide resistance is a growing global challenge that poses a major threat to the eradication of vector-borne diseases and therefore, to public health. To manage it, we all need to join forces to find new approaches and innovative solutions.

In this current edition, where I have the privilege to write the editorial for the first time as the Head of the Environmental Science Division, I am proud to acknowledge the contribution of two renowned academics, Professor Jo Lines and Professor Janet Hemingway, who share their expertise and views about insecticide resistance and its importance for vector control.

As a company with a history of over 150 years of innovation, Bayer is leading the battle against vector-borne diseases with a current portfolio of solutions to carry out resistance management. In this year’s Public Health Journal issue, we give an update about new innovative modes of action with re-designed molecules that are in the pipeline for the short and long-term.

Yet, innovation to address resistance is only possible through collaboration. Currently, primary manufacturers are working hand in hand with the Innovative Vector Control Consortium (IVCC) on in-house innovations for Indoor Residual Spraying (IRS) and Long Lasting Insecticidal Nets (LN).

This is more than encouraging and in line with the ambitious goals set by the Roll Back Malaria Partnership (RBM) in “Action and Investment to defeat Malaria covering 2016-2030 (AIM) – For a malaria free world”. Along the same lines, in its recently issued “Global Technical Strategy for Malaria 2016-2030”, the World Health Organization (WHO) highlights the key role of vector control in malaria prevention and the importance of harnessing innovation and research.

When it comes to malaria, the Asia Pacific Malaria Elimination Network (APMEN) and the PanAfrican Mosquito Control Association (PAMCA) are two prominent examples of collaboration through regional networks, proving that these are key for the successful implementation of global initiatives such as RBM. On the dengue front, we showcase “Break Dengue” and “Dengue Lab”, two innovative and ­ ollaborative online platforms that help to connect experts and key stakeholders to exchange c knowledge about this resurgent disease.

Insecticide resistance is at the center of our thinking and certainly a challenge that the international vector control community of scientists, manufacturers, governments and other stakeholders needs to tackle as a joint effort. Overcoming this problem demands innovation more than ever – so let’s bring together all our knowledge and the best of our skills to tackle this global challenge together!

I wish you a pleasant reading,

Jacqueline Applegate

4

Head of Bayer Environmental Science Division and member of the Bayer CropScience Executive Committee

PUBLIC HEALTH JOURNAL 26/2015

EDITOR’S NOTE

Vector control

Need for innovation The year 2015 represents the deadline set for the Millennium Development Goals, to be followed by the Sustainable Development Goals (SDGs). Successes in malaria control during the period since 2000 have been remarkable. But to expand or even maintain such progress, much still needs to be done.

F

or post 2015, the malaria control AIM lists the development of new community has defined new goals active ingredients for use in LNs and to cover the period 2016-2030, laid IRS as top priority, since these underdown in two essential reports: the lie key intervention strategies. The RBM’s guide for collective “Action rapid development of resistances and Investment to defeat Malaria against the widely used pyrethroids 2016-2030 (AIM) – for a malaria free have stimulated not only multiple world”, complementing the WHO’s innovation streams, including formal “Global Technical Strategy for Product Development Partnerships Malaria 2016-2030 (GTS)”. AIM and such as IVCC, but also the in-house The author: GTS share two supporting elements: innovation pipelines of primary GERHARD HESSE to strengthen the enabling environmanufacturers. In addition the ­ Head of Global ment (policies, data and health sysobservable switch from indoor biting Partnering, tem) and foster innovation, the latter to outdoor biting requires new formuBayer Environmental Science, Lyon, France accompanied by a responsive political lations of insecticides. environment incentivizing needs for R&D to bring innovations to the market, and this as Bayer as one of the companies committed to innofast as possible. vation in vector control has some very promising new insecticide candidates for IRS, which are preModels forecast that if malaria intervention cover- sented in this issue. GTS stresses that options age remains at current levels, incidences may even urgently need to be explored to ensure timely and increase moderately as a result of loss of immunity affordable access to improved vector control tools, among populations that have been protected previ- so countries need to provide the regulatory environously by interventions. This effect can be averted, ment facilitating rapid assessment and uptake of for example by optimizing the use of currently validated tools. available vector tools, if the coverage level is above 80% of the population at risk.

Two important outcome indicators for GTS 20162030 are the proportion of the population at risk One recommendation is to implement a prevention who slept under an LN the previous night, and/or strategy based on vector control incorporating the were protected by IRS over the past 12 months. We major threat of emerging resistances to insecticides hope to obtain new tools in the future from innovain the vector. However new innovative tools are tion pipelines for vector control, but to cover the needed, and it is here that seeking to better harness time to market, we must make the best out of using innovation and expanding research becomes impor- current alternative tools. tant.

Please find the important links to this column on page 60 (back cover flap): AIM, GTS, SDGs, m ­ alERA, IVCC. PUBLIC HEALTH JOURNAL 26/2015

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COVER STORY

C O V ER S TO RY

The importance of vector control in malaria elimination

The right tools for the job

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COVER STORY

In the last fifteen years, ­massive investment in the scaling-up of modern antimalaria interventions has prevented about 4.3 million deaths due to malaria. ­According to a recent ­analysis of survey data*, about 78% of the malaria cases prevented by ­modern anti-malaria interventions can be attributed to vector control. More than half of the total expenditure has been spent on vector ­control. But important ­factors need to be ­considered to sustain and extend successes gained so far.

T

he priority given to vector control, as opposed to other anti-malaria interventions, has been the subject of controversy ever since Ross discovered the role of the mosquito in transmission. In order to consider the role of vector control in the war against malaria, we must begin with some basic facts and concepts about vector control, vis-à-vis other interventions such as drugs and v­ accines. We must also consider how the role of vector control might differ according to circumstances, for example if the goal is elimination rather than disease control, and if elimination is nearly complete, or has recently been completed.

Regional patterns of malaria epidemiology Malaria exhibits very different epidemiological patterns on different continents. The ecological settings with the highest transmission, and the people who are at highest risk, are quite different in Africa, Latin America and in the various biogeographical sub-regions of Asia. These patterns reflect the specific biological contrasts between the species of Anopheles mosquito that transmit malaria in each sub-region. Other variables, such as climate, human behavior and health systems, also play a role, but the predominant patterns are clearly driven by mosquito biology. For example: • The main reason why most (>85%) of the world’s malaria deaths occur in Africa is that the Africa vector species are more efficient at transmitting the parasite than the equivalent malaria vector species in Asia and Latin America. What makes the African species so much more efficient is their longevity, i.e. long lifespan.

• In most of the Mekong sub-region, malaria is strongly associated with the forest: the most efficient (longest-lived) vector species are ­forest-dwelling species, and most transmission ------------------------------------------------* Bhatt et al. submitted for publication, and P. Gething personal communication.

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COVER STORY

occurs outside the home. Hence the main risk groups are people who work and/or live in the forest (see picture: A ricefield in the forest).

• In Africa, by contrast, the main vectors are essentially savannah species and transmission is mostly domestic and intense, so young children are the main risk group.

• In most parts of the world, malaria transmission tends to be more intense in rural areas than in towns and cities, but in India it is the other way round: malaria cases are often exported from town to the surrounding countryside. This is because India is the only continent with a ­malaria vector adapted to urban conditions and breeding in domestic water-storage containers (see picture: A rooftop in India).

This concept of “equilibrium parasite population size” is critical for elimination. In some settings, the mosquitoes are too few, too short-lived, or too isolated from people, and the parasite cannot maintain itself. Northern Europe, where malaria used to be endemic and elimination happened slowly and mostly inadvertently over the last 500 years, is one such place. The vectors are still there, and nowadays plenty of imported cases occur.

However, the vectors no longer live in close proximity to the human population, and any newly arising cases are quickly detected and treated.

Hence, in this part of the world, there is no sustained transmission, and the equilibrium parasite population size is zero.

Unstable and epidemic-prone malaria

Equilibrium parasite population size If you wish to drive an organism to extinction, it is important to understand the factors that normally regulate its population size. While the organism has a natural tendency to grow – its reproductive capacity – environmental constraints tend to restrict this growth. In most cases, the interaction between these two creates a balance, an equilibrium population size, which may be more or less stable.

In other places, where the vectors are more numerous or more efficient, the potential for parasite transmission is greater; transmission can be selfsustaining, and the infection can persist. However, it may be unstable. The potential for transmission

The parasite’s reproductive potential is determined primarily by the rate at which the local mosquito population can transmit the infection from one person to another. This “vectorial capacity”, which varies between mosquito species and depends largely on vector longevity, is one of the key factors underlying the regional epidemiological ­ patterns described above.

A ROOFTOP IN INDIA as a man-made breeding site for Anopheles stephensi. When a block of flats is being built, the concrete poured for each new floor must be cured. The floor is covered with a layer of water 5 to 10 cm deep, and left for about a week: just enough time for the mosquito larvae to complete their development. Because this species has adapted its biology to urban conditions, malaria transmission is often more intense in Indian towns than the surrounding countryside, in contrast to all other continents, where urbanization tends to exclude malaria.

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COVER STORY

depends mainly on the mosquito population. This is highly dynamic; mosquito numbers can fluctuate by five- or even ten-fold from one village to the next, and from one week to the next. Superimposed on this are seasonal cycles, which normally have even greater amplitudes.

Two factors limit this increase: saturation and immunity. Saturation simply means that as prevalence approaches 100%, most of the infective bites encounter people who are already infected. Under these conditions, more or less everyone is infected more or less permanently, and it is human immunity that limits the parasite population. Immunity to malaria is slow to develop and never complete, but the more you are exposed, the stronger your immunity becomes.

Photos: London School of Hygiene & Tropical Medicine, UK

At low-to-moderate levels of malaria, the human population has little immunity, which means that transmission intensity closely follows these dynamic shifts in the mosquito population. In other words, transmission is unstable. In some “epidemic prone” places, such as the highlands of East Africa, there may be little or no transmission for years but then a sudden and severe epidemic spreads with high incidence. Elsewhere, for example in many parts of the plains of India and Pakistan, transmission is regular and seasonal every year, but with great variation from year-toyear in the intensity of transmission. Thus, the instability of “unstable” and “epidemic-prone” malaria is driven primarily by vector-related ­factors.

Alternatively, vector factors can also produce “stable malaria”. In some places, such as lowland tropical Africa, the mosquitoes are extremely efficient, and can transmit infection from one primary case onwards to more than a hundred secondary cases in just one round of transmission. Such a rate of reproduction is exceptionally high compared to other infectious diseases: for example with measles, the equivalent ratio would be about 20 secondary cases per primary case. Under these conditions, therefore, the parasite population has a strong tendency to increase very rapidly.

A RICE FIELD IN THE FOREST near Mae Sariang, northern Thailand. Many species of Anopheles mosquitoes in the rice fields are animal-biting and short-lived, and have no importance as vectors of malaria.

The most numerous human-biting species in this valley is Anopheles minimus, which breeds in the shallow pools beside the stream. Although An. minimus is a vector, it is less important than Anopheles dirus, which is present in lower numbers, but is more efficient as a vector because of its longevity. An. dirus breeds in small muddy puddles in the deep forest.

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COVER STORY

Thus, in any given setting, the equilibrium malaria infection prevalence depends on a range of vectorrelated and other environmental factors. If you perturb the system in either direction, it will tend to return to this equilibrium; this balance is built into the biology, and it must be overcome in order to achieve and maintain elimination.

The factors maintaining the equilibrium vary in strength from setting to setting. They can be relatively weak if the vectors are only moderately efficient at transmission, in places where malaria was originally of only moderate endemicity. But if the vectors are highly efficient, as in places where transmission was once very intense, these stabilizing factors can be very strong.

How interventions affect parasite equilibrium

Photo: London School of Hygiene & Tropical Medicine, UK

Some interventions can directly affect the parasite population, and reduce it to below its equilibrium

IN MOST PARTS OF THE WORLD, the dry season is associated with reduced malaria transmission. In Sri Lanka, however, the main malaria vector is Anopheles culicifacies, and this species breeds in the rocky pools of water that can be left behind as a river recedes and dries up. This is why, in previous years when malaria was a major problem in Sri Lanka, there was a dry season peak of transmission in some parts of the country.

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size, but leave it likely to return to the same equilibrium. Others have little or no direct effect on parasites (only the vector), but can shift the parasite equilibrium population size to a new lower level.

Mass drug administration (MDA), and variants such as focal screening and treatment, are in the former category: they are not equilibrium-changing interventions. MDA certainly does reduce parasite population size, but only temporarily, in the absence of an anti-vector intervention. Such a transient reduction has indeed been observed in practice in several cases, including in Nicaragua, where national-level MDA was tried out in 1981.

In two specific situations MDA is expected to produce long-term (or even permanent) reductions in parasite population size, and can be useful for this purpose. One is in small closed human populations, where it is possible to extinguish every last parasite, with no exceptions. In this case, the state of elimination thus created may be highly u­ nstable, and vulnerable to reinvasion. Nevertheless, cases exist (e.g. small islands in Vanuatu) where this has been achieved. To be successful, it must be ­possible to achieve 100% MDA coverage, and all inward migration must be closely monitored and completely controlled.

The second less risky application of MDA is in settings where transmission has already been reduced, and this decline is expected to be permanent. In these circumstances, the parasite population is also expected to decline to the new lower equilibrium, but may do so slowly, with a substantial time lag. Cambodia is probably an example of this. As noted on page 7, in the Mekong subregion, the main malaria vectors are confined to the forest. A generation ago, most of Cambodia was forested, but clearance has been rapid, and now almost all the primary forest has gone.

Malaria is now declining in the deforested areas, but the process is patchy, and transmission is still persistent in many local foci. In particular some

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COVER STORY

people have long-term asymptomatic infections, and are never ill but are infectious. In these circumstances, MDA will probably help to reduce this infectious reservoir and hasten the decline down to the new lower equilibrium. Nevertheless, it is important to recognize that the deforestation is probably the primary driver. Without the MDA, the benefits of reduced vectorial capacity due to deforestation would eventually be realized, but it could take many years. With MDA, these benefits are reached much more quickly, and with greater confidence. On the other hand, the MDA alone without the deforestation would have only a transient effect.

Vector control, by contrast, is an “equilibriumshifting” intervention – at least as long as the vector control is sustained. Of course, the vectors also have a “natural” or “background” level of abundance in any given setting, and if vector control is withdrawn they are likely to return to their original abundance and behaviors until other factors – such the environment – change. This has important implications for the rationale of elimination, as discussed below.

IRS and ITNs amplify the impact As a means of reducing transmission, and compared to other interventions (including other forms of vector control), indoor residual spraying (IRS) and insecticide-treated nets (ITNs) are especially powerful. This is because they reduce not only vector abundance and contact with humans, but also vector longevity. This is important, because the lifespan of the average female mosquito is less than a week in tropical conditions, but it takes 8 days for the parasite to mature inside the female mosquito. Hence, only the oldest “grandmother” mosquitoes survive long enough to transmit the disease.

During the parasite maturation period of 8-12 days, the female mosquito will feed 3 or 4 times, and in a village with good IRS (or ITN) coverage, she risks being killed by the insecticide every time she tries to feed. Hence the risk of being killed is repeated, and the resulting mortality is cumulative.

PUBLIC HEALTH JOURNAL 26/2015

The author: JO LINES London School of Hygiene & Tropical Medicine, UK

For example, if just 80% of houses are sprayed, and 80% of the mosquitoes entering a sprayed house are killed, then more than 1 in 3 females will survive one feeding cycle, but only 1 in 60 will survive four successive cycles.

This in turn alters the relationship between coverage and impact. With most interventions (including larviciding and MDA), the expected degree of reduction is proportional to, and limited by, the degree of coverage actually achieved. For example, a larviciding operation that kills 90% of the larvae can reduce transmission by 90% at best.

However, IRS and ITNs can have a stronger impact on transmission with a lower level of coverage. For example, transmission can be reduced by 98% or more by IRS programs where 80% to 90% of houses are sprayed.

Interventions on the path to elimination In hyper-endemic transmission conditions, vector control is the only intervention that can bring malaria prevalence down from its initial “saturation” levels to less than 5%, or preferably less than 1%, for prolonged periods. In principle, of course, an instant reduction in parasite population size could be brought about by MDA, but in the absence of vector control, such a reduction would disappear again, almost as instantly.

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COVER STORY

In settings where overall prevalence has been reduced to less than 0.5%, it is normally very patchy: there are some hotspots with active transmission and new cases, and gaps in between where there seems to be no transmission. This provides the opportunity to concentrate intensive interventions on hotspot foci, and to root out the reservoir of infection completely, using some combination of active case finding, MDA and additional vector control. The aim is then to remove the foci one by one in turn.

The problem, of course, is that the foci of remnant infections are likely to be in places where the potential for transmission is relatively high, or where it can be high on some occasions. This potential may remain or recur after the parasite itself has disappeared. If one of these occasions happens to coincide with the arrival of an infected person from another focus elsewhere, local transmission may be re-ignited. Thus an essential ingredient in this part of the process is diligent surveillance, to both identify and remove the foci, and maintain and monitor the state of elimination afterwards.

The critical question, however, is whether and when to withdraw the general vector control cover that made elimination possible. This is one of the most difficult decisions in the whole process.

Withdrawing too early increases the risk of catastrophic re-invasion. But vector control is expensive; if this expense has to be maintained simply to prevent a few cases each year, then the cost-effectiveness of the elimination effort can be questioned. Moreover, in some settings, the long-term sustainability of insecticidal vector control in a post-elimination period may be limited by resistance, as well as by political will and finance.

Sustaining elimination Once elimination has been achieved, how will it be maintained? During the first global malaria eradication campaign, in the 1960s, the risk of reinvasion by malaria in a post-elimination area was

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assessed in terms of two key factors: “vulnerability” and “receptivity”. These are useful and important concepts. Vulnerability denotes the probability of importation: the frequency with which infected people are expected to arrive in the eliminated area. Receptivity measures the risk that an imported case will lead to an outbreak, and the speed with which this outbreak will spread. Hence, vulnerability depends on geography, migration and health system issues. Receptivity depends largely on the vectors, and therefore on whether it is possible to sustain vector control in the longterm despite elimination. This is a critical issue for poor countries close to elimination, where current success in completing the process of elimination may prompt donors to withdraw support for vector control, leading to increased receptivity and the risk of re-invasion in the future.

CONCLUSION Over the last decade, vector control has accounted for more than half of PMI and GFATM expenditure on anti-malaria interventions, and has been responsible for more than three-quarters of the malaria cases averted by these interventions. Vector control is thus the dominant intervention in the early stages of the path to elimination. In areas of intense “saturation” transmission, vector control is the only intervention capable of achieving the very large reductions in transmission that are needed. In a given locality, efforts needed to achieve elimination depend primarily on vector biology, which also determines how stable elimination will be, when the parasite is re-introduced by imported cases. In the war against malaria, the struggle against mosquitoes is not the only important campaign, but it is probably the one that will decide when and how the war will finally end.

Article on the enclosed Public Health CD-ROM

PUBLIC HEALTH JOURNAL 26/2015

I N N O VAT I O N S F O R V E C T O R C O N T R O L

Photo: Malaria Consortium

INSECTICIDE-TREATED BEDNETS have reduced malaria dramatically in many parts of Africa, so it is vital to preserve their effectiveness.

Towards eliminating vector-borne diseases

The need for insecticide resistance management Infectious diseases transmitted by insects remain major health issues, but over the last decade interventions have been scaled up to try and eradicate some of these diseases or eliminate them as public health issues by driving transmission down to very low levels. However, despite increased efforts over the last decade malaria still accounts for a large percentage of the burden of disease.

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I N N O VAT I O N S F O R V E C T O R C O N T R O L

A

comprehensive global allcause mortality rate assessment comparing the years 1990 and 2013 showed that life expectancy for both sexes increased from 65.3 years to 71.5 years. Infectious or communicable diseases account for 43% of these deaths. When ­mortality is profiled against age the numbers show that a large proportion of children still die before the age of 5 years (Fig. 1).

Although mortality in this ­category has fallen by 52% since 1990 this is still a major issue in most low-income countries.

Malaria accounted for more than 0.5 million of the under 5 deaths in 2013, making it one of the highest causes of infant mortality, with the burden falling disproportionately on sub-Saharan Africa and Asia. This level of infant mortality is unacceptable, and more needs to be done to reduce the deaths of children under five years of age.

Moving towards increased equity in health Moving collectively from international targets such as the

Millennium Development Goals (MDGs) to Sustainable Develop­ ment Goals (SDGs) raises expectations of increased equity in health. The “Lancet Commis­ sion on Global Health 2035: A World Converging within a Generation” suggests that such a grand convergence in health between rich and poor countries can be achieved by 2035.

However this will require improved health systems and services, improved tools and technologies and greater uptake of these innovative new tools.

All-cause global mortality rates 15.0

GBD super region 1990 Sub-Saharan Africa Southeast Asia, East Asia, Oceania South Asia North Africa, Middle East Latin America, Caribbean High income Central Europe, Eastern Europe, Central Asia

12.5

Deaths (millions)

10.0

2013

7.5

5.0

2.5

0

0-4

5-9

10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79

Fig. 1: Rates in 1990 and 2013 split by age.

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≥80

THE GREATEST CHANGES are seen on the left in children under 5, where death rates dropped dramatically between 1990 and 2013, and on the right, where increased death rates in 2013 reflect reduced child mortality and longer life expectancy.

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Photo: Stevo Oruma Abalo & Peris Agengo (With permission of USAID/PMI)

Historically low and middle income countries that aggressively adopt new tools and technologies would see an additional 2% per year decline in child mortality rates compared with non-adopters. Given the contribution of insect-borne disease to human morbidity and mortality, innovative new vector control tools that can be used at scale to prevent a range of these diseases will have a significant role to play if such a convergence is to be achieved.

Neglected Tropical Diseases – target for ­elimination Some diseases are excellent proxies for poverty and provide a measure of the state of the local health services. These are likely to be increasingly important as progress towards the SDG targets is monitored. The Neglected Tropical Diseases

DELIVERING IRS in remote parts of Africa can be a challenge, here by bicycle in Uganda.

(NTDs) fit within this category.

They are a group of 17 lesser known chronic infections that primarily affect poor and disenfranchised communities. NTDs are ­ endemic in 149 countries and affect an estimated 1.4 billion people. Six of these diseases are transmitted by insects or bugs. Diseases such as filariasis rank in the top 30 causes of disability in sub-Saharan Africa.

This disease, along with Onchocerciasis, is being targeted for elimination as a public health problem primarily by using Mass Drug Administration (MDA), while Chagas is being eliminated primarily by vector control. However after several rounds of MDA in many countries, and a restriction on the use of MDA in Loa Loa transmission areas, it is evident that

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d­ isease prevention through vector control will need to be ­ increased if elimination targets are to be reached.

The increased importance of vector control is acknowledged in the recent WHO report on NTDs “Investing to Overcome the Global Impact of Neglected Tropical Diseases” where the operational budget for MDA of US$ 750 million per year rises to US$ 2.7 billion per year when operational implementation of effective vector control is taken into account.

Dengue and Chikingunya causing concern In contrast to the optimism around the elimination agenda for a number of NTDs, arboviral diseases such as Dengue and Chikingunya are causing increasing concern, as they spread rapidly, often linked to 15

I N N O VAT I O N S F O R V E C T O R C O N T R O L

urbanization and population movement. Control of the mosquito vectors is the main ­ response to epidemics, but current interventions are not ­ optimal. Here there is increased opportunity for new products in this area.

The innovation pipeline While Integrated Vector Management (IVM) is recommended for prevention of insectborne diseases, in reality the majority of large-scale effective interventions are insecticide based. For example for malaria, indoor residual spraying (IRS) and long-lasting insecticidetreated nets (LNs) are the two major interventions used, ­supplemented by larviciding in

appropriate circumstances.

There are obvious gaps in the product portfolio. These include effective products for the control of outdoor biting, daytime biting and outdoor resting disease ­vectors. Alternative insecticides to supplement the very small number of insecticides that can be used in public health are badly needed, alongside improved formulations that will extend the efficacy of the control period.

IVCC and collaborative projects with Bayer To tackle some of these gaps a product development partnership the Innovative Vector Control Consortium (IVCC) was established in 2005, with a major

The current distribution of pyrethroid resistance in Anopheles in Africa

investment from the Bill and Melinda Gates Foundation. The IVCC works with the agrochemical sector to develop innovative new products for vector control against well-developed target product profiles. Bayer was one of the first major agrochemical companies to establish collaborative programs with the IVCC, with projects for an extendedlife IRS formulation of pyrethroids and a major discovery and development project to ­identify new public health insecticides that are unaffected by cross-resistance to any of the currently used insecticides.

Threat of insecticide resistance While the scale up of insecticide-based disease prevention programs is already producing enormous public health benefits, one inevitable side effect of this is the selection of resistance to the insecticides that are used.

Where the range of potential insecticides that can be used is very limited, and there is over reliance on a single insecticide class, this could have catastrophic consequences for sustainable disease prevention.

Before the large-scale distribution of pyrethroid treated bednets in 1990, there were only a RED DOTS MARK AREAS OF RESISTANCE to pyrethroids, green dots show areas where mosquito populations are still susceptible to the effect of this class of insecticide.

Fig. 2 / Source www.IRmapper.com (June 2015)

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The author: JANET HEMINGWAY Liverpool School of Tropical Medicine, Liverpool, UK

limited number of reports of pyrethroid resistance in Anopheles gambiae, a major African vector of malaria. An. funestus, another important vector, remained fully susceptible, despite pyrethroids being used extensively to control agricultural pests in Africa.

The first pyrethroid resistance mechanism to be selected in An. gambiae was a target site resistance (known as kdr). Although there are several variants of this resistance mutation, all confer only a low (<10-fold) level of resistance. This resistance mechanism in isolation appears to be operationally insignificant, and led to some complacency that resistance was unlikely to be an issue for the efficacy of LNs or IRS. The first warning that resistance may adversely affect malaria control came from An. funestus in Southern Africa. For many years this species was thought to have been eradicated from South Africa, but selection of a metabolic form of pyrethroid ­

resistance in Mozambique and the subsequent spread of this back across the border into South Africa coincided with a minor epidemic of malaria despite intensive pyrethroidbased IRS. The strain collected from Southern Africa at the time is now a standard resistant strain employed in the screening of potential new insecticides, since the 100-fold + pyrethroid resistance also produces cross resistance to a range of other ­ insecticides.

Super resistance could impede malaria control This kind of pyrethroid resistance was subsequently selected in An. funestus and An. gambiae from a range of different locations throughout Africa. Even more worrying was the recent selection of a super resistant strain of An. gambiae in West Africa. Again the resistance is metabolically based and the resistance conferred is about 1,000-fold. If this type of resistance spreads, then pyrethroids are likely to rapidly become ineffective against the resistant insects.

The level and speed of resistance selection in African vectors has led several individuals, including Alan Magill, who heads the Bill and Melinda Gates Foundation Malaria Section, and Pedro Alonso, the Head of the WHO Global Malaria Pro­ gramme, to publically state that pyrethroid resistance is probably the most important issue impeding malaria control efforts today.

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The need to relieve selection pressure on pyrethroids The need for innovation in this area is obvious and the quicker new insecticides can be brought to market to relieve the selection pressure on pyrethroids the better. However, we need to ­ learn from the lessons of the past and ensure that any new insecticides are introduced into control programs as part of a carefully planned global resistance ­management program. This will safeguard the use of these ­products for the long-term p­ ublic good.

CONCLUSION Across the agrochemical industry there is an exciting pipeline of potential new public health insecticides.

There is also increasing ­recognition that these need to be brought to market in a timely and effective manner and a growing consensus on how this should be done. The stakeholder alliance of donors, agrochemical companies, regulators, implementers and others need to ensure that the innovative efforts of the last decade are effectively translated into impact, reducing the heavy burden of ­disease that still falls on many of the world’s poorest communities.

Article on the enclosed Public Health CD-ROM

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Vector control

The challenges of developing new vector control solutions With more than half of the international funding for malaria control being spent on vector control commodities or activities, resistance by malariatransmitting mosquitoes to the limited range of insecticides currently ­recommended by the WHO is now a well acknowledged and recognized problem. Here we discuss the considerations taken into account when ­developing new public health i­nsecticides, and the potential advantages of insecticide mixtures for indoor ­residual spraying (IRS).

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anaging the spread of Return on investment support the development of new insecticide resistance is a innovative solutions must be jusshared responsibility and one The only way for the production tified against all other options to that requires what the WHO and supply of important vector generate return on investment.

Global Malaria Program refers control commodities to remain The ongoing attractiveness of to within their 2012 Global Plan sustainable is if a market exists the market is therefore important for Insecticide Resistance to justify their continued manu- in terms of the probability of Management (GPIRM) as a facture. That market must return on the investment.

“Collective Strategy”. Within remain attractive over time to this plan, one of the five key pil- justify some level of further How does that relate to the lars is the “development of new investment into innovation in option to invest in developing innovative vector control tools”, order to bring new, improved new insecticides for public a responsibility that is health? First of all, if seen to lie firmly with “Insecticide resistance is the greatest ­ we reflect on the conmanufacturers and cept of “time” within current threat to the future of malaria the discussion on Product Development Partnerships (e.g. the control and to the sustainability of the insecticide resistance IVCC). it is clear that this is achievements of recent years” not a “new” issue; it Bayer is a good exam- Pedro Alonso, Director of the WHO Global Malaria Program, Geneva; has long been talked January 2015 (http://www.rollbackmalaria.org/) ple of one of the leadabout, and many influing R&D manufacturential ­voices in the ing companies that have not only solutions to market that help malaria vector control commutaken the issue of insecticide address challenges such as nity have expressed concern for resistance management (IRM) insecticide resistance. From a the last fifteen years or more. very seriously for some time, but business perspective, especially also willingly assumes this a business where private share- Visibly growing market responsibility. But what kinds of holders expect a return on their things do we evaluate when it investment (their retirement All the insecticide modes of comes to making a decision to incomes may depend on it), the action for vector control we have internal resources required to today were already available invest?

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during the early 2000s. In recent years we have simply seen the addition of specific formulations of those compounds (e.g. for organo­ phosphates) that make them more cost-effective options than they were in the past.

Importantly, the investment into malaria control operations fifteen years ago looked very ­ different from how it does today, and so, from a manufacturer’s perspective, the visible “market” appeared much smaller.

Re­ flecting on the scale-up in vector control interventions ­ between 2000 and 2015, from any manufacturers perspective it is fair to say that the market has changed dramatically; the global distribution of long-lasting insecticide-treated nets (LNs) has increased more or less steadily from an estimated few million nets prior to 2004, to more than 200 million in 2014 (Figure 1).

IRS coverage) also increased substantially over this time ­period. For example, WHO figures indicate that approximately 22 million people were protected by IRS in Africa in 2006 (World Malaria Report) compared with about 55 million in 2013, reflecting a three-fold increase in international and domestic funding available for malaria control over that period.

In 2006 the main insecticides used for IRS were pyrethroids and DDT, both relatively cheap at the time. Market pricing for these IRS commodities in 2006 resulted in an approximate cost per household sprayed of US$ 2, and the total global market value for IRS commodities at the time was probably far less than US$ 50 million. In 2013 a larger proportion of households were sprayed with more expensive non-pyrethroid insecticides, with an average cost per house-

The visible increase in demand between 2004 and 2010 was so important and substantial that the market became attractive enough for several other suppliers: nine suppliers are linked to WHOPES recommended nets today compared with two in 2004. In doing so competition increased and pricing of nets went down (estimated average pricing for a standard sized net was well above US$ 5 per unit in 2004 and had dropped to about US$ 3 by 2012).

In the case of indoor residual spraying (IRS), the number of countries routinely implementing IRS (as well as the overall

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hold exceeding US$ 5, and the market today is estimated to well exceed US$ 50 million.

Market conditions have therefore clearly changed (i.e. grown) in terms of attractiveness over the last ten to fifteen years – which gives greater incentives for R&D companies to invest into innovation.

Robust future-oriented products Of course, the market may look more attractive now than it did ten years ago, but given the time required to bring a new product to market (from about five years for an existing compound, to fifteen years for a completely new compound), the key question is what will the market look like in ten years’ time? Market conditions at the time of commitment to developing a new

Global distribution of LNs 2004 to 2014 200,000,000 150,000,000 100,000,000 50,000,000 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Fig. 1: The volume history of global distribution of long-lasting insecticide-treated nets (LNs)

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product can be very different to the market conditions when a new product is ready to go to market. One example of this was Bayer’s experience with developing K-Othrine™ PolyZone, a deltamethrin (pyrethroid) based IRS solution with longer-lasting activity. Development of this product started in 2008 as part of the IVCC group of projects, but by the time it achieved WHOPES recommendation and was available for sale (2013), the market relevance of pyrethroids for IRS had diminished significantly as a result of resistance. Therefore it is increasingly important for companies to develop products that fit more robustly into changing market conditions and can stand the test of time.

Fig. 2

It is expected that a number of new insecticide modes of action will be added to the options available for vector control over the coming years; for example, Figure 2 illustrates what the picture might be in five years’ and ten years’ time.

Who can bring new IRM solutions to market?

There are basically two options to develop a new insecticide for public health use: either develop it from scratch or repurpose one already in use in agriculture (see below).

In the context of the market becoming more attractive for investment into development of new modes of action, distinct

differences exist between suppliers of nets and IRS solutions. Of the nine suppliers currently holding a WHOPES recommendation for a LN, three (Sumitomo, BASF and Bayer) have in-house expertise and capacity to develop new insecticides; the others rely on the supply of active ingredients from third parties. For IRS, basically four primary manufacturers have activity in this area (the three companies mentioned above plus Syngenta). All of these companies have a primary focus on developing compounds for the larger market of agriculture, and therefore potential libraries of compounds to screen and explore for public health.

The potential evolution of insecticide availability and development for IRS and LNs over the next ten years

2015

Intensification of vector control efforts LNs only with pyrethroids Pyrethroid resistance widespread

2020

3 modes of action on nets?

6-7 modes of action for IRS Greater choice available for IRS Resistance easier to manage

2025

5 modes of action on nets?

7 modes of action for IRS Competition driving prices down Resistance management a routine?

Malaria elimination in more countries

LNs

IRS

LNs

IRS

LNs

IRS

Insecticide classes available

Pyrethroids

Pyrethroids, Carbamates, Organophosphates, Organochlorines

Pyrethroids, Juvenile hormone analogue, Pyrroles

Pyrethroids, Carbamates, Organophosphates, Organochlorines, Pyrroles Neonicotinoids, Bayer Project 2

Pyrethroids, Juvenile hormone analogue, Pyrroles, +IVCC-PHI x3?

Pyrethroids, Carbamates, Organophosphates, Organochlorines, Pyrroles, Neonicotinoids, Bayer Project 2 +IVCC

Developments in process

Pyrroles, Juvenile hormone analogue, +IVCC AI’s

Pyrroles, Neonicotinoids, Bayer Project 2

IVCC-AI’s

IVCC-AI’s

???

???

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Suitability of new agricultural compounds for IRS or LNs It can take between four to seven years to develop a new product based on a repurposed, existing insecticide active ingredient (i.e. one already used in agriculture or another market). The investment required is significantly lower (typical development costs are usually less than € 10 million) than developing a new insecticide completely from scratch. The chance of success is also higher with this option.

Developing a new formulation from an existing active ingredient has a chance of success generally above 70% (within the allocated budget and timeframe). This is mainly due to the fact that the major risk of failure linked to human and environmental risk assessments of the active substance has already been addressed during the active substance development.

With the urgency associated with the need to manage insecticide resistance in malaria vectors now, and the market uncertainty already described, this option is clearly attractive – but it is still not simple. The four insecticide families (pyrethroids, carbamates, organo­ phosphates and organochlorines) that remain in use for public health today have two distinct features which have made them suitable for these use patterns: broad-spectrum contact activity and longlasting residual effect. The pyrethroids (introduced through the

The authors: JUSTIN MCBEATH

FRÉDÉRIC SCHMITT

Market Segment Manager – Malaria Vector Control

Global Project Manager – Vector Control

Bayer S.A.S. Environmental Science, Lyon, France

1970’s and 1980’s) were arguably the last group of insecticides developed that retained these features.

Shifts in target product profile The focus in developing agricultural compounds since the advent of the pyrethroids has generally moved towards more selective compounds. Contact activity has become less important as it is recognized how important it is to leave populations of beneficial insects intact in a cropping environment; the greater focus is now towards systemic activity, where a crop plant can absorb the compound and target plant-feeding insects directly. At the same time, residual activity has become less important since it is important to minimize residues in food crops.

Modes of action have also been developed that are highly selective towards specific groups of pests (e.g. towards Lepidoptera or Hemiptera). This shift in target product profile for agricul-

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tural insecticides, coupled with historical market uncertainty around public health has arguably been the key reason why no new insecticides ideally suited for public health have been available.

The importance of IVCC So what about developing a new compound from scratch, dedicated to public health and not derived from agriculture? Well, it can take ten to fifteen years of R&D and regulatory studies to develop a new insecticide compound, and it requires an investment somewhere in the range of € 60 million to € 200 million.

First of all a new active ingredient must be “discovered” – a challenge in itself when hundreds of thousands of molecules may need to be screened. The new molecule must have an activity superior or equivalent to existing solutions, ideally have an unrelated mode of action, and then be subjected to a long phase of additional screening to ensure

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its toxicological acceptable.

profile

is

Even after a candidate molecule has been identified it may still fail other tests in the early development phase. This clearly requires a large level of investment, and the uncertainty and relatively small size of the vec-

tor control market means the risk of return on investment is significant if that molecule has no potential uses in other markets. One of the ideal goals of developing new compounds for public health is to have modes of action available that are not used in agriculture, since emerging evidence suggests that agricul-

Fludora™ Fusion

Greater robustness from a combination Fludora™ Fusion is a combination of the repurposed agricultural insecticide clothianidin (a neonicotinoid) and the pyrethroid deltamethrin.

This mixture contains two insecticides with completely u­ nrelat­ed modes of action (important for resistance management ­purposes).

It is expected that this product will fit well into an insecticide resistance management strategy which incorporates pro-active rotational use with other insecticides. In the future, as we see the “mono-selection ­ pressure” of pyrethroids from nets change, ­ with the advent of new modes of action, then mixtures such as this one should become even more important for mainstream IRS use.

In the original phases of development of this product a range of insecticidal compounds were identified from agriculture (e.g. several in-house neonicotinoids, phenyl pyrazoles, and others) that had modes of action in-

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teresting enough to explore against ­pyrethroid-resistant ­mosquitoes. When the screening was first completed with the compounds on their own, using standard WHO Bio­ assay criteria, for many of the compounds the ­biological performance seemed not strong enough to justify further development. Therefore the more promising compounds were explored in mixtures with existing insecticides. Some ­in-house familiarity with combinations of pyrethroids and ­neonicotinoids had already been established with the product Temprid used in professional pest control in the USA and Australia against insecticide resist­ ant bedbugs. The combination of deltamethrin and clothianidin subsequently showed very good results in laboratory bioassays across a range of different mos­ quito strains expressing differ­ent

tural insecticide use in some areas directly affects the selection of resistance in malaria vectors.

The IVCC plays a key role, helping with some of the financial burden in the development of completely new compounds dedicated to public health uses.

The good news is that currently,

resistance mechanisms, as well as good residuality across a ­range of ­surfaces.

Results were promising enough to take evaluation of this mixture to the field, where the additional relevance of including delayed mortality in the trial protocols became apparent. Delayed mortality is clearly an important feature and must be explored and understood better in both new and older compounds. It could make more ­options available for public health use and open the door to a range of other alternatives that make it easier to manage the spread of insecticide resistance in malaria vectors. With Fludora™ Fusion we see greater efficacy and robustness of performance from this combination than we have from either active ingredient applied alone.

Finally, and very importantly, we expect to be able to deliver this more robust product at a ­price point which improves the cost effectiveness compared to other non-pyrethroid IRS solutions available today.

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the activities of Bayer and other companies in conjunction with IVCC look promising, possibly being able to deliver completely new modes of action (suitable for use on nets and for IRS) from 2022 onwards.

Drivers for developing new products To mitigate the risk of a product development outcome with diminished market relevance (see above: Robust futureorient­ed products) it is increasingly important to take potential scenarios into account, and design a target product profile that would better suit long-term needs and be more robust under changing market conditions; this robustness needs to not only reflect biological efficacy but also take into account cost-effectiveness in a potentially more competitive market environment.

A number of companies have announced their intention to bring new modes of action to market and so a position of more intense competition can be expected, with greater emphasis on cost-effectiveness. Important­ ly, this is good news for achieving wider coverage with malaria interventions.

Focusing on IRS: at present there are three clear main drivers for development of new products: • Introduce a new mode of action not yet present in malaria vector control.

• Target a residuality that ex­ceeds six months across a range of relevant surfaces.

• Improve the position of costeffectiveness compared to existing solutions (partly ­related to the residual performance).

At this point in time it is hard to see the need for reducing the emphasis on any of these three factors over the next five years.

However concerning the first point, obviously once the new insecticide is on the market for a few years it ceases to be new, and resistance can potentially develop towards it if its usage is not managed carefully. One option to protect this position is to introduce this new insecticide in combination with another mode of action (as a mixture) to help preserve the long-term effectiveness of the combination product. For precisely this reason we think insecticide mixtures are attractive as long-term solutions for IRS, which is why a mixture has been chosen as the focus of our current development product – Fludora™ Fusion (see box on the left).

Developing a new IRS mixture IRS with non-pyrethroids, in addition to being an effective intervention against malaria transmission, currently represents the only means to manage insecticide resistance in malaria vectors. As indicated in Figure 2, it seems probable that in five years’ time, alternative modes of action will already be available for use on nets. Coverage with those new solutions will be starting to build up, reducing the

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selection for pyrethroid resistance, and alongside greater choice in IRS solutions, rotation or mosaic strategies will (should) make insecticide resistance man­ agement more effective.

Anticipating a heightened aware­ ­­ness of how important it is to proactively manage resistance, the relevance of insecticide mixtures should increase.

CONCLUSION The vector control market has changed over the past ten years. This creates enough incentive for Bayer, a leading responsible company involved in the fight against malaria for 50 years, to assume the role expected of it and to invest in new solutions to help address insecticide resistance. Repurposing of existing agricultural compounds is seen as a means of achieving the goal of fast availability. However new compounds not present in agriculture also play an important role, and the vector control community needs the support of IVCC to achieve new solutions. In the future insecticide mixtures with better cost-effectiveness will become increasingly important, but any new solution must also consider the overall landscape of new insecticide availability and potentially changing dynamics of insecticide resistance selection.

Article on the enclosed Public Health CD-ROM

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Pyrethroids

Metabolic resistance of insects It is vital to understand the molecular mechanisms used by insect vectors to deactivate the insecticides used in their control, since such mechanisms lead to tolerance and then insecticide resistance. Only based on this knowledge can new active compounds and effective agents be discovered and developed for control and eradication of disease transmitting mosquitoes. This ­report summarizes the different metabolic resistance mechanisms used to breakdown the most commonly applied insecticide class in vector control, the pyrethroids.

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ll living organisms permanently exchange molecules with their environment.

Substances are taken up, metabolized and excreted by ­ breathing, ingestion or simply by transfer through the cuticle or skin. Many molecules have harmful effects and must be detoxified quickly to avoid damage. An insect’s ability to ­ degrade toxic compounds such as insecticides is essential for it to survive, where degradation means transforming a harmful target molecule into a structure that is less toxic, allowing rapid excretion.

Biocatalysts do the work Such transformation processes are managed by enzymes, biocatalysts with the ability to accelerate the speed of a chemical reaction by decreasing the activation energy necessary to open solid bindings and make

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rearrangements. With the help of enzymes a chemical reaction can take place at ambient temperatures, whereas the same reaction without the involvement of enzymes would need to be heated up before it can react in the same way. The chemical compound changed in the reaction is called the substrate, but the enzyme itself is not altered during the reaction process, and can trigger additional reactions.

The majority of enzymes are proteins with a complex physical structure required for their function. They all form a socalled catalytic center where the substrates are embedded, bound and transferred. Once the enzyme-substrate complex is created, the reaction can take place and release the resulting reaction products. For a long time it was hypothesized that the structure of the catalytic centre is complementary to its substrate, rather like a key fitting a keyhole; but nowadays it is accepted that the catalytic centre

does not need to exactly fit the form of the substrate, and that the final complex is only created after binding (induced-fit model).

The specificity of a binding domain differs among groups of enzymes. Some of them only bind one particular molecule, others are less specific and therefore cover a variety of different substrates. Enzymes responsible for the detoxification of foreign molecules (xenobiotica) need to have a flexible catalytic center or a general target structure to handle such unknown compounds. The fact that this flexibility is limited is encouraging for the agronomic industry, since they do not have to design completely new active ingredients that do not fit into the catalytic center in order to

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withstand degradation in the target insect. At the same time these compounds need to provide structural sites that can be used by degradation enzymes of beneficial insects or non-target organisms to avoid toxicity for these species.

The names of enzymes are defined by the Enzyme Commission of the International Union of Biochemistry & Molecular Biology (IUBMB).

Generally the name is based on the reaction it catalyses, combined with the ending –ases, although enzymes described before this committee was founded kept their generic names (e.g. trypsin or pepsin).

Six main enzyme-classes are described: • Oxidoreductases • Transferases • Hydrolases • Lyases • Isomerases • Ligases This article mainly focuses on the first three classes, particularly the class of oxido­reductases and the associated degradation events working against pyrethroids.

Oxidoreductases Oxidoreductases are enzymes involved in oxidation and reduction reactions in biological systems. Oxidation delivers ­ redundant electrons that at the

same time are essential for reduction processes; therefore these reactions are often linked to each other. Monooxygenases, for example, use dioxygen (O2) to insert one oxygen atom into their substrate. At the same time an H2O molecule is created using co-enzyme NADPH2 and the second oxygen atom. Since monooxygenases change two substrates in one reaction they are also called mixed function oxidases (MFO). Since these enzymes transfer one oxygen atom each to the corresponding substrate, they are called monooxygenases, in contrast to ­dioxygenases, which transfer both oxygen atoms to one substrate.

Cytochromes degrade pyrethroids To handle oxygen atoms the dioxygenase proteins contain a heme-complex to bind dioxygen1. These proteins are called cytochromes, and if they are analyzed in a spectrometer, a characteristic peak is visible at a wavelength of 450 nm (called the Soret band). Therefore this class of enzymes can be accurately described as Cytochrome P450 monooxygenases (CYPs)1.

To date, 170 CYP genes have been described for mosquitoes belonging to the genus Culex2.

This spotlights their important role in many metabolic processes.

The author: SEBASTIAN HORSTMANN Bayer CropScience, Monheim, Germany

are found in more or less every insect-tissue, but significantly concentrated in the mitochondria and microsomes. For some decades now, these enzymes are known to be involved in adaptive mechanisms of insects that live on plants creating toxic substances3, and in insecticide resistance4. Growing tolerance towards a certain insecticide is often indicated in bioassays where two different strains of the same species are compared.

The involvement of cytochrome P450 monooxygenases in pyrethroid-detoxification processes were often shown indirectly by using monooxygenase inhibitors such as piperonyl-butoxide (PBO). This inhibitor is known to not only block cytochrome P450 monooxygenases but also increase the uptake of active ingredients through the insect cuticle. As a result, the blocked enzymes are unable to degrade the pyrethroid molecule and the tolerance towards it is no longer measurable.

In addition to many other functions, CYP enzymes are involved in the degradation of xenobiotica. Importantly, these enzymes

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Several institutes have performed metabolite studies with pyrethroids using microsomal extracts. Microsomes are vesicle-like cell structures con­ taining high amounts of P450 monooxygenases. Incubation of pyrethroids with the microsomal extracts of different organisms revealed the first metabolite of the degradation process of pyrethroids, which is often hydroxylth ated in the 4 position of the phenoxybenzyl-ring (see Figures 1 and 2).

Detoxification of e.g. permethrin (Figure 2) takes place in different steps and starts with hydroxylation at the phenoxy-

benzyl-moiety. Here binding of the monooxygenase at this moiety is essential and the product of this reaction step is 4´hydroxypermethrin5.

A similar way of degradation is described for many other pyrethroids including deltamethrin6,7.

Here the first metabolite is 4´hydroxydeltamethrin. This principle of degradation also works on non-pyrethroids such as pyriproxyfen. This insect juvenile-hormone mimic also contains a phenoxybenzyl group and after incubation with flymicrosomes the 4´hydroxypyriproxyfen metabolite can be 8 identified .

Avoiding cross-resistance For the design of new active ingredients knowledge about detoxification pathways is highly important to avoid cross-resistance. Moreover these findings are valuable regarding the application of known insecticides. In the case of pyrethroid resistance triggered by the CYP class of enzymes, the use of structurally different active ingredients can avoid the degradation and therefore overcome the metabolic resistance. The active ingredient transfluthrin for example belongs to the class of pyrethroids, but lacks a phenoxybenzyl-moiety (Figure 3).

Transfluthrin

Permethrin

phenoxybenzyl-moiety

Figure 1: Permethrin as an example of a pyrethroid containing a phenoxybenzyl-moiety.

tetrafluorobenzylmoiety

Figure 3: Transfluthrin as example of a pyrethroid containing a tetrafluorobenzyl-moiety.

Permethrin

4-hydroxypermethrin

Figure 2: First step of the degradation pathway of permethrin triggered by monooxygenases starting at the phenoxybenzyl-group.

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Therefore this molecule cannot act as a binding partner or substrate for the respective ­ monooxygenases and the hydroxylation reaction will not take place. Transfluthrin offers the possibility to control this kind of pyrethroid-resistance in insects. Further description of the resistance-breaking potential of transfluthrin and more detailed analysis will be published soon.

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Transferases The second enzyme class comprises the transferases, which trigger the transfer of functional groups, e.g. methyl-groups or others, from one donor molecule to another. For example, the main reaction of glutathion-S transferases is conjugating glutathion to the substrate. One main effect of this reaction is the conversion of a lipophilic substrate to a more hydrophilic compound in order to transfer it out of the cell and excrete it. A popular example is the detoxi­ fication of dichlordiphenyl­ trichlorethan (DDT) to the ­non-toxic form dichlordiphenyldichlorethan (DDE). In this reaction a nucleophilic form of glutathion (GSH) interacts with DDT and removes hydrogen, which also leads to eliminating chlorine and creating DDE. In terms of pyrethroid detoxification it is reported that glutathione is possibly conjugated to the active site of pyrethroids, causing an inhibitory effect on pyrethroid activity at the sodium channel9.

Hydrolases Members of the third class of enzymes are called hydrolases e.g. esterases. These are able to split compounds at the ester connection into an acid and alcohol part. Besides other classifications the esterases can be divided into two important types, the carboxylesterases and the phosphatases. The carboxylesterases focus on the ester-bindings con-

taining a carbon atom (Figure 4), as in pyrethroids or organophosphates.

Figure 4: Target binding site for carboxylesterases.

The phosphatases target the phosphorester binding (Figure 5) containing a phosphor atom, as in many organophosphates.

Figure 5: Target binding site for phosphatases.

Regarding pyrethroid detoxifi­ cation, a target site for carboxylesterases exists in nearly all pyrethroids except for the nonester pyrethroid etofenprox.

Cleavage at the ester bond performed by esterases seems to be a major degradation step, and the pyrethroid-acid as well as the alcohol-moieties are detectable as metabolites in the urine of rats given cypermethrin10.

Notably, also the 4´hydroxyphenoxybenzyl metabolite is detectable, which indicates that the pyrethroid was modified beforehand at the phenoxybenzyl-moiety by the CYPs described above. It is possible that this modification improves the conditions for esterase ­activity.

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Increased esterase levels were also observed in pyrethroid resistant mosquitoes together with monooxygenases11. This shows that different detoxification pathways can work closely together and make the processes more complex. Insecticidal compounds that can prevent certain metabolic pathways, as transfluthrin does, will be of tremendous importance for future vector control in order to face the upcoming resistance threat.

CONCLUSION A deeper understanding of the metabolic pathways and enzymes involved in detoxification pathways will help support the design of more effective insecticides avoiding cross-resistance as well as taking into account potential structural modifications of existing active agents. Such targeted development should help the discovery of resistance-breaking active ingredients for future vector ­control products. Never­­the­ less, it is essential to apply resistance management programs from the IRAC (In­­sec­ ticide Resistance Manage­ment Committee) like mode of action rotation or mosaic treatments to avoid or at least delay future resistance developing against new active ingredients. www.irac-online.org/ Article with references on the enclosed Public Health CD-ROM

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Photo: arctec

IN VITRO ASSAY for head lice products.

arctec

Evaluation of arthropod control products

T

he London School of Hygiene & Tropical Medicine (LSHTM) is a worldleading centre for research and postgraduate education that specialises in public health, with an outstanding global reputation as a leading authority on insect vector and disease control.

Within the Faculty of Infectious and Tropical Diseases, through the work of the late Nigel Hill and Chris Curtis, the LSHTM pioneered the use of insect repel28

Launched in 2010 at the London School of Hygiene & Tropical Medicine, arctec – the Arthropod Control Product Test Centre – builds on the School’s longstanding tradition of outstanding research in insect repellents and insecticides. With high quality control standards, it adds rigorous and internationally recognised testing facilities for novel and existing arthropod control products. lents as an instrument of public health. In the 1980s these ­scientists used their expertise to provide efficacy testing of arthropod control materials for commercial companies.

The artec team In November 2010, this service was formalised to create arctec (the Arthropod Control Product Test Centre) – a professional commercial service to external

clients, operating within the LSHTM. arctec was launched by James Logan, who is the Director of arctec, a Senior Lecturer in Medical Entomology and an active research group leader at the LSHTM. Over the past five years, arctec has grown from a team of just two staff members to a bustling 14-member team.

The team is made up of highly skilled entomologists, research nurses and clinical trial coordiPUBLIC HEALTH JOURNAL 26/2015

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arctec is now a Division of Chariot Innovations Limited, the newly formed commercial arm of the LSHTM, which aims to use research and knowledge to impact innovation through products, services, practices and ­policies, resulting in social and economic benefits.

Driving innovations to solutions With some of the world’s leading expertise in the field of entomology and vector control, the team behind arctec has become a thought leader in the field of efficacy testing. Having formed successful partnerships with key academic experts, leading pharmaceutical and chemical manufacturer stakeholders in industry as well as regulatory agencies, arctec is at the heart of bridging innovation and markets through providing the high quality standards necessary in efficacy evaluation.

Photo: arctec

nators, many of whom have studied to PhD level. Together they have many years of valuable experience in laboratory and field-based entomology as well as clinical trials. It also has several academic key advisors who are world-leading experts in their field that it can bring on board as consultants for specific projects. In addition to the scientific team, arctec has recently expanded its business development team to respond effectively to the increasing number of customer requests while pursuing its steep growth even further.

EXPERIMENTAL HUTS at a PAMVEREC field site in Tanzania.

As well as standard testing, the team at arctec enjoys the challenge of developing new ­ experimental protocols with its partners to help streamline the transition of novel technologies from the laboratory to the market. In the quest to help combat insecticide resistance and reduce outdoor transmission of vectorborne diseases, this includes evaluating new active ingredients and liaising with regulatory agencies on modifications of standard methods.

Services offered by arctec arctec’s services are focused on the development, consultancy and evaluation of arthropod control products from initial stages of efficacy testing for raw materials and active ingredients through to registration of fully formulated, commercially viable products. Product types range from repellents including sprays, lotions, wipes, sticks and patches; insecticides including formulation variations, treated fabrics

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and textiles such as bednets, clothing and blankets; treated paints and coatings; and attractants and lures in laboratorybased behavioral arenas and olfactometers.

Field testing around the world Clinical trials are also available for head lice and after-bite treatment products. The state-of-theart laboratories at Keppel Street allow high quality testing, while access to valuable field sites around the world enables full field trials of products. arctec has access to a global network of field laboratories and testing stations, some of which are centres for WHO Pesticide Evaluation Scheme approved testing.

Access to a range of arthropods The vast insectaries at the LSHTM give arctec access to a plentiful source of arthropods including mosquitoes from the genera Aedes, Anopheles and Culex. In addition, they rear

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Photo: arctec

PREPARING FOR AN ARM-IN-CAGE EXPERIMENT for evaluation of a repellent product.

house dust mites, sandflies, cockroaches, bed bugs, house flies and triatomine bugs. They have links with external agencies, which means they also have access to an increasing range of other arthropods such as ants, head lice, Culicoides midges, Stomoxys flies, food storage pests and clothes moths, as well as resistant strains of mosquitoes.

Standardised quality assurance With a large student base at the LSHTM, arctec has access to a large supply of volunteers who have signed up to their database and can be called upon to participate in clinical trials. arctec follows standardised scientifically rigorous protocols which comply with regulatory authorities such as the Health and

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Safety Executive and the Medicines and Healthcare Products Regulatory Agency in the UK, and equivalent regulatory bodies in the USA, Canada, and worldwide, for the evaluation of technical material and final products. arctec’s clinical trials are also monitored and audited by the LSHTM’s Clinical Trials Quality Assurance Manager and undergo thorough quality control. All its staff are trained in Good Clinical Practice (GCP) and they liaise with the LSHTM’s inhouse Ethics Committee, local Research Ethics Committees, the Medicines and Healthcare Products Regulatory Agency and the Health and Safety Executive. The regulatory landscape can often be challenging for manufacturers to navigate, and arctec prides itself in offering consultancy services to help guide clients with this.

CONCLUSION arctec provides services that cover all aspects of development, consultancy and evaluation of arthropod control products at every stage. From initial discovery, through testing in the lab and field trials, to clinical trials and registration of finalized products, arctec’s team of highly qualified experts use research and knowledge to drive inno­ vation through products, services, practices and poli­ cies, resulting in social and economic benefits. http://arctec.lshtm.ac.uk arctec@lshtm.ac.uk.

Article on the enclosed Public Health CD-ROM

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Malaria eradication

Innovative vector control is vital The Bill & Melinda Gates Foundation aims to make leveraged investments toward eradicating malaria from the face of the planet. This admittedly ambitious goal cannot happen without a large dose of optimism and a careful strategy ranging from the most general considerations to the most specific activities on the ground.

The current simple equation followed by the Bill & Melinda Gates Foundation to achieve elimination of malaria is to detect the parasites in the human reservoir, eliminate parasites from people, and prevent transmission. Vector control is the key activity to prevent transmission, and until practical vaccines are available, the only way to do it.

Having eliminated malaria from 81 countries since 1945 and bringing the incidence of malaria down by about 50% over the last 15 years, we have many reasons for optimism. Most of the recent gains against the disease have been due to two interventions: insecticidetreated bed nets (ITN) and indoor residual spraying (IRS). These gains are now threatened by insecticide resistance, particularly pyrethroid resistance. Those familiar with the history of pesticide use are not at all surprised by this challenge – in fact, pyrethroids have maintained their effectiveness remarkably well.

The Foundation’s contribution to a solution has included working with industry and academic partners through a product development partnership, the Innovative Vector Control Consortium (IVCC). It has taken ten years for IVCC and its partners to identify three entirely new active ingredients suitable for use in ITNs and IRS. IVCC and industry have also

created ITNs and IRS products that use existing active ingredients that offer choices for selecting the mode of action. The bottom line is that we can overcome the resistance problem associated with ITNs and IRS, preserving the gains we have made against malaria thanks to industrial innovation.

We also need improvements in vector control ranging from better use of existing interventions to inventing transformative technol­ ogy. Vector control enjoys a large The author: DAN STRICKMAN Bill & Melinda Gates Foundation, Senior Program Officer, Vector Control, Seattle, USA.

toolbox of existing methods, including larval source management through civil engineering, chemical larval control, personal protection products, and adulticides applied in a wide variety of formats (e.g. outdoor residual sprays, ultra-low volume application, etc.). New methods, such as attract-and-kill products and spatial repellents, will further expand this toolbox. The challenge is to put these tools together into costeffective programs that gain efficiency through responding to entomo­ logical and epidemiologi-

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cal data. We all hope for large technological advances that will simplify the task of preventing transmission. Some problems seem unsolvable without such invention, such as being able to reach inaccessible populations isolated by distances, politics, or conflict. The Foundation has invested in such technologies and continues to do so, trying to perfect genetic manipulation of vector populations, develop advanced behavioraltering chemicals, and support creative methods of biological control.

The Bill & Melinda Gates Foundation and partners, including the World Health Organization, the Global Fund to Fight AIDS, Tuberculosis, and Malaria, the President’s Malaria Initiative, CropLife, and many industrial stakeholders have worked hard over the last two years to create a business environment that supports innovation of vector control tools that work against malaria transmission. Called Innovation to Impact (I2I), this partnership transitioned from concept to action in 2015, thanks to cooperation from all partners and initial funding from the foundation. We hope that I2I will release the tremendous creativity and potential of the entire vector control community, making the prevention of malaria transmission a worldwide reality.

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REGIONAL NETWORKS

Asia Pacific Malaria Elimination Network (APMEN)

The Asia Pacific region faces particular challenges in malaria control since it has twice as many vector species as other global regions, many of which bite and breed outdoors. Effective strategies require Integrated Vector Management that includes ­ knowledge about vector breeding sites and ­ ­behavior as well as monitoring insecticide resistance. In 2009 the Asia Pacific Malaria Elimination Network (APMEN) was established to support ­regional malaria elimination efforts through knowledge exchange, capacity building, leadership and advocacy.

V

ector control is a major technical challenge facing the Asia Pacific region. Although most countries in the region scaled up the distribution of vector control during the 2000s, they continue to rely on bed nets and indoor residual spraying (IRS) as the mainstays of their vector control strategies.

Although these strategies are highly effective in a high transmission context, many are concerned that these strategies may not be sufficient in an elimination setting when malaria becomes more concentrated in localized settings.

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The Asia Pacific also has 19 dominant vector species, compared to 7 in sub-Saharan Africa and 9 in the Americas1. Many of these are outdoor biting or outdoor breeding mosquitoes, which are more difficult to target through conventional vector control strategies2. Despite this vector complexity, many countries in the region lacked entomological capacity, so that they did not have sufficient knowledge about the breeding sites and behaviors of the vectors they were trying to control.

A serious and emerging threat to countries’ vector control strategies is that of insecticide resistance. Pyrethroid resistance has been identified as widespread globally and requires urgent

Photo: APMEN

Working towards malaria elimination

APMEN FELLOWSHIP ­RECIPIENT MAJHALIA TORNO IN THAILAND: Entomological knowledge about the breeding sites and behaviors of the vectors is essential to devise effective control strategies.

action in order to maintain the effectiveness of vector control interventions3. Despite the lack of comprehensive data on the extent of insecticide resistance within the Asia Pacific Region, recent data collection has confirmed that pyrethroid resistance is present in numerous Asia Pacific countries, with resistance to other insecticides including DDT, Carbamate and Organo­ phosphate also suspected. These initial findings highlight the threat insecticide resistance poses to achieving elimination goals in the Asia Pacific region, and the continuing importance of further investing in vector control methods on a country, regional and global level4.

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REGIONAL NETWORKS

APMEN The Asia Pacific Malaria Elimination Network (APMEN) was established to address such vector control problems in this region of the world (see box on the right). APMEN brings together country program managers with a range of other partners, including representatives from development agencies, scientific and academic institutions, the private sector and global leaders, working towards malaria elimination. APMEN supports countries to collaboratively pursue regional malaria elimination efforts through knowledge exchange, capacity building, and building the evidence base, as well as leadership and advocacy for elimination.

cerning Plasmodium vivax and vector ­control, and more recently surveillance and response.

Much of this has been carried out or coordinated by APMEN’s three Technical Working Groups.

APMEN Vector Control Working Group The APMEN Vector Control Working Group comprises

APMEN has carried out a number of activities to build up ­evidence around issues of special significance to the Asia Pacific region, especially con-

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APMEN Country Partners and Partner Institutions with special expertise in entomology and vector control. The Vector Control Working Group convenes each year, often in conjunction with APMEN’s Annual Meetings, to discuss key issues affecting the region as well as consider strategies and tools to overcome these challenges. The group’s objectives include advocating for the scale of vector control capacity at regional and country levels required to attain and maintain malaria elimination, as well as stimulating, and where possible coordinating, operational research on questions directly related to inten­ sified malaria control and ­elimination.

The Working Group also carries out an annual study tour where members and observers visit field sites of special interest to the host country, and share knowledge and experience surrounding vector issues, as well

WHAT IS APMEN? The Asia Pacific Malaria Elimination Network (APMEN) is a network of Asia Pacific countries and other stakeholders that are committed to working collaboratively to achieve malaria elimination in the region. Beginning with ten countries in 2009, by 2015, APMEN had grown to include 17 countries: Bangladesh; Bhutan; Cambodia; ­ ­China; the Democratic People’s Republic of Korea; India; Indonesia; Lao People’s Democratic Republic; Malaysia; Nepal; the ­Philippines; the Republic of Korea; the Solomon Islands; Sri Lanka; Thailand; Vanuatu and Vietnam.

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REGIONAL NETWORKS

APMEN ANNUAL VECTOR CONTROL WORKING GROUP MEETING, MALAYSIA, 2015: Meetings each year discuss key issues affecting the region, such as the degree of vector control required at regional and country levels.

as witness innovative and successful approaches for local vector control management.

A recent APMEN study tour to Sri Lanka in July, 2015, visited an entomological sentinel surveillance site where regular monitoring occurs to determine seasonal changes in vector densities and any changes in vector bionomics and characteristics.

The tour observed: hand collec-

Photos: APMEN

ACTIVE DISCUSSIONS AT THE APMEN ANNUAL WORKING GROUP MEETING IN THE PHILIPPINES, 2014: APMEN organizes annual meetings and workshops for knowledge sharing and expanding regional awareness about malaria elimination.

tion, larval identification, cattle baited hut collection, cattle baited net trap collection and pyrethrum spray sheet collection.

Learning from how Sri Lanka, who is nearing elimination status, operates their sentinel sites is an important capacity building activity that allows network participants to experience first-hand the changes required to move from control to elimination.

tors and vector control strategies to identify the entomological capacity and resourcing of vector control in the region, and performing a literature review on the efficacy of larviciding and repellents in an elimination setting.

APMEN has supported a number of other activities to build up the regional capacity on vector control. Five APMEN Fellow­

Other activities carried out by the Vector Control Working Group include a survey on vec34

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REGIONAL NETWORKS

APMEN VECTOR CONTROL WORKING GROUP LARVICIDING TOUR, INDONESIA, 2013: A Working Group study tour where members and observers visit field sites to share knowledge and observe innovative and successful approaches for local vector control management.

Moving towards elimination

ships have been awarded to vector control-related placements, including a special Thematic Fellowship supported by VecNet.

APMEN sees capacity building in vector control as a crucial area that needs support as countries move towards elimination.

Integrated Vector Management (IVM) becomes an important strategy for specific countries as they move closer to malaria elimination. Supporting atten-

HIGHLIGHTS OF THE FIRST FIVE YEARS OF APMEN • Played a lead role in establishing elimination as a shared, regional goal and brought global attention to the achievements and challenges faced by Asia Pacific countries.

• Established a country-led platform for elimination with robust governance processes.

• Developed a collegial space for knowledge sharing and partnerships and expanding regional awareness for elimination through well-run annual meetings, workshops, study tours and other events.

• Advocated for and built evidence around the safe and radical cure of Plasmodium

vivax, especially through the Vivax Working Group.

• Established additional Technical Working Groups on Vector Control and Surveillance and Response to build evidence and regional capacity for elimination in these priority areas.

• Built the capacity of future leaders in elimination through the APMEN Fellowship Program and other capacity building activities.

dance at IVM training was identified by the Vector Control Working Group as important to develop country teams and equip them with the necessary ­knowledge and skills to support capacity building and application of IVM approaches in their countries. APMEN has supported 16 participants from Country Partners to attend the IVM course hosted by the Malaysian Ministry of Health in both 2012 and 2014.

CONCLUSION Although awareness of regional challenges and capacity surrounding vector control are developing, vector control remains an important challenge facing the Asia Pacific region. Ongoing efforts will be necessary to continue to build evidence and capacity in these areas.

APMEN supports a range of activities, to share knowledge and experience among country program managers, partners and other stakeholders committed to working collaboratively to achieve m ­ alaria elimination in the region.

Moreover, APMEN has brought global attention to the achievements and challenges faced by Asia Pacific countries. www.apmen.org

• Continued to expand and adapt to an ever-changing malaria and public health landscape.

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Article (with references) on the enclosed Public Health CD-ROM

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REGIONAL NETWORKS

Pan African Mosquito Control Association (PAMCA)

Malaria – Africa’s modern scourge

M

alaria remains the most debilitating mosquitoborne disease, especially in SubSaharan Africa where it is one of the main causes of morbidity and a large contributor to mortality1 particularly among pregnant women and children under five years old (WHO, 2013).

Although over 290 million people across the world in over a hundred malaria-endemic countries are exposed to malaria transmission risk, Africa remains the most affected region, with 90 percent of all malaria deaths.

The problem of malaria in Africa is further aggravated by the complexity of the vectorial system. This comprises highly ­ efficient malaria vectors, including members of the Anopheles gambiae Giles and Anopheles

funestus Giles species complexes, which are widespread and difficult to control.

Despite ongoing efforts to ­combat the disease through integrated malaria management strategies targeting both the vectors and human reservoirs, the disease still persists across the African continent. According to the latest malaria reports over 600 000 people are still dying from malaria every year2.

Despite these daunting statistics, malaria is preventable and

c­urable. In the mid-twentieth century we came close to controlling it with the widespread use of insecticides and other control methods. Malaria was hugely controlled in the Americas, Brazil and in Europe through an integrated program that relied overwhelmingly upon larval control3. This experience was soon repeated in Egypt and another larval control program successfully suppressed malaria for over 20 years around a Zambian copper mine. These affordable approaches were neglected after the advent of dichlorodiphenyltrichloroethane (DDT) and global malaria control policy shifted toward domestic adulticide methods.

1

Breman, 2001 World Malaria Report, 2014 3 Killeen et al 2002; 2004 2

TO DEFEAT ANOPHELES is the primary goal of PAMCA in the war against malaria.

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PUBLIC HEALTH JOURNAL 26/2015

Photo: PeterO / Fotolia.com

African mosquito experts recently took charge in Africa’s war against malaria and mosquito-borne diseases by launching an Africa-based, African-led organization called the Pan-African Mosquito Control Association (PAMCA). The aim is to ensure that African scientists remain vigilant in the war against ­malaria and mosquitoes in their own backyard. PAMCA was created to increase the health and reduce the disease burden in Africa by promoting the control of and research on mosquitoes and to disseminate valuable information on mosquitoes across Africa and worldwide.

Photo: Malaria Consortium

REGIONAL NETWORKS

Larval-control methods should now be re-prioritized for research, development, and implementation as an additional way to roll back malaria. Since 2000, stepped up investments in malaria control (IRS, ITNs, LNs) and treatment have contributed to significant progress.

Malaria mortality rates have decreased by more than one-half in Africa and by 26 percent globally (WHO 2014). For the first time in history, defeating the disease is within reach. But we must make sure that we do not let progress reverse.

The birth of PAMCA Mosquitoes cause more human suffering than any other organism and over one million people worldwide die from mosquitoborne diseases every year.

Mosquito-borne diseases include protozoan diseases, i.e. malaria, filarial diseases, and viruses such as Dengue, Yellow fever,

Chikungunya, Rift valley fever, etc. In recent times, a number of these neglected tropical diseases have risen in prominence, such as the large-scale outbreaks of Chikungunya and Dengue in the Americas and Asia; however the extent of this problem in Africa is not known.

PAMCA is the first organization comprising Africa-based entomologists and mosquito control specialists and provides a unified voice for these professionals. PAMCA was conceptualized in 2009 after the realization that the many agencies committed to tackling malaria and other vector borne diseases are situated or based in the north, run by individuals with the best of intentions but often constrained in understanding of the local context and cultural dynamics so crucial to engaging communities. The idea for forming PAMCA was initiated by a small group of African scientists who recognized the need to empower and build the capacity of local

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AFRICA CREATES CHALLENGES for continuous distribution of lifesaving commodities, here bales of treated bed nets.

scientists to tackle mosquitoes and mosquito vector-borne diseases.

PAMCA is registered in Kenya as an international not-for-profit association and was then launched in South Africa on October 10, 2013, when the Goodwill Ambassador for the Roll Back Malaria Partnership, Yvonne Chaka Chaka officially launched the organization during a brief ceremony held at the International Conference Center (ICC), Durban, South Africa during the 6th Multilateral Initiative of Malaria (MIM) conference. The timely launch of PAMCA in 2013 in Durban, South Africa, with the vision of information sharing and providing leadership is excellent. The launch was attended by over 150

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REGIONAL NETWORKS

ticular understanding the mosquito transmission dynamics, including mosquito behavior, mosquito biodiversity and interactions with other organisms, dispersal ranges, climate change and its effects, available control tools, and insecticide resistance.

health experts, mosquito researchers, academics, healthrelated Non-Governmental Organization (NGO) agencies and other vector control specialists.

Building a capable African workforce The author:

Currently available methods to control mosquito vectors of malaria and mosquito-borne diseases are based on using insecticides and eliminating breeding sites. When considering the potential of new technologies to address the unmet needs of mosquito control, it is necessary to evaluate the risks and benefits in the context of the current situation. Thus the risk incurred by testing new and unproven strategies should be assessed against

CHARLES M. MBOGO President of PAMCA & Chief Public Health Entomologist, Kenya Medical Research Institute (KEMRI)

the risks to human health and the environment posed by maintaining the status quo, which includes both ongoing disease and exposure to broad-spectrum insecticides. However, there are many challenges in the control of mosquitoes in Africa: in par-

To overcome such challenges, countries should be provided with adequate entomological information on identifying major vector species, the bionomic of vectors, the intensity of transmission, entomological inoculation rates (EIRs) and the status of insecticide resistance. Such information is not readily available for real-time decision making because very few countries have the capacity to measure them. From an operational viewpoint, it is debated whether

NETWORKING, PARTNERSHIPS AND FUTURE AIMS Country Chapter Since its inception in 2011, PAMCA has established country offices in Tanzania and Nigeria.

These regional offices are referred to as ­PAMCA Country Chapters.

Partnerships & Links PAMCA has established formal partnerships and links with the Kenya Medical Research ­Institute (KEMRI), the International Centre of Insect Physiology and Ecology (icipe), the World Mosquito Control Association (WMCA), the European Mosquito Control Association (EMCA), the American Mosquito Control ­Association (AMCA), and the Biovision Foundation. We are developing futher partnerships with other organizations.

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Annual Networking meetings PAMCA successfully held the first networking meeting in 2014 where several resolutions and discussions were reached on the way forward for the control of mosquitoes and mosquitoborne diseases. The next network meeting is scheduled to take place in Dar-es-Salaam, ­Tanzania on October 6-9, 2015.

Future aims The following activities are planned: • Developing a strategic plan • Capacity building • Diaspora engagement • Cross border and joint projects • Advocacy and research • Information sharing • Linking research to operational programming

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REGIONAL NETWORKS

information is needed on transmission for routine monitoring purposes (EIRs and malaria incidence). The capacity to measure EIRs is important for National Malaria Control Programs (NMCP) to answer specific questions relating to the effectiveness of control operations, whereas measurements related to vectorial capacity (biting rates, mosquito survival, feeding behavior and feeding patterns) can provide valuable information on why control programs are or are not working.

PAMCA’s purpose therefore is to provide leadership, create awareness through networking and sharing information, and to build capacity at all levels across the continent in order to tackle the unique challenges faced by African entomologists and allied health professionals. We must continue to build a robust cohort of entomologists who are dedicated to tackling malaria and other mosquito-borne diseases on the home front. PAMCA is geared to focus on capacity building for vector surveillance, with the objective of ensuring at least the availability of basic and advanced capacities within the country. After all, who knows Africa better than Africans?

Training at all levels PAMCA aims to add value by engaging not just with African scientists, but with the many Africans residing outside of Africa. With approximately 9 million Africans living in Europe alone, this untapped population

ORGANIZATION MEMBERSHIP PAMCA has over 100 members from 21 countries, 3 Country Chapters, and is growing. This demonstrates the desire of Africans to be at the vanguard of addressing the health challenges in their countries of origin. Membership to the Organization is open to any individual of high professional and ethical standing who works on mosquito/vector control across the entire African continent and who supports the ­following main objectives: • Promoting the study, prevention and control of­ ­mos­quito borne diseases • Developing and implementing new materials, techniques and tools for mosquito control • Enhancing control measures based on Integrated ­Vector Management principles by favoring methods with low toxicological profiles and low environmental impacts • Organizing educational and training courses, visits and staff exchanges between the members of the Organization in order to achieve better professional skills • Advocacy and Social mobilization about mosquito control and related insects • Networking through exchange of information and knowledge on mosquitoes and mosquito-borne ­diseases.

could play a crucial role in the armory against malaria and other vector-borne diseases by providing social, financial and intellectual capital. Despite ongoing control efforts, diseases transmitted by mosquitoes, such as malaria, filariasis, dengue, and arboviruses, continue to pose an enormous global health burden.

Currently, the major vector control interventions rely almost exclusively on the use of long

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lasting insecticidal nets (LNs) and indoor residual spraying (IRS). However, an emerging problem in malaria control is increased resistance by mosquitoes to insecticides used in bed nets and sprays. According to the Centers for Disease Control and Prevention, more than 125 mosquito species have documented resistance to one or more insecticides, and insecticide resistance has been identified in malaria vectors in 64 countries 39

REGIONAL NETWORKS

with ongoing transmission. In areas of high resistance, we must be diligent in deploying the most appropriate preventative tools for each situation. This includes rational selection of bed nets and sprays that have the highest efficacy against resistant mos­

and elimination. PAMCA therefore aims to build regional capacity for mosquito suppression through practical and innovative capacity building ­ activities that transfer expertise between countries and between future leaders and established

“PAMCAs mission is providing leadership in ­promoting control, research and dissemination of information on mosquitoes in Africa and beyond” quitoes. But many malaria programs lack qualified ento­ mologists and or vector control specialists who would provide better data to drive informed decisions about which tools to deploy where and when.

PAMCA will increase human resources by developing training programs at all levels.

Coordinating efforts towards mosquito-free Africa PAMCA is playing a critical role in working together with the industrial sector, scientific and academic organizations, and global health agencies including the World Health Organization (WHO) and others to collaboratively address the unique challenges of mosquito control and possible elimination in Africa.

We aim to achieve this through advocacy and leadership, capacity building, as well as ­ knowledge creation and exchange for mosquito control

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global experts in vector disease control.

we work towards a mosquitofree Africa. So much progress has been made in the war against malaria. But so much still needs to be done. We need every resource dedicated to this effort in Africa and across the globe.

We cannot slow down and we must work more ingeniously than ever before in terms of the time and money we invest in malaria prevention and control.

We know all too well from our recent past and by the tally of millions of lives lost, that a decrease in momentum can have a devastating impact.

CONCLUSION

PAMCA’s main function is to coordinate information sharing concerning vector control activities among Africans, while also promoting control of and research on mosquitoes, especially disseminating information on the bionomics of mosquitoes across Africa and worldwide.

PAMCA provides a forum for entomologists, vector control managers, policy developers and researchers to share knowledge, experiences and opportunities through annual network meetings and conferences. To overcome the challenges facing Africa, PAMCA is engaging with WHO Africa Region (AFRO), Roll Back Malaria Partnership - Vector Control Working Group (VCWG), WHO and other leading private and Non-Governmental Organization (NGO) agencies.

The mission of PAMCA is to provide African leadership, information, training and education, as well as a platform of discussion leading to the enhancement of health and quality of life in Africa as well as worldwide. PAMCA aims to improve the efficiency of control measures against mosquitoes and mosquitotransmitted diseases, and reduce annoyance levels caused by mosquitoes and other vectors and pests of public health importance, to ultimately remove a huge global health burden. www.pamca.org info@pamca.org

Article on the enclosed Public Health CD-ROM

PAMCA is helping to ensure that countries continue to receive technical and political support as

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NGO

Break Dengue & Dengue Lab

Building a global community Created by The Synergist, Break Dengue is a non-profit online portal facilitating sharing of information and building a global community dedicated to reducing and eventually eradicating dengue. Anyone can join the online community, in addition to specific member groups such as Dengue Lab for experts in the field, and the Dengue Tribe, which encourages people to use social media such as Facebook and Twitter to put a face on dengue and mobilize global leaders.

Photo: http://www.breakdengue.org/

F

achieved without raising rom 8% users in public awareness.

2005 to 73% in Conducting awareness 20131, from Facebook to campaigns, especially Pinterest, social media is through social media, can changing online dialogue highlight the consefrom one-to-many to quences of this disease many-to-many at pheand how populations can nomenal speed2. This avoid it. One organizainstantaneous communition focusing on dengue cation channel has four is using precisely these unique characteristics tools as their main stratethat have changed the gy: Break Dengue. nature of interactions among people and orgaBreak Dengue nizations: community, rapid distribution, user Break Dengue is an NGO generated content, and created by The Synergist, open, two-way dialogue2.

ONLINE CAMPAIGN launched for ASEAN Dengue Day 2015. a nonprofit organization Thus, such tools help to that helps social causes reach more people and have more impact in a minimum diseases that are often unknown through communication with the amount of time, with fewer by the general public such as public and experts. This initiaactions. This is where social Neglected Tropical Diseases tive was founded by different media can play an important role (NTDs). Today, half of the partners such as Bayer, Sanofi worldâ&#x20AC;&#x2122;s population is exposed to Pasteur, Fondation Merieux and for health issues. the risk of dengue, classified as Partnership for Dengue Control It is now easier to raise aware- an NTD by the World Health ness and communicate about Organization (WHO). The WHO wants to reduce dengue mortality by at least 50% and morbidity by at least 25%3. This cannot be

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NGO

(PDC). Break Dengue contributes to building a multi-stakeholder partnership to help address the burden of dengue. It works towards connecting patients, governments, NGOs, doctors, the pharmaceutical industry and other stakeholders seeking to end suffering caused by dengue.

Break Dengue’s goals are to combat a disease that affects some of the most marginalized populations in the world, by uncovering some of the success stories in one corner of the globe and replicating them in another, and by bringing patients closer to potential treatments and effective prevention strategies3. These goals are reached through different tools, the main one being its website, www.breakdengue.org.

This website gathers all kinds of information about dengue, including news articles, infographic information, a healthmap to find the location of ­incidents, and a barometer to see what major diseases people are concerned about and how dengue compares with other diseases.

In addition to being informative, the website includes a blog written by Alejandra Laiton, a travel blogger and communication expert. Her role is to travel in countries where dengue is an

42

The author: MYRIAM HASSINE Bayer CropScience, South East Asia.

issue and meet up with communities and governments to check out activities and events that are being conducted in these countries, and that aim to connect online and offline dengue prevention activities worldwide.

Break Dengue’s website also highlights up-to-date campaigns launched by the organization.

For example, Red Card to Dengue, which was organized during the World Cup 2014 in Brazil, set out to raise awareness around a problem that Brazilians have to face on a daily basis.

However the way the campaign is conducted is always designed to be enthusiastic and fun.

Break Dengue mainly targets the public to make sure that dengue is no longer a disease that concerns only one part of the world, and that the consequences of this disease are known to all. Public awareness and education, especially about the vector of the disease, are keys to eradicating dengue. However, in addition to

the public, it is essential that experts work together to find a sustainable solution against the virus and Aedes mosquitoes.

Thus, to facilitate partnerships not only between academics but also private companies, as well as to share information, Break Dengue created a special platform called Dengue Lab. Dengue Lab: An online platform for dengue experts Dengue Lab is a closed platform created to encourage stakeholders to share their ideas, knowledge and experience. “Current efforts to prevent dengue tend to be isolated, short-lived and limited to specific geographics.

Groups are working in silos when in fact everyone should be working together as they are two sides of a story that is looking for the same positive ending” said Nicholas Brook, founder of The Synergist. Different content can be shared through Dengue Lab: academic publications, event announcements, wikis, photos, videos, and podcasts.

Dengue Lab is divided into four communities involved in different subjects but having a common goal:

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• Prevention and control • Treatment and vaccine • Surveillance • Bayer Vector Control Vector control and vaccine are well represented, since these two approaches must be combined to fight dengue.

LinkedIn and Twitter

platform5. About 300 million members across 200 countries use LinkedIn5; 39% of medical researchers and healthcare professionals visit LinkedIn regularly, and 11% of them use it to comment on research papers4.

Created in 2003, LinkedIn is an online professional networking tool that has evolved from a human resource (HR) platform into a corporate communication, and number one social network

Bayer Vector Control community is a closed sub-group that allows experts who are working on Bayer Dengue Vector Control trials around the world, especially in East Asia Pacific and Latin America, to share pictures and videos and ask questions about the products or protocols, since every country has different features (type of housing, Aedes species, etc.). Some of the experts are more experienced with a certain type of use, but their location makes it difficult for them to share or answer questions raised by a new use.

This community helps the experts with their daily work.

Platforms most visited by researchers and healthcare professionals Yes (% of full sample) 12%

Twitter

32%

Facebook Frontiers Academia.edu

7% 3% 51%

ResearchGate 39%

LinkedIn 10%

BioMedExperts

Platforms most used by researchers and healthcare professionals to comment on research papers Yes (% of service users) 25%

Twitter

Break Dengue and Dengue Lab are platforms focused on Dengue but other social tools could be used for the same purpose. As part of the academic online platform, LinkedIn, Facebook and Twitter are the most used by medical researchers and health4 care professionals (Fig.1).

13%

Facebook

9%

Frontiers

7%

Academia.edu

16%

ResearchGate

11%

LinkedIn BioMedExperts

3%

Fig. 1: Research Gate is a social networking site for scientists with 7 million researcher users and over 80 million publications. BioMedExperts with almost 0.5 million users went off line end of 2014, and all users were transferred to join the Mendeley network, which has over 3 million users. Mendeley, Nature Network, PubMed and other more specialist platforms were not included in this study.

PUBLIC HEALTH JOURNAL 26/2015

43

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Global heatmap of Twitter users

Fig. 2 / Source: www.beevolve.com

Twitter, created in 2006, has over 100 million daily active users, and more than 230 million monthly active users worldwide6. This platform allows people to send out short messages, called Tweets, of up to 140 characters. Twitter can be used to spread health-related information and share articles or other content. To make Tweets more visible to others, hashtags followed by key words help reach people interested in the subject (#dengue). The global distribution of Twitter users can be visualized using a heatmap (Fig. 2).

Bayer has a closed group on LinkedIn, Bayer Vector Control web­s ite, as well as a Twitter account for malaria, @BayerMalaria.

44

0

100,000

Bayer’s Twitter account is used to give updates and share news about malaria. The LinkedIn group is used to provide experts with insights into issues related to Vector Control, such as product use and efficacy, community engagement, etc. These experts are from all around the world and share the same interest.

More www.breakdengue.com

Article with references and dengue statistics on the ­enclosed Public Health CD-ROM

CONCLUSION Today, private companies and public organizations can no longer ignore social media and its impact. Therefore, Break Dengue, as an NGO, has fully integrated social media into its strategy, which is based on four key words: connect, share, measure and act. Bayer shares the same idea, which is why the 360° Vector Control strategy, based on five pillars: history and expertise, advocacy and support, portfolio and innovation, training and education, and partnership and cooperation, uses social media as a key tool to fight vector borne diseases. Initiatives and ideas must be link to be effective over the long-term in the fight against dengue.

PUBLIC HEALTH JOURNAL 26/2015

BOOK REVIEW

Dengue Global Status: The A to Z of a (re)emerging disease This is not a book to read but a compilation of huge amounts of data presented in simple graphical forms, extensive notes, and lists of worldwide sourced ­references. For medical workers in the field, clinicians, public health stakeholders, researchers, and all those interested in the symptoms, history, geographical distribution, prevalence, statistics, and other data pertaining to ­dengue fever – this is a useful and fascinating up-to-date resource.

H

ow does one recognize the symptoms of dengue fever, what distinguishes dengue from chikungunya or malaria, and what could be other complications? What are the indications that dengue fever has progressed to dengue hemorrhagic fever (DHF) or dengue shock syndrome? When were dengue epidemics first reported? When and where did DHF first emerge?

When were the most notable outbreaks of dengue and in which countries? Which global regions or countries bear the greatest burden of dengue today?

Has this burden been decreasing or increasing over the last decades? How many deaths have occurred due to dengue, globally, in each region or in different countries, and in which years?

Answers to such questions can all be found in this ebook.

Afghanistan to Zambia Arranged in alphabetical order for each country, these chapters are preceded by sections on descriptive epidemiology, clinical symptoms, and the global

situation. The world distribution map illustrates the 144 countries where dengue is endemic or partially endemic, followed by a worldwide overview further split into Africa, the Americas, Southeast Asia, Western Pacific and Europe. Should you want to visit a particular region you may like to know that the risks for travelers peak during June and September in Southeast Asia, October in central Asia, March in South America, and August and October in the Caribbean.

The book’s content then proceeds through 191 countries, using a consistent format of graphs, notes and references, from Afghanistan to Zambia.

Clinical symptoms for accurate diagnosis The overview of epidemiology includes the agent, an RNA Flavivirus with four serotypes, although a fifth was reported in Malaysia, but seems not to have clinical significance. The vectors, diagnostic tests, and therapy are followed by the clinical

PUBLIC HEALTH JOURNAL 26/2015

descriptions based on WHO definitions for surveillance and the US Centers for Disease Control (CDC) case definitions.

These comprise detailed and descriptive (in precise medical terms) lists of clinical symptoms and complications that can be used for accurate diagnosis of dengue fever. For example, the rash caused by dengue, which occurs in 50% of patients, can be mistaken for measles or rubella, and while the symptoms of chikungunya are similar, dengue patients are more likely to suffer from sore throats, nausea, vomiting and abdominal pain. Raised levels of serum biliruben from red blood cell breakdown, or C-reactive protein (CRP) as a marker for inflammation indicate malaria rather than dengue.

Dengue hemorrhagic fever Indications for DHF include all those listed for dengue, plus additional bleeding and plasma pathologies (plasma leakage, increased vascular permeability). Dengue shock syndrome includes all the pathologies of 45

BOOK REVIEW

Dengue Global Status Gideon eBook 237 pages, 261 graphs, 4,268 references, 5.81 MB PDF format 2015 edition ISBN: 978-1-4988-0716-6 US$ 49.99

DHF, progressing to dangerously low blood pressure and weak pulse, i.e. blood circulation failure that is usually fatal.

Although the WHO designations introduced in 1997 of dengue fever, dengue hemorrhagic fever and dengue shock syndrome were replaced in 2009 by the designations dengue and severe dengue, the term DHF is still used throughout the book for clarity. The risk of DHF is 0.2% during the first attack of dengue fever, but increases 10-fold during re-infection. For reasons as yet unknown, a long interval between dengue fever attacks may increase the risk of developing DHF. Also of note is the fact that DHF is a recent manifestation of the disease, first arising in the early 1950s, whereas dengue fever has been described for hundreds of years.

A brief history The first dengue-like epidemics were reported in 1635 in 46

Martinique and Guadeloupe, and 1699 in Panama, although the fever’s Caribbean / Latin American origin is thought to be due to imported African slaves.

However this geographical association continues today, with Central and South America suffering from the highest annual disease burden worldwide. The disease acquired a number of names in the 17th and 18th centuries, such as Bouquet, Breakbone, Dandy or Giraffe fever, and was first called dunga, later changed to dengue, during an outbreak in Cuba in 1828.

Outbreaks of DHF started emerging in the 1950s, with the world’s first epidemic reported in the Philippines in 1953. At that time over 50% of the country’s population were seropositive for dengue antibodies. But until the 1970s only a total of nine countries had suffered DHF epidemics; by 2012 over 100 countries worldwide were endemic for DHF.

When possible the vectors are mentioned for each region, including the rare Aedes hensilli, Ae. marshallensis, Culex quinquefasciatus, Cx. annulirostris, and Cx. Kusaiensis, but these are restricted to Pacific territories.

Generally, S. aegypti is the most common vector for dengue. This mosquito is found in most tropical and subtropical regions and in all countries in the American region except Canada and Uruguay.

The next most common vector, S. albopictus originated in Asia, but as of 2003 was also found in 10 American countries. In Europe S. albopictus was first found in Albania in 1979, Italy in 1990, France in 1998, Spain in 2004 and Germany in 2011.

However it was S. aegypti that proved to be responsible for the first outbreak of dengue in Europe. First detected on the island of Madeira in 2004, this mosquito caused the epidemic of 2012-2013, with a total of 2168 cases.

Vectors Data surfing Those familiar with the field are reminded that the recommended genus name for the mosquito transmitting dengue is Stegomyia. Previously classified as belonging to the genus Aedes, subgenus Stegomyia, a publication in the Zoological Journal of the Linnean Society in 2004 recommended that Stegomyia be raised to the level of genus; however many experts still use the name Aedes, and this is given in parenthesis.*

How does one deal with such huge amounts of data? Well, you can choose a region or country of interest and use the index hotlinks to go directly to these pages. The uniform graph format makes comparisons easy: They all depict numbers of dengue or DHF cases or deaths on * The suggested mosquito genus name Stegomyia is under revision, so this genus is still officially called Aedes.

PUBLIC HEALTH JOURNAL 26/2015

BOOK REVIEW

the left y-axis, rates per 100,000 people on the right y-axis, and years along the bottom x-axis.

The scales may be different, but these are chosen to optimally represent the available data. For example, the numbers of cases might span 0 to100 or 0 to 7000; the years along the bottom might span 1962 until 2012, or 2002 until 2013.

The graphs are preceded by a section on “Time and place”, when available, and followed by lists of notes with specific points of interest and numbers referring to the references in the list.

These numbers as well as the full citations in the reference list are hyperlinked to the actual texts and/or their source links (e.g. PubMed) archived within GIDEON’s huge collection of online data on their website. The references include peer-reviewed scientific journals, Health Ministry Reports, standard text books, medical literature, and ProMED, the Internet-based Program for Monitoring Emerging Diseases reporting system. The subsequent sections cover “Prevalence surveys”, “Seroprevalence surveys”, “Vectors”, “Notable outbreaks”, and “References” (as described above) where these data exist.

Alternatively, you can scroll through the pages simply looking at trends, differences and unusual points of interest. Since each graph has a clear title at the top – “Country, Dengue, cases”,

“Country, Dengue, deaths”, or “Country, DHF, cases” – it is easy to pinpoint where you are in the alphabetical world list.

Scrolling will reveal interesting features: Sometimes there are no notes, such as for Ireland; sometimes references cover some three pages as for Brazil and India, and sometimes there are no graphs at all, such as for Afghanistan, Angola, Portugal or Zambia. Other interesting things one might notice are the two pages of extensive geographical notes for Brazil, or the whole page of notable outbreaks for India, and perhaps surprising entries such as Australia, Norway, Scotland and Sweden.

Re-emerging The clearest trend revealed by either “reading” method is the increase in dengue cases, DHF, and deaths over the last 20 years.

Worldwide during 1994 to 1996 average numbers of dengue cases were estimated at between 20.2 and 32.3 million per year; as of 2011 the number of cases are estimated as 50 to 100 million per year. An estimated 100,000 deaths occur worldwide each year due to DHF. Particularly in the Americas, the incidence of dengue has been increasing since 2002 from rates of 150 per 100,000 to 350 per 100,000 in 2013. For example, 17,457 dengue cases were reported, with 333 DHF cases and 28 deaths in 2002, and about

Source http://www.gideononline.com/ebooks/disease/dengue-global-status/

PUBLIC HEALTH JOURNAL 26/2015

2.3 million cases, with 1244 deaths in 2013. A glance at the graphs clearly shows that DHF incidence has been increasing since about 2001, and deaths since 2006.

Two-thirds of the world’s population live in dengue endemic regions and an estimated 2.5 billion people are at risk of catching dengue fever. However, among all dengue endemic regions the incidence of DHF is highest in Southeast Asia. Here annual deaths due to dengue have been fluctuating between 1000 and over 2000 since 1985.

Two thirds of regional cases are in Vietnam and Thailand, and dengue is the 8th leading cause of death in Indonesia.

CONCLUSION The range of information in this eBook and its simple, clear, concise presentation represent a huge amount of work to make a highly valuable resource for anyone working in the field. Backed up by the links to all the reference sources it represents a vast collection of knowledge on dengue. Yet it also manages to present easily accessible take-home messages, particularly that dengue is reemerging or emerging for the first time in countries all over the world.

Author: Avril Arthur-Goettig Article and dengue info­ graphic on the enclosed Public Health CD-ROM

47

Photo: Malaria Consortium

Index case follow-up in Pailin, Cambodia: Collecting blood samples to test for malaria infection.

Malaria Consortium

Putting the last mile first Malaria Consortium is one of the world’s leading specialist non-profit health organizations. Its strength lies in its ability to design and implement tailored, evidence-based interventions that not only provide the solution to a specific issue, but that also have a positive impact on national health systems and economies. This report focuses on two areas of the organization’s work: v­ ector control and resistance management.

M

alaria Consortium works with diverse partners, including all levels of government, to improve the lives of all, especially the poorest and most marginalized, in Africa and Asia.

The organization targets key health burdens, including malaria, pneumonia, diarrhea, dengue and other neglected tropical diseases (NTDs), along with other factors that affect child and maternal health.

Malaria Consortium achieves its goals by:

• Selectively scaling up and delivering sustainable, evidence-based health programs.

• Providing technical assistance and consulting services that shape and strengthen national and international health policies, strategies and systems, and build local capacity.

• Seeking to ensure its experience, through leadership, practical findings and research results, are effectively communicated and contribute to coordinating improved access to, and quality of healthcare.

• Designing and conducting cutting edge implementation research, surveillance, monitoring, and evaluation.

Malaria Consortium focuses on a range of disease response areas, including vector control, chemoprevention and other types of

48

prevention; diagnosis and case management; quality improvement; resistance management; elimination, and child and maternal health. It does this with a pragmatic approach to two crosscutting areas of expertise: health and strengthening systems, as well as policy development, advocacy and use of evidence.

Resistance management The organization has focused on helping to strengthen monitoring, evaluation and surveillance systems to support efforts to control emerging resistance to artemisinin in Southeast Asia, particularly among vulnerable and (continued on page 51) PUBLIC HEALTH JOURNAL 26/2015

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Case study I

Tackling outdoor malaria transmission in the Greater Mekong Subregion Complete interruption of malaria parasite transmission in the Greater Mekong Subregion (GMS) cannot be achieved by current best practice tools of long-lasting insecticidal nets and indoor residual spraying alone, because ­Anopheles dirus, the principal malaria vector in the r­ egion, displays outdoor biting and resting behavior.

Photos: Malaria Consortium

As part of MOTIve (Mekong Outdoor Transmission Initia­ tive), Malaria Consortium is implementing several intervention trials on community acceptability of, and preference for permethrin-treated clothing used by migrant rubber workers in rubber plantations (USAID/ PMI/UK government-funded) and the efficacy of spatial repellent and an insect growth regulator in outdoor settings. The human, animal and ecological niches play a critical role in outdoor malaria transmission during the lifecycle of the Anopheles mosquito1.

By conducting these studies, an improved understanding will be gained on how best to tackle outdoor transmission, not only contributing to better control of the spread of drug resistant parasites, but also guiding more effective interventions in areas of the vector lifecycle currently not reached by other interventions. This information will be a very valuable, if not essential, addition to the strategy to eliminate Plasmodium falciparum and P. vivax infections in

Myanmar and Thailand as well as other GMS countries.

Insecticide-treated clothing Insecticide-treated clothing (ITC) offers a solution in situations where, for occupation or necessity, at-risk populations – primarily those who are mobile and migrant – are unable to benefit from core vector control measures (sleeping under longlasting or insecticide-treated mosquito nets, and indoor residual spraying). In these situations, humans are at greatest risk from the forest malaria vectors Anopheles dirus that bite and rest outdoors and contribute to the residual transmission of malaria.

ITC, if culturally appropriate, has the advantage of being easily adopted by communities, requiring little behavioral change and, by preventing outdoor vector biting, conferring direct protection against vector-borne diseases2. Although scientists have just begun to test insecticidetreated school uniforms to protect against malaria and dengue

PUBLIC HEALTH JOURNAL 26/2015

Construction workers wearing krama, traditional Cambodian scarves.

Demonstrating rubber tapping in Myanmar.

People living in the forest without protection in Thailand.

49

NGO

fever, the military and other outdoor recreational and occupational groups have been using clothes treated with insecticides for decades to protect against ticks and mosquito bites.

Permethrin is the synthetic chemical typically used to treat this kind of clothing; it is a potent insecticide, has low toxic-

among migrant night-time workers on rubber plantations. A rapid qualitative assessment through focus group discussions and indepth interviews was conducted to understand the community’s preferences (by gender) of type, color, texture and sizes of clothing to ensure the cultural appropriateness of the distributed clothes. The study area of Wae Kha Mi in Thanphyuzayat, Mon State is classified as malarious, with annual parasite incidence of 7.8 per 1000 people, statewide in 20134. The total number of severe cases reported at Than­ byuzayat township in-patient hospital ward was 26 in 20125.

Photos: Malaria Consortium

Ideal habitats for mosquitoes: rubber plantations

Rubber tappers wearing non-treated standard clothing (left) and insecti­ cide-treated work clothing (right).

ity in mammals and is used widely in nuisance and disease vector pest control treatments 3 for humans and cattle .

Type, color, texture and size of clothing The success of ITC as a strategy depends on communities’ acceptance and adherence, but there is limited information to inform policymakers and donors regarding targeted distribution to mobile and migrant populations. To investigate this, in Mon State, Myanmar, Malaria Consortium is conducting operational research on ITC for malaria prevention 50

Rubber plantations are associated with malaria transmission and create suitable micro-climatic conditions for potent Anopheles vectors by promoting the survival, reproduction and lifecycle of An. dirus during the rainy season.

The shaded ecology of rubber plantations can facilitate feeding and breeding of An. dirus mosquitoes even in the dry season.

The abundance and distribution of An. dirus depend on both seasonal variation, such as increasing density of mosquitoes with increasing rainfall, and geospatial variation6.

Generally, malaria transmission is confined to the hilly areas of rubber plantations where rubber tapping and rubber processing activities take place. Most rubber tappers work through the night, which coincides with the time

when An. dirus mosquitoes are active. The geographical area that a rubber tapper can cover in a night’s work is relative to the size of the plantation, and ranges from 100 to 150 trees a night. Rubber tappers who routinely practice rubber tapping are more frequently exposed to multiple bites in multiple locations when they revisit areas with malaria trans7 mission foci .

Important tool in elimination efforts Recent intervention trials of ITC have shown a marked reduction in the risk of malaria infection among users; for example, the calculated pooled relative risk from studies using ITC, bedsheets or top-sheets was 0.62 (95% CI 0.52 to 0.74)8.

Malaria Consortium will perform field and laboratory assessments on the performance of ITC and micro-encapsulated insecticide formulations when routinely used in forest work, and on skin absorption and potential side effects. If further evidence demonstrates that ITC can be a safe, effective, acceptable, and cost-effective strategy for vector control, it could prove to be an important tool in addressing outdoor biting and residual transmission of malaria, and help to strengthen elimination efforts in the region.

Zooprophylaxis with ­insecticide treated cattle In the GMS, cattle-owning ­settlements are typical of ­malaria

PUBLIC HEALTH JOURNAL 26/2015

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(continued from page 48) 9

transmission hotspots , and cattle-related sites are also visited by large numbers of ­ malaria vector mosquitoes of the An. dirus and An. minimus sibling species complexes.

Small­ holders dominate cattle and buffalo production over much of the region, including forested areas, which supports over 30 million cattle used for 10 draught and meat production .

Malaria Consortium will evaluate interventions that exploit both the mosquitoes’ attraction to cattle and their ability to auto-disseminate larvicide.

Regarding community engagement, Malaria Consortium will conduct in-depth community orientation on the research project to explain its objectives and engage them in every step to address their concerns and obtain their support for the research. The organization will also address ethical obligations of individuals living within the trial site(s) who are not, in a traditional sense, subjects of the research, but who nonetheless may be affected by the conduct of research. Without innovative approaches like this one to protect the highest risk population groups in the region, taking into account their lifestyles, elimination of malaria in the region might not be achieved.

The authors: Jeffrey Hii, Muhammad Shafique and Alison Crawshaw (Malaria Consortium Asia)

­h ard-to-reach populations.

Malaria Consortium has a strong record of implementing successful projects across this region. It is recognized as being among the foremost experts on the development of resistance response ­strategies in this area, with the organization’s Technical Director, Sylvia Meek, on the WHO Malaria Policy Advisory Committee and WHO’s Technical Expert Group for Antimalarial Drug Resistance and Contain­ ment. Malaria Consortium senior staff participate in WHO Technical Expert Groups, including the Technical Expert Group for Vector Control and the Technical Expert Group on Surveillance, Monitoring and Evaluation. Malaria Consortium is also a member of the Surveillance and M&E Task Force under the Emergency Response to Artemisinin Resis­ tance (ERAR) WHO platform.

Vector control Malaria Consortium continues to play an important role in the distribution and promotion of the use of long-lasting insecticidal nets (LNs), one of the most effective interventions to prevent malaria. Malaria Consortium is developing context-specific models for continuous distribution of LNs through routine channels such as antenatal care clinics, routine immunizations, schools and community-based delivery systems. Malaria Consortium is also working to engage the commercial sector in this effort.

Currently, the organization is carrying out comprehensive efforts at scale in several countries,

PUBLIC HEALTH JOURNAL 26/2015

including Nigeria and Uganda, to distribute and promote the use of LNs to achieve both high and sustained impact. Through its Beyond Garki multi-country project (see page 52) it is engaged in a long-term analysis of changes in vector behavior as interventions are deployed to reduce malaria transmission intensity.

Other vector control priorities for the organization are tackling insecticide resistance, and protecting populations who are working outdoors when mosquitoes bite.

CONCLUSION Working with partners worldwide, Malaria Consortium is contributing to global efforts to combat malaria. Geograph­ ical and vectorial factors, human behavior, climate change, socio-economic drivers, as well as development of insecticide resistance, will all influence efforts to eliminate the disease. Only through a scale-up of interventions that we know are working, an increased understanding of changes in malaria epidemiology, improved surveillance and sustained global investment, will we ensure the effectiveness of efforts to combat malaria and accelerate progress towards elimination.

Please find case study II overleaf Article, references and short portraits of the authors on the enclosed Public Health CD-ROM. www.malariaconsortium.org

51

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Case study II

Understanding changes in malaria vectors in Africa Changes in vector behavior can potentially render control tools less effective. Furthermore, substantial variations in transmission due to gradual shifts in vector species composition means different areas would require different types of interventions at varying degrees of intensity. Control approaches should be adapted to temporal ­changes as well as spatial variations in transmission and factors of transmission.

The fight against malaria in the past ten to fifteen years involved wide-scale use of vector control, rapid diagnostic tests, and effective treatment using artemisinin-

Photos: Malaria Consortium

Entomology survey training in Ethiopia.

A trap used to catch mosquitoes when they exit a dwelling in Awassa, Ethiopia.

52

based combination therapy.

Between 2000 and 2013, malaria mortality declined by 47% globally and by 54% in the WHO’s 11 Africa Region . The scale-up of key interventions undoubtedly contributed to the decline12.

However, the decline is not uniform across countries or regions.

Additional factors, possibly interacting with the increased intensity of interventions, may have played a role in the reduction of transmission. A clear under­ standing of the epidemiological changes and causes of the heterogeneity in transmission and impact of control measures will be required to recommend appropriate adaptive strategies13.

Furthermore, some targeting will be needed based on prevailing conditions if control efforts are to be sustainable.

Among malaria vectors, there have been certain trends both in terms of susceptibility to commonly used insecticides and behavioral patterns affecting transmission. The increasing problem of resistance against pyrethroid insecticides used in insecticide-treated nets (ITNs) has become a threat to malaria control in Africa14. This problem remains a threat, although nets

treated with insecticides still seem to be more protective than untreated nets irrespective of the presence of resistance, as a recent meta-analysis and systematic 15 review has shown .

Monitoring malaria transmission and control Beyond Garki* is a project led by Malaria Consortium to monitor changes in the epidemiology of malaria in selected sites. The project has been monitoring malaria transmission and control at four sites in Ethiopia and Uganda since 2012 and has already made some important observations. As an example, entomological studies in the Ugandan sites showed that considerable variation in vector composition exists between study sites. The majority of humanvector contact with Anopheles gambiae s.s. and A. arabiensis occurred indoors after midnight, confirming the potential continued efficacy of ITNs against these two species. However, insecticide resistance to pyre---------------------*Beyond Garki multi-country project: www.malariaconsortium.org/beyondgarki/

PUBLIC HEALTH JOURNAL 26/2015

Photos: Malaria Consortium

NGO

A net set up in Uganda to promote the use of long-lasting insecticidal nets.

throids varied considerably between the species and the impact on malaria transmission requires further investigation.

Other studies have reported recent changes in species composition and biting habits of malaria vectors in some areas of Africa.

Increased ITN coverage in Zambia seems to have caused heterogeneity in biting rates of A. arabiensis, whereby biting focused onto a smaller fraction of the population and spatial clustering was also observed16. In southwestern Uganda, malaria prevalence decreased over time, but a high degree of variation in transmission and an early biting habit of vectors has been ­reported17. A study in the coastal area of Kenya showed that the density of malaria vectors declined between 1990 and 2010, and that anthropophilic vectors have been replaced by more zoophilic ones18.

Effects of social, demographic and climatic trends Ecological changes have modified the natural environment of malaria vectors. Man-made changes such as deforestation, agricultural development and

urbanization have been associated with changes in vector densities and malaria transmission in different parts of the world19.

Temporal variations in climatic determinants of malaria transmission include transient weather disturbances as well as long-term climatic and ecological changes that may be coupled with social, economic and demographic trends.

miological changes, including heterogeneity of transmission, and to quantify the impact of 21 interventions . Changes in demo­graphic, socio-economic, political, technological, and environmental factors may have had an impact on malaria, in addition to control measures, resulting in changing patterns of transmission. Understanding variations in the temporal and spatial heterogeneity of transmission and monitoring impacts of interventions in different epidemiological settings will help in adapting control

Monitoring weather phenomena in cooler environments or arid areas can help to detect conditions that can cause abnormal upsurges in transmission. Moni­ toring longer-term climatic data can help us understand the impact of interventions that could modify the influence of determinant factors. A study of climate data in Ethiopia indicated that despite more favorable climatic conditions during 2006-2010 compared with 2000-2005, incidence nevertheless declined during periods of intensified control efforts: thus the decline was not attributable to unsuitability of the climate20.

strategies accordingly and preventing resurgence22. It is essential to separate the roles played by climate change, social and economic development and malaria interventions in causing variability in malaria epidemiology. This understanding will ensure a longer term, sustainable effort and a systematic adaptation of response to the changing landscape of malaria.

A balanced approach in the use of survey data, routine surveillance and modeling will help to measure and understand epide-

The authors: Tarekegn Abeku and Michelle Helinski (Malaria Consortium)

PUBLIC HEALTH JOURNAL 26/2015

Net distribution in Kano, Nigeria.

53

NOTES

Malaria: First vaccine worldwide to be approved The European Medicines Agency EMA recommended approval of the first candidate vaccine for preventing malaria at the end of July 2015. After 30 years of research, this will be the first malaria vaccine worldwide, with the target group being Sub-Saharan children aged 6 weeks to 17 months. The WHO has announced that it will formulate recommendations on its use later this year.

GlaxoSmithKline (GSK) developed RTS,S, also called Mosquirix, in partnership with PATH Malaria Vaccine Initiative, with additional funding from the Bill & Melinda Gates Foundation. The vaccine contains a protein from the malaria pathogen Plasmodium falciparum that stimulates the production of antibodies against this parasite and prevents it

reaching the liver. Researchers reported that the vaccine is well tolerated, although a few cases of meningitis were recorded in vaccinated infants. It is not yet known whether this was associated with the vaccine.

As studies published in 2011 and 2012 showed, the vaccine has moderate efficacy. Following a phase III vaccine trial conducted in eight African countries and including more than 16,000 children, the data showed that three doses of RTS,S reduced malaria cases by 46% in children vaccinated at ages 5 to 17 months and by 27% in infants vaccinated between 6 and 12 weeks old. EMA recommends that the vaccine should be used in both age groups.

David Kaslow stress that Mosquirix vaccination on its own is not the complete answer to malaria. But along with existing tools such as bednets and insecticides currently recommended for prevention, the vaccine should make an important contribution to controlling the impact of malaria on young children in Africa. Moreover, the technical achievement of this first generation vaccine validates continuing research and investment into developing next-generation vaccines.

GSK has promised to set the price to cover production costs plus a five percent profit, which will be reinvested in research on vaccines against malaria or other neglected tropical diseases.

Sources www.spiegel.de (search: Erster Malaria-Impfstoff) www.healio.com (search: malaria vaccine)

Both GSK’s CEO Sir Andrew Witty and PATH’s Vice President

Antibiotics: Increase vector efficiency Antibiotics ingested by Anopheles gambiae mosquitoes make them more likely to become infected. The malaria parasite Plasmodium falciparum reproduces in the mosquito gut, but must compete with gut microbes.

Mosquitoes feeding on blood containing antibiotics lost

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about 70% of their gut bacteria and were 21% more likely to develop malaria parasite infection.

The results published in “Nature Communications” also showed that exposure to antibiotics increases mosquito survival and fertility, both important factors in vector

efficiency. The authors stress that people with malaria taking antibiotics should use extra protection, such as sleeping under nets, to avoid being bitten by mosquitoes.

Source Nature Communications: doi.org/zfn

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Dengue: Vaccine is more than 80% effective collected in two, phase III clinical trials with 10,275 children in the Asia Pacific region and 20,869 in Latin America, both dengue endemic regions.

The results of trials of an experimental vaccine against dengue show that it is more than 80% effective, according to an independent analysis published in the New England Journal of Medicine (NEJM) at the end of July 2015. The vaccine was developed by the French pharmaceutical concern Sanofi.

The follow-up periods ranged from three to six years, and the data also revealed that the vaccine conferred protection against the most serious forms of the disease: among the older children at 93.2% and among the two to eight year olds at a rate of 44.5%.

However, there was an unexplained increase in hospitalization due to dengue in the third year of vaccination

The vaccine reduced the risk of contracting dengue among vaccinated children, and prevented the hospitalization of 80.8% of children aged nine or over, and 56% of two to eight-year-olds. This data was

among the younger children that needs to be “carefully monitored” over the longterm. The multi-author report in NEJM assessing the candidate tetravalent dengue vaccine in three clinical trials (two addressing hospitalization) concluded that the risk among children of 2 to 16 years of age was lower in the vaccinated group than the control group. Overall, the ­ vaccine “has the potential to significantly reduce the burden of disease in countries where this disease is endemic” said Sanofi in a statement.

Source www.nejm.org (search: dengue)

Malaria: Rapid non-invasive laser diagnosis A new 20-second technique to diagnose malaria requires no blood samples, reagents, facilities or trained personnel, just a short pulse with a laser. This pulse causes no harm to human tissue, but optically excites hemozoin, waste crystals produced by the parasite Plasmodium falciparum after digesting blood. An oscilloscope placed on the skin beside the laser acoustically detects vaporized nano-bubbles produced by hemozoin.

Recently published in Emerging Infectious Diseases, one of the authors, Dimitri Lapotko of Rice University in Houston, Texas, said: “It’s the first true non-invasive diagnostic.” The device is safe, sensitive and specific, even detecting low-level asympto­ matic infections. It also detects parasite infection in Anopheles mosquitoes.

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Soon to be tested in trials in Gambia, it could cut the costs of a malaria test from around 50 cents to less than 8 cents and give almost instant test results. The use of such a device to rapidly detect malaria parasites not only in humans and livestock but also in mosquitoes could become a powerful tool in malaria control and elimination.

Source New Scientist June 27, 2015: www.newscientist.com Emerging Infectious Diseases: doi.org/5hr

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Elephantiasis The disease has a long history and equally long list of names. But a common feature over the ages is association with elephants, which vividly describes the swelling and severe ­disfiguration of the arms, legs, or genitals to elephant-like proportions and appearance. The earliest depictions of elephantiasis date back to around 2000 BC in Egypt, and the earliest written accounts to ancient Greek and Roman times. The major form is lymphatic filariasis caused by parasitic infections of round worms obstructing the lymphatic system.

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Photo: George Henry Fox (1886)

n 1673, Benjamin Neisius of the University of Strasburg described elephantiasis as an “Iliad of diseases” due to the multitude of diseases it described and numerous names it had acquired historically and geographically. In India it was known as Slipada (elephant leg), as recorded in the Sushruta Samhita, the name used by the Roman medical encyclopedist Celsus (30 BC to 50 AD), although it was also known as satyrisis, leontiasis, and sarcocele. The Greeks and Romans could distinguish between leprosy and lymphatic filariasis, calling the former elephantiasis graecorum and the latter elephantiasis arabum.

Later elephantiasis was called skiapodes (shadow leg) to describe people from Ethiopia shaded from the sun by their swollen legs, or St. Thomas’ leg among Christians in India who thought they were cursed. Ali ibn Sahl Rabban al-Tabbari (807 to 870 AD) called elephantiasis Daa al-Fil (disease of elephant)

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and described treatments in Firdows al-Hikmat (Paradise of Wisdom), the first medical book in medieval Persia. Other names for elephantiasis included bucnemia tropica, Barbados leg, yam leg, Kaal (also meaning elephant), morbus herculeus, mal de Cayenne, and myelolymphangioma.

Egyptian artifacts Ancient artifacts suggest that lymphatic filariasis was already present in the Nile region over 4000 years ago. A statue of Pharaoh Mentuhotep II depicts swollen limbs suggestive of elephantiasis. About 500 years later in the funeral temple of Queen Hatshepsut of Dier-al Bahari a lime stone relief depicts the prince of Punt and his wife who is clearly suffering from elephantiasis.

Japanese scrolls

ELEPHANTIASIS can cause limbs to swell and look like an elephant’s leg in size, texture and color.

In Japan, pictures in scrolls dating to 1100 to 1200 AD depict a woman with possible elephantiasis of the legs (“Disease Picture Scroll”, Tokyo National Museum), and a man with elephantiasis of the scrotum (“Strange Disease Picture Scroll”, Kyoto National Museum).

In the “Unofficial History of Kuma” describing the war fought in 1555 between the Satsuma (Kago­ shima) and Sagara (Kumamoto), a young soldier

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called Yohyoe Kitazaki boasted to his comrades that his war trophy was the head of a Satsuma enemy. However, wrapped up in the cloth was a scrotum hydrocele as big as a human head cut off from a dead soldier.

Apparently this form of elephantiasis was not uncommon in Japan in those times.

A contagious disease There are other causes of (nonfilarial) elephantiasis such as leishmaniasis, repeated streptococcal infection, surgical removal of lymph nodes (usually due to cancer) and a hereditary birth defect (Milroy disease). But the major form is lymphatic filariasis endemic in Asia and Africa for millennia. The disease seemed to be linked to filariasis, which was suspected to be an infectious disease and first associated with elephantiasis in the Ebers Papyrus in 1550 BC. Elephantiasis was also linked to leprosy, which was first recognized as being contagious by the monk Anglicus in 1246. Some speculate that lymphatic filariasis spread from India to Northern Africa and Europe with Alexander the Great, but indeed his soldiers have been implicated in spreading many diseases across Eurasia. It was later introduced to the Americas through the slave trade.

Photo: Wikipedia

INDICATIONS OF ELEPHANTIASIS in ancient artefacts: Pharaoh Mentuhotep II (left) depicting swollen limbs; and the princess of Punt (below) at the Terrace of Queen Hatshepsut’s temple.

The first reliable documentation of elephantiasis symptoms was during an exploration of the Portuguese colony of Goa between 1588 and 1592. During this trip, Jan Huygen Linschoten wrote that inhabitants were “all born with one of their legs and one foot from the knee downwards as thick as an elephant’s leg.”

Discovering the worm In 1863, French surgeon JeanNicolas Demarquay first observed microfilariae in hydrocele fluid extracted from a Cuban.

Three years later in Brazil, Otto Henry Wucherer (1820-1873) detected microfilariae of the worm in urine samples. However, these two discoveries were not connected until Timothy Lewis noted microfilariae in both blood and urine in 1872. Lewis was the first to make the association between these microfilariae and elephantiasis. In 1876, Yushitaro Matsuura found a female adult worm in an inguinal lymph node in Kuma­moto, Japan, and in the

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same year Joseph Bancroft (1836-1894), a British physician who immigrated to Australia, discovered a female adult worm in a lymph node ulcer of the arm.

Ultimately, the (primary) parasite causing lymphatic filariasis was named Wuchereria bancrofti.

Mosquito vectors Perhaps the most important discovery was made a year later by the Scottish parasitologist Patrick Manson working in Taiwan. In 1877, he discovered microfilariae in the stomach of a blood-fed mosquito, demonstrating that the parasite’s embryos are transmitted by the mosquito Culex fatigans. For the first time an arthropod had been identified as a vector of human diseases, marking the start of medical entomology.

The discovery was later applied to other tropical diseases such as malaria.

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But Manson incorrectly hypothesized that transmission occurred when mosquitoes deposited the filaria in water, which then infected humans by directly penetrating the skin or when they drank contaminated water. This was also what most local people believed in endemic regions. Only when in 1900, George Carmichael Low dis­ covered microfilariae in the proboscis of mosquitoes, did the mechanism of transmission become clear: a bite from a mosquito that recently ingested blood from someone suffering from lymphatic filariasis.

Parasitic life cycle Lymphatic filariasis is caused by infection with three closely related nematode worms (round worms): Wuchereria bancrofti (90% of cases), Brugia malayi, and Brugia timori. All the three parasites have similar life cycles in humans, the only host for W. bancrofti. The thread-like adult worms, which reach 4 to 10 cm in length over a number of years, live in the lymphatic system, where they initially cause a­ llergic lymphangitis, with symptoms of fever, headaches, vomiting and pain. The female worms produce microfilariae containing the

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Patrick Manson (left), George Carmichael Low

embryo, which circulate in large numbers in the peripheral blood during the night. Mosquitoes ingest the microfilariae and spread the infection. Culex, Aedes, and Anopheles mosquitoes are the vectors of W. bancrofti., Anopheles and Mansonia mosquitoes transmit B. malayi, and Anopheles mosquitoes B. timori.

Disfiguring disease By blocking the lymphatic system and preventing fluid ­ draining from tissues into the bloodstream, recurrent episodes lead to lymphatic obstruction, dilation, rupture, and swelling called lymphedema. Limbs can swell to resemble an elephant’s leg in size, texture and color, or genitals collect fluids in hydroceles, causing the severely disfiguring and disabling condition called elephantiasis.

Today lymphatic filariasis is a disease of underdeveloped regions in South America, Central Africa, Asia, the Pacific Islands and the Caribbean.

Globally more than 1.1 billion people are at risk of infection, and about 600 million people

live in areas endemic for lymphatic filariasis. Of the ­ estimated 120 million people infected, about 40 million are disfigured and incapacitated by the disease, one of the most common causes of disability worldwide.

Prevention and treatment Progress has been made towards eliminating lymphatic filariasis in some countries, but more research is needed on prevalence, prevention methods, and transmission cycles. Transmission can be broken with combined oral medicines, but annual treatment must be maintained over at least seven years. A vaccine is under development and antibiotic treatment to kill the symbiotic bacteria Wolbachia that live in the worm has proven effective in tests.

Attempts to treat elephantiasis over the ages have included leeches, scarring, bloodletting, fluid draining, compression bandaging, and rigorous cleaning of the skin, the last three still used today. Few new therapies have been developed in recent times.

Clearly, the history of lymphatic filariasis is still being written.

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Link List With reference to the topics in this issue of Public Health Journal we include a summary of the main Internet links, where you can find further information, the latest reports and statements.

Action and Investment to defeat Malaria 2016-2030 (AIM) www.rollbackmalaria.org/about/about-rbm/aim-2016-2030 arctec http://arctec.lshtm.ac.uk Asia Pacific Malaria Elimination Network (APMEN) www.apmen.org/ Asia Pacific Network for Vector Resistance (APNVR) http://apmen.org/storage/apmen-iv/vcwg/Insecticide%20resistance%20 monitoring.pdf Bill & Melinda Gates Foundation / Malaria Strategy http://www.gatesfoundation.org/What-We-Do/Global-Health/Malaria Break Dengue www.breakdengue.com Dengue Global Status (eBook) http://www.gideononline.com/ebooks/disease/dengue-global-status/ Global Plan for Insecticide Resistance Management in Malaria Vectors (GPIRM) www.who.int/malaria/publications/atoz/gpirm/en/ Global Technical Strategy for Malaria 2016-2030 (GTS) www.who.int/malaria/areas/global_technical_strategy/en/ IVCC www.ivcc.com/ Malaria Consortium www.malariaconsortium.org

Events ASTMH 64th Annual Meeting The American Society of Tropical Medicine and Hygiene October 25-29, 2015 Philadelphia, Pennsylvania, USA www.astmh.org/Home.htm International Congress for Tropical Medicine and Malaria September 18-22, 2016 Brisbane, Australia http://tropicalmedicine2016.com/ ASTMH 65th Annual Meeting The American Society of Tropical Medicine and Hygiene November 13-17, 2016 Atlanta, Georgia, USA www.astmh.org/Future_Meetings. htm

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Malaria Eradication Research Agenda (malERA) www.who.int/malaria/elimination/maleraupdate.pdf

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Pan African Mosquito Control Association (PAMCA) www.pamca.org

Eastern Asia Pacific Jason Nash email: jason.nash@bayer.com

Roll Back Malaria (RBM): Progress & Impact series www.rollbackmalaria.org/ProgressImpactSeries/ Sustainable Development Goals (SDGs) https://sustainabledevelopment.un.org/topics/sustainabledevelopmentgoals UNITAID http://www.unitaid.org/en/

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