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.

PUBLIC HEALTH JOURNAL 26/2015

C O N T E N T

Cover photo: Mosquito trap used in Awassa, Ethiopia (With permission of Malaria Consortium).

41Break Dengue & Dengue Lab

Building a global community

Malaria: First vaccine worldwide to be approved 54Antibiotics: Increase vector efficiency 54Dengue: Vaccine is more than 80% effective 55Malaria: Rapid non-invasive laser diagnosis 55

HistoryElephantiasis 56

CD-ROM 59

48Malaria Consortium

Putting the last mile first

N O T E S

K E Y F A C T S

32Asia Pacific Malaria Elimination Network (APMEN)

Working towards malaria elimination

36

Pan African Mosquito Control Association (PAMCA)

Malaria – Africa’s modern scourge

Available as poster on the enclosed Public Health CD-ROMPUBLIC HEALTH JOURNAL 26/2015

45Book review Dengue Global Status: The A to Z of a (re)emerging disease

R E G I O N A L N E T W O R K S

N G O

MALARIA: FACT & FIGURES

PROGRESS SINCE 2000 ON ALERT SINCE 2010

47%MORTALITY RATEDECREASE

30%DECREASE IN THE NUMBER OF CASES

EVOLUTION OF MOSQUITOES

INSECTICIDE RESISTANCE

DECLINING EFFICIENCY OF VECTOR CONTROL SOLUTIONS

A GLOBAL TEAM OF 50 PEOPLEINVOLVED IN VECTOR CONTROL.

INVESTMENT INTO PRODUCTION CAPACITY OF VECTOR CONTROL PRODUCTS IN SOUTH AFRICA, FOR AFRICA.

FIVE-FOLD INCREASE IN OUR INVESTMENT INTO NEW VECTOR CONTROL PRODUCT DEVELOPMENT OVER THE LAST 10 YEARS.

BAYER SOLUTIONSTO COMBAT RESISTANCE

INTRODUCINGA NEW MODE OF ACTION FOR VECTOR CONTROL.

1ST MIXTURE PRODUCTFOR INDOOR RESIDUAL SPRAY.

CONTINUED INVESTMENTTO BRING RESISTANCE MANAGEMENT TOOL TO MARKET.

DANGER : RISK OF MALARIA RESURGENCE WITH ABOUT

120 000 NEW VICTIMS PER YEAR*.

100 MILLION LIVES PROTECTED THANKS TO BAYER SOLUTIONS.

* Sou

rce

WHO

+

+

103 COUNTRIES AND TERRITORIES HIGH RISK FOR 1,2 BILLION PEOPLE.

REGIONS AT RISK

EXISTING SOLUTIONS TO FIGHT MALARIA

MEDICAL TREATMENT

PREVENTIVE OR CURATIVE

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.

MALARIA: THE DEADLIEST VECTOR-BORNE DISEASE

3,2 BILLION PEOPLE AT RISK 45% OF THE GLOBAL POPULATION

50 CHILD DEATHS EVERY HOUR198 MILLION CASES A YEAR

584 000 DEATHS A YEAR MALARIA REPRESENTS 80,55%

OF 725 000 DEATHS CAUSED BY MOSQUITOES

Person infected by Malaria

Infected peopleHealthy peopleInfected mosquito

Mosquito

INSECTICIDES

INDOOR RESIDUAL SPRAY TREATED BEDNETS

BAYER-infographie Malaria-GB-A4paysage_(2A5)-.indd Toutes les pages 07/08/15 14:35

31

Malaria eradication

Innovative vector control is vitalby Dan Strickman

Public Health

2 PUBLIC HEALTH JOURNAL 26/2015

C O N T E N T

6

The importance of vector control in malaria elimination

The right tools for the jobby Jo Lines

C O V E R S T O R Y

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

Editorialby Jacqueline Applegate 4

13

Towards eliminating vector-borne diseases

The need for insecticide resistance managementby Janet Hemingway

5

Editor’s note

Vector control

Need for innovationby Gerhard Hesse

18

Vector control

The challenges of developing new vector control solutions by Justin McBeath and Frédéric Schmitt

24

Pyrethroids

Metabolic resistance of insects by Sebastian Horstmann

28

arctec

Evaluation of arthropod control products


C O N T E N T

Cover photo: Mosquito trap used in Awassa, Ethiopia (With permission of Malaria Consortium).

41Break Dengue & Dengue Lab


Malaria: First vaccine worldwide to be approved 54Antibiotics: Increase vector efficiency 54Dengue: Vaccine is more than 80% effective 55Malaria: Rapid non-invasive laser diagnosis 55

HistoryElephantiasis 56

CD-ROM 59

48Malaria Consortium

Putting the last mile first

N O T E S

32Asia Pacific Malaria Elimination Network (APMEN)


36



45Book review Dengue Global Status: The A to Z of a (re)emerging disease


N G O

31

Malaria eradication

Innovative vector control is vitalby Dan Strickman


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 exper-tise 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 Pan-African 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 collaborative online platforms that help to connect experts and key stakeholders to exchange knowledge about this resurgent disease.

Insecticide resistance is at the center of our thinking and certainly a challenge that the interna-tional 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,

E D I T O R I A L

Head of Bayer Environmental Science Division and member of the Bayer CropScience Executive CommitteeJacqueline Applegate

5PUBLIC HEALTH JOURNAL 26/2015

E D I T O R ’ S N O T E

or post 2015, the malaria control community has defined new goals

to cover the period 2016-2030, laid down in two essential reports: the RBM’s guide for collective “Action and Investment to defeat Malaria 2016-2030 (AIM) – for a malaria free world”, complementing the WHO’s “Global Technical Strategy for Malaria 2016-2030 (GTS)”. AIM and GTS share two supporting elements: to strengthen the enabling environ-ment (policies, data and health sys-tem) and foster innovation, the latter accompanied by a responsive political environment incentivizing needs for R&D to bring innovations to the market, and this as fast as possible.

Models forecast that if malaria intervention cover-age remains at current levels, incidences may even increase moderately as a result of loss of immunity among populations that have been protected previ-ously by interventions. This effect can be averted, for example by optimizing the use of currently available vector tools, if the coverage level is above 80% of the population at risk.

One recommendation is to implement a prevention strategy based on vector control incorporating the major threat of emerging resistances to insecticides in the vector. However new innovative tools are needed, and it is here that seeking to better harness innovation and expanding research becomes impor-tant.

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.

Vector control

AIM lists the development of new active ingredients for use in LNs and IRS as top priority, since these under-lie key intervention strategies. The rapid development of resistances against the widely used pyrethroids have stimulated not only multiple innovation streams, including formal Product Development Partnerships such as IVCC, but also the in-house innovation pipelines of primary manufacturers. In addition the observable switch from indoor biting to outdoor biting requires new formu-lations of insecticides.

Bayer as one of the companies committed to inno-vation in vector control has some very promising new insecticide candidates for IRS, which are pre-sented in this issue. GTS stresses that options urgently need to be explored to ensure timely and affordable access to improved vector control tools, so countries need to provide the regulatory environ-ment facilitating rapid assessment and uptake of validated tools.

Two important outcome indicators for GTS 2016-2030 are the proportion of the population at risk who slept under an LN the previous night, and/or were protected by IRS over the past 12 months. We hope to obtain new tools in the future from innova-tion pipelines for vector control, but to cover the time to market, we must make the best out of using current alternative tools.

The author: GERHARD HESSE

Head of Global Partnering,

Bayer Environmental Science, Lyon, France

F

Please find the important links to this column on page 60 (back cover flap): AIM, GTS, SDGs, malERA, IVCC.

C O V E R S T O R Y


The importance of vector control in malaria elimination

COVER STORY

6

The right tools for the job

C O V E R S T O R Y


In the last fifteen years, massive investment in the scaling-up of modern anti-malaria 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.

7

he priority given to vector control, as opposed to other anti-malaria interven-tions, 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 vaccines. We must also consider how the role of vector control might differ accord-ing 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 bio-geographical 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 trans-mitting the parasite than the equivalent malaria vector species in Asia and Latin America. What makes the African species so much more effi-cient 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

T

-------------------------------------------------* Bhatt et al. submitted for publication, and P. Gething personal communication.

C O V E R S T O R Y


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 prox-imity to the human population, and any newly arising cases are quickly detected and treated. Hence, in this part of the world, there is no sus-tained transmission, and the equilibrium parasite population size is zero.

Unstable and epidemic-prone malaria In other places, where the vectors are more numer-ous or more efficient, the potential for parasite transmission is greater; transmission can be self-sustaining, and the infection can persist. However, it may be unstable. The potential for transmission

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 surround-ing countryside, in contrast to all other continents,

where urbanization tends to exclude malaria.

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).

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 equilibri-um population size, which may be more or less stable.

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.

C O V E R S T O R Y


depends mainly on the mosquito population. This is highly dynamic; mosquito numbers can fluctu-ate by five- or even ten-fold from one village to the next, and from one week to the next. Super-imposed on this are seasonal cycles, which nor-mally have even greater amplitudes.

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 exam-ple in many parts of the plains of India and Pakistan, transmission is regular and seasonal every year, but with great variation from year-to-year 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 effi-cient, 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 mea-sles, the equivalent ratio would be about 20 sec-ondary cases per primary case. Under these condi-tions, therefore, the parasite population has a strong tendency to increase very rapidly.

Two factors limit this increase: saturation and immunity. Saturation simply means that as preva-lence 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 immu-nity 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.

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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.

C O V E R S T O R Y


Thus, in any given setting, the equilibrium malaria infection prevalence depends on a range of vector-related 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 rela-tively 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 stabiliz-ing factors can be very strong.

How interventions affect parasite equilibrium

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

size, but leave it likely to return to the same equi-librium. Others have little or no direct effect on parasites (only the vector), but can shift the para-site 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-chang-ing 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 pro-duce long-term (or even permanent) reductions in parasite population size, and can be useful for this purpose. One is in small closed human popula-tions, where it is possible to extinguish every last parasite, with no exceptions. In this case, the state of elimination thus created may be highly unstable, 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 perma-nent. In these circumstances, the parasite popula-tion is also expected to decline to the new lower equilibrium, but may do so slowly, with a substan-tial time lag. Cambodia is probably an example of this. As noted on page 7, in the Mekong sub-region, 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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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.

C O V E R S T O R Y


people have long-term asymptomatic infections, and are never ill but are infectious. In these cir-cumstances, 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 tran-sient effect.

Vector control, by contrast, is an “equilibrium-shifting” intervention – at least as long as the vec-tor control is sustained. Of course, the vectors also have a “natural” or “background” level of abun-dance 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 com-pared 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.

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 cover-age and impact. With most interventions (includ-ing larviciding and MDA), the expected degree of reduction is proportional to, and limited by, the degree of coverage actually achieved. For exam-ple, 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 cov-erage. 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 “satura-tion” 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.

The author:

JO LINES

London School of Hygiene & Tropical Medicine, UK

C O V E R S T O R Y


In settings where overall prevalence has been reduced to less than 0.5%, it is normally very patchy: there are some hotspots with active trans-mission and new cases, and gaps in between where there seems to be no transmission. This provides the opportunity to concentrate intensive interven-tions 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 trans-mission 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 cata-strophic re-invasion. But vector control is expen-sive; if this expense has to be maintained simply to prevent a few cases each year, then the cost-effec-tiveness of the elimination effort can be ques-tioned. Moreover, in some settings, the long-term sustainability of insecticidal vector control in a post-elimination period may be limited by resis-tance, 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 eradi-cation campaign, in the 1960s, the risk of reinva-sion by malaria in a post-elimination area was

Over the last decade, vector control has account-ed for more than half of PMI and GFATM expenditure on anti-malaria interventions, and has been responsible for more than three-quar-ters of the malaria cases averted by these inter-ventions. 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 interven-tion capable of achieving the very large reduc-tions 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.

CONCLUSION

Article on the enclosed Public Health CD-ROM

assessed in terms of two key factors: “vulnerabil-ity” and “receptivity”. These are useful and impor-tant concepts. Vulnerability denotes the probabili-ty of importation: the frequency with which infected people are expected to arrive in the elimi-nated 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 long-term 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.



Towards eliminating vector-borne diseases

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.

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

The need for insecticide resistance management

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

Malaria accounted for more than 0.5 million of the under 5 deaths in 2013, making it one of the highest causes of infant mortali-ty, with the burden falling dis-proportionately 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 inter-national targets such as the

comprehensive global all-cause 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 com-municable 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.

A

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 in-creased death rates in 2013 reflect reduced child mortality and longer life expectancy.

All-cause global mortality rates

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15.0

12.5

10.0

7.5

5.0

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00-4 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 ≥80

GBD super regionSub-Saharan AfricaSoutheast Asia, East Asia, OceaniaSouth AsiaNorth Africa, Middle EastLatin America, CaribbeanHigh incomeCentral Europe, Eastern Europe, Central Asia

1990 2013

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.


Historically low and middle income countries that aggres-sively adopt new tools and tech-nologies would see an additional 2% per year decline in child mortality rates compared with non-adopters. Given the contri-bution 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 impor-tant as progress towards the SDG targets is monitored. The Neglected Tropical Diseases

(NTDs) fit within this category. They are a group of 17 lesser known chronic infections that primarily affect poor and disen-franchised communities. NTDs are endemic in 149 countries and affect an estimated 1.4 bil-lion people. Six of these diseases are transmitted by insects or bugs. Diseases such as filariasis rank in the top 30 causes of dis-ability in sub-Saharan Africa. This disease, along with Onchocerciasis, is being target-ed 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 coun-tries, and a restriction on the use of MDA in Loa Loa transmis-sion areas, it is evident that

DELIVERING IRS in remote parts of Africa can

be a challenge, here by bicycle in Uganda.

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disease 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



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 recom-mended for prevention of insect-borne diseases, in reality the majority of large-scale effective interventions are insecticide based. For example for malaria, indoor residual spraying (IRS) and long-lasting insecticide-treated 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 partner-ship the Innovative Vector Control Consortium (IVCC) was established in 2005, with a major

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.

The current distribution of pyrethroid resistance in Anopheles in Africa

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

investment from the Bill and Melinda Gates Foundation. The IVCC works with the agrochem-ical 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 collabor-ative programs with the IVCC, with projects for an extended-life IRS formulation of pyre-throids and a major discovery and development project to identify new public health insec-ticides that are unaffected by cross-resistance to any of the currently used insecticides.

Threat of insecticide resistance

While the scale up of insecti-cide-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 catastroph-ic consequences for sustainable disease prevention.

Before the large-scale distribu-tion of pyrethroid treated bed-nets in 1990, there were only a



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 compa-nies, regulators, implement-ers and others need to ensure that the innovative efforts of the last decade are effectively translated into impact, reduc-ing the heavy burden of disease that still falls on many of the world’s poorest com-munities.

CONCLUSION


limited number of reports of pyrethroid resistance in Anopheles gambiae, a major African vector of malaria. An. funestus, another important vec-tor, remained fully susceptible, despite pyrethroids being used extensively to control agricul-tural pests in Africa. The first pyrethroid resistance mechanism to be selected in An. gambiae was a target site resis-tance (known as kdr). Although there are several variants of this resistance mutation, all confer only a low (<10-fold) level of resistance. This resistance mech-anism 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 pyrethroid-based 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 resis-tance also produces cross resistance to a range of other insecticides.

Super resistance could impede malaria control

This kind of pyrethroid resis-tance was subsequently selected in An. funestus and An. gambiae from a range of different loca-tions 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 resis-tance 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, includ-ing 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 imped-ing malaria control efforts today.

The author:

JANET HEMINGWAY

Liverpool School of Tropical Medicine, Liverpool, UK

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 insecti-cides 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 public good.



Return on investment

The only way for the production and supply of important vector control commodities to remain sustainable is if a market exists to justify their continued manu-facture. That market must remain attractive over time to justify some level of further investment into innovation in order to bring new, improved

solutions to market that help address challenges such as insecticide resistance. From a business perspective, especially a business where private share-holders expect a return on their investment (their retirement incomes may depend on it), the internal resources required to

anaging the spread of insecticide resistance is a

shared responsibility and one that requires what the WHO Global Malaria Program refers to within their 2012 Global Plan for Insecticide Resistance Management (GPIRM) as a “Collective Strategy”. Within this plan, one of the five key pil-lars is the “development of new innovative vector control tools”, a responsibility that is seen to lie firmly with manufacturers and Product Development Partnerships (e.g. the IVCC).

Bayer is a good exam-ple of one of the lead-ing R&D manufactur-ing companies that have not only taken the issue of insecticide resistance management (IRM) very seriously for some time, but also willingly assumes this responsibility. But what kinds of things do we evaluate when it comes to making a decision to invest?

Vector control

The challenges of developing new vector control solutionsWith more than half of the international funding for malaria control being spent on vector control commodities or activities, resistance by malaria-transmitting 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).

M support the development of new innovative solutions must be jus-tified against all other options to generate return on investment. The ongoing attractiveness of the market is therefore important in terms of the probability of return on the investment. How does that relate to the option to invest in developing new insecticides for public

health? First of all, if we reflect on the con-cept of “time” within the discussion on insecticide resistance it is clear that this is not a “new” issue; it has long been talked about, and many influ-ential voices in the

malaria vector control commu-nity have expressed concern for the last fifteen years or more.

Visibly growing market

All the insecticide modes of action for vector control we have today were already available

“Insecticide resistance is the greatest current threat to the future of malaria control and to the sustainability of the

achievements of recent years”

Pedro Alonso, Director of the WHO Global Malaria Program, Geneva; January 2015 (http://www.rollbackmalaria.org/)



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 insec-ticide-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).

The visible increase in demand between 2004 and 2010 was so important and substantial that the market became attractive enough for several other suppli-ers: 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 implement-ing IRS (as well as the overall

IRS coverage) also increased substantially over this time period. For example, WHO fig-ures indicate that approximately 22 million people were protect-ed by IRS in Africa in 2006 (World Malaria Report) com-pared 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 pro-portion of households were sprayed with more expensive non-pyrethroid insecticides, with an average cost per house-

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

Market conditions have there-fore 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 ques-tion is what will the market look like in ten years’ time? Market conditions at the time of com-mitment to developing a new

Fig. 1: The volume history of global distribution of long-lasting insecticide-treated nets (LNs)

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



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 devel-oping 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 avail-able 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 chang-ing market conditions and can stand the test of time.

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 pic-ture 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 suppli-ers of nets and IRS solutions. Of the nine suppliers currently holding a WHOPES recommen-dation for a LN, three (Sumitomo, BASF and Bayer) have in-house expertise and capacity to develop new insecti-cides; the others rely on the sup-ply 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.

IVCC-AI’s

Pyrethroids,Carbamates,Organophosphates,Organochlorines,PyrrolesNeonicotinoids,Bayer Project 2

IRS

20203 modes of action on nets?6-7 modes of action for IRSGreater choice available for IRSResistance easier to manage

IVCC-AI’s

Pyrethroids,Juvenile hormone analogue, Pyrroles

LNs

20255 modes of action on nets?7 modes of action for IRSCompetition driving prices downResistance management a routine?Malaria elimination in more countries

???

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

LNs

???

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

IRS

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

Fig. 2

Insecticide classes available

Developments in process

2015Intensification of vector control effortsLNs only with pyrethroidsPyrethroid resistance widespread

Pyrroles,Juvenile hormoneanalogue,+IVCC AI’s

Pyrethroids

LNs

Pyrroles,Neonicotinoids,Bayer Project 2

Pyrethroids,Carbamates,Organophosphates,Organochlorines

IRS



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 invest-ment required is significantly lower (typical development costs are usually less than € 10 mil-lion) 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 ingredi-ent has a chance of success gen-erally above 70% (within the allocated budget and time-frame). This is mainly due to the fact that the major risk of failure linked to human and environ-mental risk assessments of the active substance has already been addressed during the active substance development.

With the urgency associated with the need to manage insecti-cide resistance in malaria vec-tors now, and the market uncer-tainty 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-spec-trum contact activity and long-lasting residual effect. The pyre-throids (introduced through the

1970’s and 1980’s) were argu-ably the last group of insecti-cides developed that retained these features.

Shifts in target product profile

The focus in developing agricul-tural compounds since the advent of the pyrethroids has generally moved towards more selective compounds. Contact activity has become less impor-tant as it is recognized how important it is to leave popula-tions 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, resid-ual 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 selec-tive towards specific groups of pests (e.g. towards Lepidoptera or Hemiptera). This shift in tar-get product profile for agricul-

tural insecticides, coupled with historical market uncertainty around public health has argu-ably 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, dedi-cated 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 com-pound, and it requires an invest-ment somewhere in the range of € 60 million to € 200 million. First of all a new active ingredi-ent must be “discovered” – a challenge in itself when hun-dreds 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

The authors:

JUSTIN MCBEATH

Market Segment Manager – Malaria

Vector Control

FRÉDÉRIC SCHMITT

Global Project Manager – Vector

Control

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



its toxicological profile is acceptable.

Even after a candidate molecule has been identified it may still fail other tests in the early devel-opment phase. This clearly requires a large level of invest-ment, 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 mar-kets. 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-

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 finan-cial burden in the development of completely new compounds dedicated to public health uses. The good news is that currently,

This mixture contains two insec-ticides with completely unrelat ed 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 insecti-cides. 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 deve-lopment 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-

Fludora™ Fusion

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

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 crite-ria, for many of the compounds the biological performance see-med not strong enough to justify further development. Therefore the more promising compounds were explored in mixtures with existing insecticides. Some in-house familiarity with combi-nations of pyrethroids and neonicotinoids had already been established with the product Temprid used in professional pest control in the USA and Aus-tralia 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 differ ent

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 mor-tality is clearly an important fea-ture 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 alterna-tives that make it easier to mana-ge the spread of insecticide resi-stance in malaria vectors. With Fludora™ Fusion we see greater efficacy and robustness of per-formance 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 solu-tions available today.



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 resis-tance. Repurposing of exist-ing agricultural compounds is seen as a means of achiev-ing the goal of fast availabil-ity. 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 solu-tion must also consider the overall landscape of new insecticide availability and potentially changing dynam-ics of insecticide resistance selection.

CONCLUSION


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 future-orient ed products) it is increas-ingly 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-effec-tiveness 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 achiev-ing 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 vec-tor control.

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

• Improve the position of cost-effectiveness compared to existing solutions (partly related to the residual perfor-mance).

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 rea-son we think insecticide mix-tures are attractive as long-term solutions for IRS, which is why a mixture has been chosen as the focus of our current develop-ment 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 repre-sents 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 start-ing to build up, reducing the

selection for pyrethroid resis-tance, and alongside greater choice in IRS solutions, rotation or mosaic strategies will (should) make insecticide resistance man agement more effective. Anticipating a heightened awareness of how important it is to proactively manage resistance, the relevance of insecticide mix-tures should increase.


24

ll living organisms perma-nently 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, bio-catalysts with the ability to accelerate the speed of a chemi-cal reaction by decreasing the activation energy necessary to open solid bindings and make

Pyrethroids

Metabolic resistance of insects

A rearrangements. With the help of enzymes a chemical reaction can take place at ambient tempera-tures, whereas the same reaction without the involvement of enzymes would need to be heat-ed up before it can react in the same way. The chemical com-pound changed in the reaction is called the substrate, but the enzyme itself is not altered dur-ing the reaction process, and can trigger additional reactions.

The majority of enzymes are proteins with a complex physi-cal structure required for their function. They all form a so-called 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 sub-strate, 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 dif-ferent substrates. Enzymes responsible for the detoxifica-tion of foreign molecules (xeno-biotica) need to have a flexible catalytic center or a general tar-get 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

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 devel-oped 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.




withstand degradation in the tar-get insect. At the same time these compounds need to pro-vide 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, com-bined 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, particu-larly the class of oxido reductases and the associated degradation events working against pyre-throids.

Oxidoreductases

Oxidoreductases are enzymes involved in oxidation and reduc-tion 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 mono-oxygenases, in contrast to dioxygenases, which transfer both oxygen atoms to one sub-strate.

Cytochromes degrade pyrethroids

To handle oxygen atoms the dioxygenase proteins contain a heme-complex to bind dioxy-gen1. 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 accu-rately 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 process-es.

In addition to many other func-tions, CYP enzymes are involved in the degradation of xenobioti-ca. Importantly, these enzymes

are found in more or less every insect-tissue, but significantly concentrated in the mitochon-dria and microsomes. For some decades now, these enzymes are known to be involved in adaptive mechanisms of insects that live on plants creating toxic sub-stances3, and in insecticide resis-tance4. 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 pyre-throid-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.

The author:

SEBASTIAN HORSTMANN

Bayer CropScience, Monheim, Germany



Several institutes have per-formed metabolite studies with pyrethroids using microsomal extracts. Microsomes are vesi-cle-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 pyre-throids, which is often hydroxyl-ated in the 4th position of the phenoxybenzyl-ring (see Figures 1 and 2).

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

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

A similar way of degradation is described for many other pyre-throids 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 fly-microsomes the 4´hydroxypyri-proxyfen metabolite can be identified8.

Avoiding cross-resistance

For the design of new active ingredients knowledge about detoxification pathways is high-ly important to avoid cross-resis-tance. Moreover these findings are valuable regarding the appli-cation 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 there-fore overcome the metabolic resistance. The active ingredient transfluthrin for example belongs to the class of pyre-throids, but lacks a phenoxyben-zyl-moiety (Figure 3).

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

phenoxybenzyl-moiety

Permethrin

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

Permethrin

4-hydroxypermethrin

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

tetrafluorobenzyl-moiety

Transfluthrin

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 pub-lished soon.



taining a carbon atom (Figure 4), as in pyrethroids or organo-phosphates.

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

Regarding pyrethroid detoxifi-cation, a target site for carboxy-lesterases exists in nearly all pyrethroids except for the non-ester pyrethroid etofenprox. Cleavage at the ester bond per-formed by esterases seems to be a major degradation step, and the pyrethroid-acid as well as the alcohol-moieties are detect-able as metabolites in the urine of rats given cypermethrin10. Notably, also the 4´hydroxy-phenoxybenzyl metabolite is detectable, which indicates that the pyrethroid was modified beforehand at the phenoxyben-zyl-moiety by the CYPs described above. It is possible that this modification improves the conditions for esterase activity.

Transferases

The second enzyme class com-prises 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 glu-tathion to the substrate. One main effect of this reaction is the conversion of a lipophilic sub-strate 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 dichlordiphenyl-dichlorethan (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 detoxifica-tion it is reported that glutathi-one is possibly conjugated to the active site of pyrethroids, caus-ing an inhibitory effect on pyre-throid 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 con-nection into an acid and alcohol part. Besides other classifica-tions the esterases can be divid-ed into two important types, the carboxylesterases and the phos-phatases. The carboxylesterases focus on the ester-bindings con-

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

Figure 4: Target binding site for carboxylesterases.

Figure 5: Target binding site for phosphatases.

A deeper understanding of the metabolic pathways and enzymes involved in detoxifi-cation pathways will help support the design of more effective insecticides avoid-ing cross-resistance as well as taking into account potential structural modifications of existing active agents. Such targeted development should help the discovery of resis-tance-breaking active ingre-dients for future vector control products. Never the-less, it is essential to apply resistance management pro-grams from the IRAC (In sec-ticide Resistance Manage ment Committee) like mode of action rotation or mosaic treatments to avoid or at least delay future resistance devel-oping against new active ingredients.

CONCLUSION

Article with references on the enclosed Public Health CD-ROM

www.irac-online.org/



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arctec

Evaluation of arthropod control products

Launched in 2010 at the London School of Hygiene & Tropical Medicine, arctec – the Arthropod Control Product Test Centre – builds on the School’s long-standing tradition of outstanding research in insect repellents and insecticides. With high quality con-trol standards, it adds rigorous and internationally recognised testing facilities for novel and existing arthropod control products.

he London School of Hygiene & Tropical

Medicine (LSHTM) is a world-leading centre for research and postgraduate education that spe-cialises 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 repel-

T 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 coordi-

IN VITRO ASSAY for head lice products.



nators, many of whom have studied to PhD level. Together they have many years of valu-able 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 scien-tific team, arctec has recently expanded its business develop-ment team to respond effectively to the increasing number of cus-tomer requests while pursuing its steep growth even further. 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 prod-ucts, services, practices and policies, resulting in social and economic benefits.

Driving innovations to solutions

With some of the world’s lead-ing expertise in the field of ento-mology 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 phar-maceutical and chemical manu-facturer stakeholders in industry as well as regulatory agencies, arctec is at the heart of bridging innovation and markets through providing the high quality stan-dards necessary in efficacy eval-uation.

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 mar-ket. In the quest to help combat insecticide resistance and reduce outdoor transmission of vector-borne diseases, this includes evaluating new active ingredi-ents 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 con-trol products from initial stages of efficacy testing for raw mate-rials and active ingredients through to registration of fully formulated, commercially viable products. Product types range from repellents including sprays, lotions, wipes, sticks and patch-es; insecticides including formu-lation variations, treated fabrics

and textiles such as bednets, clothing and blankets; treated paints and coatings; and attrac-tants and lures in laboratory-based behavioral arenas and olfactometers.

Field testing around the world

Clinical trials are also available for head lice and after-bite treat-ment products. The state-of-the-art 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 sta-tions, 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

EXPERIMENTAL HUTS at a PAMVEREC field site in Tanzania.

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house dust mites, sandflies, cockroaches, bed bugs, house flies and triatomine bugs. They have links with external agen-cies, 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 mosqui-toes.

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 par-ticipate in clinical trials. arctec follows standardised scientifi-cally rigorous protocols which comply with regulatory authori-ties such as the Health and

arctec provides services that cover all aspects of develop-ment, consultancy and evalu-ation of arthropod control products at every stage. From initial discovery, through test-ing in the lab and field trials, to clinical trials and registra-tion of finalized products, arctec’s team of highly quali-fied experts use research and knowledge to drive inno-vation through products, services, practices and poli-cies, resulting in social and economic benefits.

CONCLUSION


http://arctec.lshtm.ac.uk [email protected].

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

Safety Executive and the Medicines and Healthcare Products Regulatory Agency in the UK, and equivalent regula-tory bodies in the USA, Canada, and worldwide, for the evalua-tion 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 under-go thorough quality control. All its staff are trained in Good Clinical Practice (GCP) and they liaise with the LSHTM’s in-house Ethics Committee, local Research Ethics Committees, the Medicines and Healthcare Products Regulatory Agency and the Health and Safety Executive. The regulatory land-scape can often be challenging for manufacturers to navigate, and arctec prides itself in offer-ing consultancy services to help guide clients with this.

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Malaria eradication

Innovative vector control is vitalThe 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 fol-lowed 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 transmis-sion, and until practical vaccines are available, the only way to do it.Having eliminated malaria from 81 countries since 1945 and bring-ing 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: insecticide-treated bed nets (ITN) and indoor residual spraying (IRS). These gains are now threatened by insec-ticide resistance, particularly pyre-throid resistance. Those familiar with the history of pesticide use are not at all surprised by this chal-lenge – in fact, pyrethroids have maintained their effectiveness remarkably well. The Foundation’s contribution to a solution has included working with industry and academic part-ners through a product develop-ment partnership, the Innovative Vector Control Consortium (IVCC). It has taken ten years for IVCC and its partners to identify three entirely new active ingredi-ents 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 resis-tance 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

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 iso-lated by distances, politics, or con-flict. The Foundation has invested in such technologies and continues to do so, trying to perfect genetic manipulation of vector popula-tions, develop advanced behavior-altering 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 trans-mission. Called Innovation to Impact (I2I), this partnership tran-sitioned 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.

toolbox of existing methods, including larval source manage-ment through civil engineering, chemical larval control, personal protection products, and adulti-cides applied in a wide variety of formats (e.g. outdoor residual sprays, ultra-low volume applica-tion, etc.). New methods, such as attract-and-kill products and spa-tial repellents, will further expand this toolbox. The challenge is to put these tools together into cost-effective programs that gain effi-ciency through responding to entomo logical and epidemiologi-

The author:

DAN STRICKMAN

Bill & Melinda Gates Foundation,Senior Program Officer, Vector

Control, Seattle, USA.




32

ector control is a major technical challenge facing

the Asia Pacific region. Although most countries in the region scaled up the distribution of vec-tor 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 trans-mission context, many are con-cerned that these strategies may not be sufficient in an elimina-tion setting when malaria becomes more concentrated in localized settings.

Asia Pacific Malaria Elimination Network (APMEN)


V The Asia Pacific also has 19 dominant vector species, com-pared to 7 in sub-Saharan Africa and 9 in the Americas1. Many of these are outdoor biting or out-door breeding mosquitoes, which are more difficult to target through conventional vector control strategies2. Despite this vector complexity, many coun-tries in the region lacked ento-mological capacity, so that they did not have sufficient knowl-edge about the breeding sites and behaviors of the vectors they were trying to control.

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

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 con-firmed 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.

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 resis-tance. In 2009 the Asia Pacific Malaria Elimination Network (APMEN) was established to support regional malaria elimination efforts through knowl-edge exchange, capacity building, leadership and advocacy.


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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.



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 man-agers with a range of other part-ners, including representatives from development agencies, sci-entific and academic institu-tions, the private sector and global leaders, working towards malaria elimination. APMEN supports countries to collabora-tively pursue regional malaria elimination efforts through knowledge exchange, capacity building, and building the evi-dence base, as well as leadership and advocacy for elimination.

APMEN has carried out a num-ber of activities to build up evidence around issues of spe-cial significance to the Asia Pacific region, especially con-

cerning Plasmodium vivax and vector control, and more recent-ly 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 Country Partners and Partner Institutions with special expertise in entomology and vector control. The Vector Control Working Group con-venes each year, often in con-junction 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 advo-cating for the scale of vector control capacity at regional and country levels required to attain and maintain malaria elimina-tion, as well as stimulating, and where possible coordinating, operational research on ques-tions 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 sur-rounding vector issues, as well

The Asia Pacific Malaria Elimination Network (APMEN) is a network of Asia Pacific countries and other stakehold-ers 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.

WHAT IS APMEN?



as witness innovative and suc-cessful approaches for local vec-tor control management.

A recent APMEN study tour to Sri Lanka in July, 2015, visited an entomological sentinel sur-veillance site where regular monitoring occurs to determine seasonal changes in vector den-sities and any changes in vector bionomics and characteristics. The tour observed: hand collec-

tion, larval identification, cattle baited hut collection, cattle bait-ed net trap collection and pyre-thrum spray sheet collection. Learning from how Sri Lanka, who is nearing elimination sta-tus, operates their sentinel sites is an important capacity building activity that allows network par-ticipants to experience first-hand the changes required to move from control to elimination.

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

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

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

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.

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.

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• Played a lead role in estab-lishing elimination as a shared, regional goal and brought global attention to the achieve-ments 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 re-gional awareness for elimina-tion through well-run annual meetings, workshops, study tours and other events.

• Advocated for and built evi-dence around the safe and radical cure of Plasmodium

HIGHLIGHTS OF THE FIRST FIVE YEARS OF APMEN

vivax, especially through the Vivax Working Group.

• Established additional Tech-nical Working Groups on Vec-tor Control and Surveillance and Response to build evi-dence and regional capacity for elimination in these priori-ty areas.

• Built the capacity of future leaders in elimination through the APMEN Fellowship Pro-gram and other capacity build-ing activities.

• Continued to expand and adapt to an ever-changing ma-laria and public health land-scape.

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

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.

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 coun-try program managers, part-ners and other stakeholders committed to working collab-oratively to achieve malaria elimination in the region. Moreover, APMEN has brought global attention to the achievements and chal-lenges faced by Asia Pacific countries.

CONCLUSION

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

dance at IVM training was iden-tified 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 applica-tion of IVM approaches in their countries. APMEN has support-ed 16 participants from Country Partners to attend the IVM course hosted by the Malaysian Ministry of Health in both 2012 and 2014.

Moving towards elimination

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-

www.apmen.org


36

alaria remains the most debilitating mosquito-

borne disease, especially in Sub-Saharan Africa where it is one of the main causes of morbidity and a large contributor to mor-tality1 particularly among preg-nant women and children under five years old (WHO, 2013). Although over 290 million peo-ple across the world in over a hundred malaria-endemic coun-tries 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, includ-ing members of the Anopheles gambiae Giles and Anopheles



M funestus Giles species complex-es, which are widespread and difficult to control.

Despite ongoing efforts to combat the disease through inte-grated malaria management strategies targeting both the vec-tors 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 con-trolling 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 con-trol policy shifted toward domes-tic adulticide methods.

African mosquito experts recently took charge in Africa’s war against malaria and mosquito-borne diseases by launching an Africa-based, African-led orga-nization 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 mosqui-toes across Africa and worldwide.

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


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1 Breman, 20012 World Malaria Report, 20143 Killeen et al 2002; 2004



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 con-tributed 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 organ-ism and over one million people worldwide die from mosquito-borne 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 ento-mologists and mosquito control specialists and provides a uni-fied voice for these profession-als. PAMCA was conceptualized in 2009 after the realization that the many agencies committed to tackling malaria and other vec-tor borne diseases are situated or based in the north, run by indi-viduals with the best of inten-tions but often constrained in understanding of the local con-text and cultural dynamics so crucial to engaging communi-ties. 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

scientists to tackle mosquitoes and mosquito vector-borne dis-eases.

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 dur-ing a brief ceremony held at the International Conference Center (ICC), Durban, South Africa during the 6th Multilateral Initiative of Malaria (MIM) con-ference. The timely launch of PAMCA in 2013 in Durban, South Africa, with the vision of information sharing and provid-ing leadership is excellent. The launch was attended by over 150

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

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health experts, mosquito researchers, academics, health-related Non-Governmental Organization (NGO) agencies and other vector control special-ists.

Building a capable African workforce

Currently available methods to control mosquito vectors of malaria and mosquito-borne dis-eases are based on using insecti-cides and eliminating breeding sites. When considering the potential of new technologies to address the unmet needs of mos-quito control, it is necessary to evaluate the risks and benefits in the context of the current situa-tion. Thus the risk incurred by testing new and unproven strate-gies should be assessed against

the risks to human health and the environment posed by maintain-ing 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-

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

To overcome such challenges, countries should be provided with adequate entomological information on identifying major vector species, the bionomic of vectors, the intensity of trans-mission, entomological inocula-tion rates (EIRs) and the status of insecticide resistance. Such information is not readily avail-able for real-time decision mak-ing because very few countries have the capacity to measure them. From an operational view-point, it is debated whether

Country ChapterSince its inception in 2011, PAMCA has estab-lished 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 Foun-dation. We are developing futher partnerships with other organizations.

NETWORKING, PARTNERSHIPS AND FUTURE AIMS

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 mosquito-borne 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

The author:

CHARLES M. MBOGO

President of PAMCA & Chief Public Health Entomologist, Kenya Medical Research Institute

(KEMRI)



information is needed on trans-mission for routine monitoring purposes (EIRs and malaria inci-dence). The capacity to measure EIRs is important for National Malaria Control Programs (NMCP) to answer specific questions relating to the effec-tiveness of control operations, whereas measurements related to vectorial capacity (biting rates, mosquito survival, feeding behavior and feeding patterns) can provide valuable informa-tion 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 dedi-cated 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

PAMCA has over 100 members from 21 countries, 3 Country Chapters, and is growing. This dem-onstrates 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 mos quito borne diseases

• Developing and implementing new materials, tech-niques and tools for mosquito control

• Enhancing control measures based on Integrated Vector Management principles by favoring meth-ods with low toxicological profiles and low envi-ronmental 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.

ORGANIZATION MEMBERSHIP

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

Currently, the major vector con-trol interventions rely almost exclusively on the use of long

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



The mission of PAMCA is to provide African leadership, information, training and education, as well as a plat-form of discussion leading to the enhancement of health and quality of life in Africa as well as worldwide. PAMCA aims to improve the efficien-cy of control measures against mosquitoes and mosquito-transmitted 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.

CONCLUSION


www.pamca.org [email protected]

we work towards a mosquito-free 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.

“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 collabora-tively address the unique chal-lenges 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

global experts in vector disease control.

PAMCA’s main function is to coordinate information sharing concerning vector control activi-ties among Africans, while also promoting control of and research on mosquitoes, espe-cially 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 meet-ings and conferences. To over-come 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.

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

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 there-fore aims to build regional capacity for mosquito suppres-sion through practical and innovative capacity building activities that transfer expertise between countries and between future leaders and established

N G O


Break Dengue & Dengue Lab


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.

rom 8% users in 2005 to 73% in

20131, from Facebook to Pinterest, social media is changing online dialogue from one-to-many to many-to-many at phe-nomenal speed2. This instantaneous communi-cation channel has four unique characteristics that have changed the nature of interactions among people and orga-nizations: community, rapid distribution, user generated content, and open, two-way dialogue2. Thus, such tools help to reach more people and have more impact in a minimum amount of time, with fewer actions. This is where social media can play an important role for health issues.

It is now easier to raise aware-ness and communicate about

F

diseases that are often unknown by the general public such as Neglected Tropical Diseases (NTDs). Today, half of the world’s population is exposed to the risk of dengue, classified as an NTD by the World Health Organization (WHO). The WHO wants to reduce dengue mortali-ty by at least 50% and morbidity by at least 25%3. This cannot be

achieved without raising public awareness. Conducting awareness campaigns, especially through social media, can highlight the conse-quences of this disease and how populations can avoid it. One organiza-tion focusing on dengue is using precisely these tools as their main strate-gy: Break Dengue.

Break Dengue

Break Dengue is an NGO created by The Synergist, a nonprofit organization that helps social causes

through communication with the public and experts. This initia-tive was founded by different partners such as Bayer, Sanofi Pasteur, Fondation Merieux and Partnership for Dengue Control

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ONLINE CAMPAIGN launched for ASEAN Dengue Day 2015.

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(PDC). Break Dengue contrib-utes to building a multi-stake-holder 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 effec-tive prevention strategies3. These goals are reached through differ-ent tools, the main one being its website, www.breakdengue.org. This website gathers all kinds of information about dengue, including news articles, info-graphic information, a health-map 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 writ-ten by Alejandra Laiton, a travel blogger and communication expert. Her role is to travel in countries where dengue is an

issue and meet up with commu-nities and governments to check out activities and events that are being conducted in these coun-tries, and that aim to connect online and offline dengue pre-vention 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 con-cerns only one part of the world, and that the consequences of this disease are known to all. Public awareness and education, espe-cially about the vector of the disease, are keys to eradicating dengue. However, in addition to

The author:

MYRIAM HASSINE

Bayer CropScience, South East Asia.

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 plat-form called Dengue Lab.

Dengue Lab: An online platform for dengue experts Dengue Lab is a closed platform created to encourage stakehold-ers to share their ideas, knowl-edge and experience. “Current efforts to prevent dengue tend to be isolated, short-lived and lim-ited 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 differ-ent subjects but having a com-mon 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.

Bayer Vector Control communi-ty is a closed sub-group that allows experts who are working on Bayer Dengue Vector Control trials around the world, espe-cially 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.

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 plat-form, LinkedIn, Facebook and Twitter are the most used by medical researchers and health-care professionals4 (Fig.1).

LinkedIn and Twitter

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

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

Platforms most visited by researchers and healthcare professionals

Twitter

Facebook

Frontiers

Academia.edu

ResearchGate

LinkedIn

BioMedExperts

Yes (% of full sample)

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32%

7%

3%

51%

39%

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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.

Platforms most used by researchers and healthcare professionals to comment on research papers

Twitter

Facebook

Frontiers

Academia.edu

ResearchGate

LinkedIn

BioMedExperts

Yes (% of service users)

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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 sup-port, portfolio and innova-tion, training and education, and partnership and coopera-tion, 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.

CONCLUSION

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

Twitter, created in 2006, has over 100 million daily active users, and more than 230 million monthly active users world-wide6. This platform allows peo-ple to send out short messages, called Tweets, of up to 140 char-acters. Twitter can be used to spread health-related informa-tion and share articles or other content. To make Tweets more visible to others, hashtags fol-lowed by key words help reach people interested in the subject (#dengue). The global distribu-tion of Twitter users can be visu-alized using a heatmap (Fig. 2).

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

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 prod-uct use and efficacy, community engagement, etc. These experts are from all around the world and share the same interest.

Global heatmap of Twitter users

Fig. 2 / Source: www.beevolve.com 0 100,000

More

www.breakdengue.com

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ow does one recognize the symptoms of dengue fever,

what distinguishes dengue from chikungunya or malaria, and what could be other complica-tions? What are the indications that dengue fever has progressed to dengue hemorrhagic fever (DHF) or dengue shock syn-drome? When were dengue epi-demics 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, global-ly, 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, clini-cal symptoms, and the global

situation. The world distribution map illustrates the 144 countries where dengue is endemic or par-tially 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 pro-ceeds 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 vec-tors, diagnostic tests, and thera-py are followed by the clinical

Dengue Global Status: The A to Z of a (re)emerging diseaseThis 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 stake-holders, researchers, and all those interested in the symptoms, history, geo-graphical distribution, prevalence, statistics, and other data pertaining to dengue fever – this is a useful and fascinating up-to-date resource.

H 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 chi-kungunya are similar, dengue patients are more likely to suffer from sore throats, nausea, vom-iting and abdominal pain. Raised levels of serum biliruben from red blood cell breakdown, or C-reactive protein (CRP) as a marker for inflammation indi-cate 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 permeabili-ty). Dengue shock syndrome includes all the pathologies of

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DHF, progressing to dangerous-ly low blood pressure and weak pulse, i.e. blood circulation fail-ure 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 dur-ing re-infection. For reasons as yet unknown, a long interval between dengue fever attacks may increase the risk of devel-oping DHF. Also of note is the fact that DHF is a recent mani-festation 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

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 asso-ciation continues today, with Central and South America suf-fering from the highest annual disease burden worldwide. The disease acquired a number of names in the 17th and 18th centu-ries, such as Bouquet, Break-bone, 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 coun-try’s population were seroposi-tive 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.

Vectors

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 publica-tion 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.*

When possible the vectors are mentioned for each region, including the rare Aedes hensilli, Ae. marshallensis, Culex quin-quefasciatus, 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 tropi-cal 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.

Data surfing

How does one deal with such huge amounts of data? Well, you can choose a region or country of interest and use the index hot-links to go directly to these pages. The uniform graph for-mat makes comparisons easy: They all depict numbers of den-gue or DHF cases or deaths on

Dengue Global StatusGideon eBook237 pages, 261 graphs, 4,268 references, 5.81 MB PDF format2015 editionISBN: 978-1-4988-0716-6 US$ 49.99

* The suggested mosquito genus name Stegomyia is under revision, so this genus is still officially called Aedes.

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Article and dengue infographic on the enclosed Public Health CDROM

Source

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

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 look-ing 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; some-times 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 geo-graphical notes for Brazil, or the whole page of notable outbreaks for India, and perhaps surprising entries such as Australia, Norway, Scotland and Sweden.

Reemerging

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 mil-lion 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

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 popu-lation live in dengue endemic regions and an estimated 2.5 bil-lion people are at risk of catch-ing 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 valu-able resource for anyone working in the field. Backed up by the links to all the refer-ence sources it represents a vast collection of knowledge on dengue. Yet it also man-ages to present easily acces-sible take-home messages, particularly that dengue is re-emerging or emerging for the first time in countries all over the world.

Author: Avril Arthur-Goettig


Malaria Consortium

Putting the last mile firstMalaria 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: vector control and resistance management.

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

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

• Seeking to ensure its experi-ence, through leadership, prac-tical findings and research results, are effectively commu-nicated and contribute to coor-dinating improved access to, and quality of healthcare.

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

alaria Consortium works with diverse partners,

including all levels of govern-ment, to improve the lives of all, especially the poorest and most marginalized, in Africa and Asia. The organization targets key health burdens, including malar-ia, pneumonia, diarrhea, dengue and other neglected tropical dis-eases (NTDs), along with other factors that affect child and maternal health.

Malaria Consortium achieves its goals by:

• Designing and conducting cut-ting edge implementation research, surveillance, moni-toring, and evaluation.

M prevention; diagnosis and case management; quality improve-ment; resistance management; elimination, and child and mater-nal health. It does this with a pragmatic approach to two cross-cutting 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 sys-tems to support efforts to control emerging resistance to artemis-inin in Southeast Asia, particu-larly among vulnerable and

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

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As part of MOTIve (Mekong Outdoor Transmission Initia-tive), Malaria Consortium is implementing several interven-tion trials on community accept-ability 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 repel-lent and an insect growth regu-lator 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 par-asites, but also guiding more effective interventions in areas of the vector lifecycle currently not reached by other interven-tions. This information will be a very valuable, if not essential, addition to the strategy to elimi-nate Plasmodium falciparum and P. vivax infections in

Tackling outdoor malaria transmission in the Greater Mekong Subregion

Myanmar and Thailand as well as other GMS countries.

Insecticide-treated clothing

Insecticide-treated clothing (ITC) offers a solution in situa-tions 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 long-lasting or insecticide-treated mosquito nets, and indoor resid-ual spraying). In these situa-tions, 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, requir-ing little behavioral change and, by preventing outdoor vector biting, conferring direct protec-tion against vector-borne dis-eases2. Although scientists have just begun to test insecticide-treated school uniforms to pro-tect against malaria and dengue

Case study I

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 region, displays outdoor biting and resting behavior.

Construction workers wearing krama, traditional Cambodian scarves.

Demonstrating rubber tapping in Myanmar.

People living in the forest without protection in Thailand.

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fever, the military and other out-door recreational and occupa-tional 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 work-ers on rubber plantations. A rapid qualitative assessment through focus group discussions and in-depth interviews was conducted to understand the community’s preferences (by gender) of type, color, texture and sizes of cloth-ing to ensure the cultural appro-priateness 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.

Ideal habitats for mosqui-toes: rubber plantations

Rubber plantations are associated with malaria transmission and create suitable micro-climatic conditions for potent Anopheles vectors by promoting the surviv-al, reproduction and lifecycle of An. dirus during the rainy season. The shaded ecology of rubber plantations can facilitate feeding and breeding of An. dirus mos-quitoes even in the dry season. The abundance and distribution of An. dirus depend on both sea-sonal variation, such as increas-ing 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 fre-quently exposed to multiple bites in multiple locations when they revisit areas with malaria trans-mission foci7.

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, bed-sheets or top-sheets was 0.62 (95% CI 0.52 to 0.74)8.

Malaria Consortium will per-form field and laboratory assess-ments 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, accept-able, 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 elimina-tion efforts in the region.

Zooprophylaxis with insecticide treated cattle

In the GMS, cattle-owning settlements are typical of malaria

ity in mammals and is used widely in nuisance and disease vector pest control treatments for humans and cattle3.

Type, color, texture and size of clothing

The success of ITC as a strategy depends on communities’ accep-tance and adherence, but there is limited information to inform policymakers and donors regard-ing 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

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


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Working with partners world-wide, Malaria Consortium is contributing to global efforts to combat malaria. Geograph-ical and vectorial factors, human behavior, climate change, socio-economic driv-ers, 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 epidemiol-ogy, improved surveillance and sustained global invest-ment, will we ensure the effectiveness of efforts to combat malaria and accelerate progress towards elimination.

CONCLUSION

Article, references and short portraits of the authors on the enclosed Public Health CD-ROM.

hard-to-reach populations. Malaria Consortium has a strong record of implementing success-ful projects across this region. It is recognized as being among the foremost experts on the develop-ment 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, includ-ing 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 dis-tribution and promotion of the use of long-lasting insecticidal nets (LNs), one of the most effec-tive interventions to prevent malaria. Malaria Consortium is developing context-specific mod-els 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 com-mercial sector in this effort. Currently, the organization is car-rying out comprehensive efforts at scale in several countries,

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 chang-es in vector behavior as interven-tions are deployed to reduce malaria transmission intensity. Other vector control priorities for the organization are tackling insecticide resistance, and pro-tecting populations who are working outdoors when mosqui-toes bite.

transmission hotspots9, 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 draught and meat production10. Malaria Consortium will eval-uate interventions that exploit both the mosquitoes’ attraction to cattle and their ability to auto-disseminate larvicide.

Regarding community engage-ment, 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 nonethe-less 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)


(continued from page 48)

www.malariaconsortium.org

Please find case study II overleaf


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

Understanding changes in malaria vectors in Africa

Case study II

Changes in vector behavior can potentially render control tools less effective. Further-more, 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.

based combination therapy. Between 2000 and 2013, malaria mortality declined by 47% glob-ally and by 54% in the WHO’s Africa Region11. The scale-up of key interventions undoubtedly contributed to the decline12. However, the decline is not uni-form across countries or regions. Additional factors, possibly inter-acting with the increased intensi-ty of interventions, may have played a role in the reduction of transmission. A clear under-standing of the epidemiological changes and causes of the hetero-geneity in transmission and impact of control measures will be required to recommend appro-priate 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 com-monly 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 review has shown15.

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 con-siderable variation in vector com-position exists between study sites. The majority of human-vector contact with Anopheles gambiae s.s. and A. arabiensis occurred indoors after midnight, confirming the potential contin-ued efficacy of ITNs against these two species. However, insecticide resistance to pyre-

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A trap used to catch mosqui-toes when they exit a dwelling in Awassa, Ethiopia.

Entomology survey training in Ethiopia.

----------------------*Beyond Garki multi-country project: www.malariaconsor-tium.org/beyondgarki/


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

Other studies have reported recent changes in species compo-sition 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 clus-tering 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 zoo-philic ones18.

Effects of social, demo-graphic and climatic trends

Ecological changes have modi-fied the natural environment of malaria vectors. Man-made changes such as deforestation, agricultural development and

urbanization have been associat-ed with changes in vector densi-ties and malaria transmission in different parts of the world19. Temporal variations in climatic determinants of malaria trans-mission include transient weather disturbances as well as long-term climatic and ecological changes that may be coupled with social, economic and demographic trends.

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

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

miological changes, including heterogeneity of transmission, and to quantify the impact of interventions21. Changes in demo graphic, socio-economic, political, technological, and envi-ronmental factors may have had an impact on malaria, in addition to control measures, resulting in changing patterns of transmis-sion. Understanding variations in the temporal and spatial hetero-geneity of transmission and mon-itoring impacts of interventions in different epidemiological set-tings will help in adapting control

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

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strategies accordingly and pre-venting resurgence22. It is essen-tial to separate the roles played by climate change, social and economic development and malaria interventions in causing variability in malaria epidemiol-ogy. This understanding will ensure a longer term, sustainable effort and a systematic adaptation of response to the changing land-scape of malaria.

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

Net distribution in Kano, Nigeria.


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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 world-wide, 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) devel-oped RTS,S, also called Mosquirix, in partnership with PATH Malaria Vaccine Initiative, with additional fund-ing 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 associ-ated with the vaccine.

As studies published in 2011 and 2012 showed, the vaccine has moderate efficacy. Following a phase III vaccine trial con-ducted 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 chil-dren 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.

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

David Kaslow stress that Mosquirix vaccination on its own is not the complete answer to malaria. But along with exist-ing tools such as bednets and insecticides currently recom-mended for prevention, the vac-cine should make an important contribution to controlling the impact of malaria on young chil-dren in Africa. Moreover, the technical achievement of this first generation vaccine validates continuing research and invest-ment into developing next-gen-eration 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.

Malaria: First vaccine worldwide to be approved

Antibiotics ingested by Anopheles gambiae mosqui-toes make them more likely to become infected. The malaria parasite Plasmodium falci-parum reproduces in the mos-quito gut, but must compete with gut microbes. Mosquitoes feeding on blood containing antibiotics lost

Antibiotics: Increase vector efficiency

about 70% of their gut bacte-ria 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 tak-ing antibiotics should use extra protection, such as sleep-ing under nets, to avoid being bitten by mosquitoes.

Source

Nature Communications: doi.org/zfn

Sources

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


N O T E S

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 con-cern Sanofi.

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

Dengue: Vaccine is more than 80% effective

collected in two, phase III clinical trials with 10,275 chil-dren in the Asia Pacific region and 20,869 in Latin America, both dengue endemic regions.

The follow-up periods ranged from three to six years, and the data also revealed that the vac-cine 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 unex-plained increase in hospital-ization due to dengue in the third year of vaccination

among the younger children that needs to be “carefully monitored” over the long-term. The multi-author report in NEJM assessing the candi-date tetravalent dengue vac-cine in three clinical trials (two addressing hospitaliza-tion) 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 bur-den of disease in countries where this disease is endemic” said Sanofi in a statement.

A new 20-second technique to diagnose malaria requires no blood samples, reagents, facili-ties or trained personnel, just a short pulse with a laser. This pulse causes no harm to human tissue, but optically excites hemozoin, waste crystals pro-duced by the parasite Plasmodium falciparum after digesting blood. An oscilloscope placed on the skin beside the laser acoustically detects vapor-ized nano-bubbles produced by hemozoin.

Malaria: Rapid non-invasive laser diagnosis

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-inva-sive diagnostic.” The device is safe, sensitive and specific, even detecting low-level asympto-matic infections. It also detects parasite infection in Anopheles mosquitoes.

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

www.nejm.org (search: dengue)

Source

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


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

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 ele-phantiasis. 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

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

N O T E S

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.

Elephantiasis

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 geo-graphically. In India it was known as Slipada (elephant leg), as recorded in the Sushruta Samhita, the name used by the Roman medical ency-clopedist Celsus (30 BC to 50 AD), although it was also known as satyrisis, leontiasis, and sarcocele. The Greeks and Romans could dis-tinguish between lepro-sy and lymphatic filaria-sis, calling the former elephantiasis graecorum and the latter elephanti-asis arabum.

Later elephantiasis was called skiapodes (shad-ow leg) to describe peo-ple from Ethiopia shad-ed 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)

I

ELEPHANTIASIS can cause limbs to swell and look

like an elephant’s leg in size, texture and color.

H I S T O R YP

hoto

: G

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enry

Fox

(18

86)

N O T E S


H I S T O R Y

called Yohyoe Kitazaki boasted to his comrades that his war tro-phy was the head of a Satsuma enemy. However, wrapped up in the cloth was a scrotum hydro-cele as big as a human head cut off from a dead soldier. Apparently this form of elephan-tiasis was not uncommon in Japan in those times.

A contagious disease

There are other causes of (nonfi-larial) elephantiasis such as leish-maniasis, repeated streptococcal infection, surgical removal of lymph nodes (usually due to can-cer) 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 dis-ease and first associated with elephantiasis in the Ebers Papyrus in 1550 BC. Elephantiasis was also linked to leprosy, which was first recognized as being conta-gious by the monk Anglicus in 1246. Some speculate that lym-phatic 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.

same year Joseph Bancroft (1836-1894), a British physician who immigrated to Australia, dis-covered 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 dis-covery 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 transmit-ted by the mosquito Culex fati-gans. For the first time an arthro-pod had been identified as a vec-tor of human diseases, marking the start of medical entomology. The discovery was later applied to other tropical diseases such as malaria.

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 down-wards as thick as an elephant’s leg.”

Discovering the worm

In 1863, French surgeon Jean-Nicolas Demarquay first observed microfilariae in hydro-cele 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 Kuma moto, Japan, and in the

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

Pho

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N O T E S


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 mosqui-toes are the vectors of W. ban-crofti., 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 hydro-celes, causing the severely dis-figuring 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

But Manson incorrectly hypothesized that transmis-sion 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 pro-boscis of mosquitoes, did the mechanism of transmission become clear: a bite from a mos-quito that recently ingested blood from someone suffering from lymphatic filariasis.

Parasitic life cycle

Lymphatic filariasis is caused by infection with three closely relat-ed 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 allergic lymphangitis, with symptoms of fever, headaches, vomiting and pain. The female worms produce microfilariae containing the

H I S T O R Y

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 com-mon causes of disability world-wide.

Prevention and treatment

Progress has been made towards eliminating lymphatic filariasis in some countries, but more research is needed on prevalence, prevention methods, and trans-mission 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 treat-ment to kill the symbiotic bacte-ria 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 ban-daging, 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.

Patrick Manson (left), George Carmichael Low

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