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  • 1. Control of dengue vectors: tools and strategiesWorking paper for the Scientific Working Group on Dengue Research, convened by the Special Programme for Research andTraining in Tropical Diseases, Geneva, 1-5 October 2006Full text source: Scientific Working Group, Report on Dengue, 1-5 October 2006, Geneva, Switzerland, Copyright © WorldHealth Organization on behalf of the Special Programme for Research and Training in Tropical Diseases, 2007, McCall1 and Pattamaporn Kittayapong21 Vector Group, Liverpool School of Tropical Medicine, Liverpool, England. 2 Center for Vectors and Vector-BorneDiseases and Department of Biology, Faculty of Science, Mahidol University, Bangkok, ThailandIntroductionDengue is a vector-borne disease of tropical and subtropical human populations, which occurspredominantly, but not only, in urban areas. The global increase in urbanization, such that the world’surban population of 1.7 billion in 1980 is expected to double by 2010 [85], is likely to lead to anincrease in dengue in the future. Control of peridomestic vectors is the only effective preventivemeasure currently available. With dengue occurring in a range of different geographic, socioeconomicand cultural contexts (high-density urban to lower-density periurban and rural situations), and withgeographic variation in vector (sometimes two vectors) and host behaviour, one intervention strategyis very unlikely to suit all situations, and a range of control methods and strategies is needed.Dengue is transmitted by Aedes sp. mosquitoes that breed in container habitats. The main vector,Aedes aegypti, is a cosmotropical species that proliferates in water containers in and around houses.Secondary vectors include Ae. albopictus, an important vector in south-east Asia and that has spreadto the Americas, western Africa and the Mediterranean rim, Ae. mediovittatus in the Caribbean, andAe. polynesiensis and Ae. scutellaris in the western Pacific region. Although zoonotic cycles involvingmonkeys occur in some forest areas of western Africa and south-eastern Asia, there is no evidencethat these play any role in epidemics of human disease. Consequently, control can be directed at Ae.aegypti breeding and biting in the household and immediate vicinity. Ae. aegypti breeds in many typesof household containers, such as water storage jars, drums, tanks and plant or flower containers. Theydo not fly far, dispersing probably no more than 100 m beyond the emergence location [28,32,54,69]and are highly anthropophilic, rarely feeding on non-human hosts. Given these limits, control or indeedelimination of peridomestic vector populations might appear feasible, but experience has provenotherwise. Many eradication attempts have failed, for various reasons: vertical programmes wereinefficient and unsustainable, outdoor space spraying was ineffective; larviciding was often rejected bycommunities and educational messages to the population were often unsuccessful [27,63,82,91].Today it is not unusual to find that more than 50% of houses in many endemic areas are infested withAedes larvae, and the risk of epidemics is high [58,62,89]. Eradication of Ae. aegypti populations maybe achievable, but it is rarely sustainable. The present aim is to control, to below certain thresholdlevels, rather than eliminate vector populations.The previous UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in TropicalDiseases (TDR) Scientific Working Group on Dengue (Scientific Working Group on Dengue, 2000) [74]stated the need for the “development and evaluation of new tools to reduce mosquito populations,including source reduction” and “to increase evidence based vector control programmes and to supportstate-of-the-art research on human behaviour and behaviour change in relation to mosquito breeding”.
  • 2. Partly in response to this call, a range of promising intervention tools are now ready for furtherinvestigation for prevention of oviposition or biting or suppression of vector populations, whiledevelopments in molecular genetic research have increased the likelihood that novel methods will bedeveloped.Control of immature stagesVector control, either by elimination of breeding sites (‘clean-up’ campaigns) or by larviciding withinsecticides, has led many dengue programmes in the past. Although still widely used and promoted,and successes have been achieved in many contexts, clean-up campaigns are limited by the level ofcompliance by the community and by the fact that often the most productive containers (i.e. thosefrom which most Ae. aegypti emerge) cannot be disposed of or emptied (e.g. drinking-water stores).Larvicidal treatment of such water is possible. Only temephos, permethrin, Bti (see below) andpyriproxyfen are approved by WHO for use in drinking-water [15]. The organophosphate temephos(Abate) has been most widely used and, although it is effective, acceptance levels are often low andcoverage poor. Placing additives with persistent flavour into domestic water, particularly drinking-water is, understandably, often viewed with suspicion and not well accepted. Additionally, regularwater usage or emptying of containers (often encouraged in simultaneous ‘clean-up’ campaigns) canreduce or negate the intended effect. The situation would be improved, first, if attention could belimited to known productive, rather than all potential, breeding sites and secondly, if more acceptablelarvicides were available. A major new multi-country study using pupal/demographic surveys hasdemonstrated that accurate identification of epidemiologically important breeding sites/containers ispossible and should enable targeting of control [24,59]. This is a very important development as,although initial surveys will have to be more intensive, the potential increase in effectiveness gainedby directing control at productive containers is very significant. With this strategy in mind, we havelooked at the potential for a range of new larval control tools.Insect growth regulator (IGR)—pyriproxyfenPyriproxyfen is an insect juvenile-hormone analogue, which is active against many arthropods andwhich has been in use for agricultural pest control for about 15 years. It is extremely effective againstmosquitoes and can prevent the emergence of Ae. aegypti at concentrations as low as 1 ppb or less,while extremely high concentrations do not inhibit oviposition [34,78]. Treated water does not tastetainted. Interestingly, very low doses of pyriproxyfen can also sublethally affect adults by decreasingfecundity or fertility, and the contaminated adult female can transfer effective doses to any breedingsite she subsequently visits [23,34]. New pyriproxyfen formulations can retain efficacy for 6 months[77], reducing the need for frequent reapplication, and new studies [78] are indicating its high level ofefficacy. Clearly further trials are now called for. Worryingly, however, this intervention was notaccepted by communities in Mexico [45], suggesting that suspicion of domestic-water treatments fordengue control remains an obstacle to larval control. Moreover, since pyriproxyfen only preventseclosion, larvae and pupae remain visibly active in breeding sites, conveying the false impression of alack of efficacy and further compromising acceptance. A current trial in Thailand is investigating theseareas further.Predatory copepodsVarious predatory Mesocyclops spp. (Crustacea; Eudecapoda) have been studied for their potential tocontrol mosquito larvae. Two species in particular, M. thermocyclopoides and M. aspericornis, haveproven effective against dengue vectors [9,39,50,52,57,70,73]. However, although copepods cansurvive up to 6 months in containers, they are often lost when water is removed, containers arecleaned or (copepod) food is limited, and reintroduction may be necessary for sustainable control
  • 3. [14,46,50,73]. However, in certain contexts Mesocyclops can be very effective. A large-scale vector-control programme using copepods and clean-up campaigns in Viet Nam successfully controlleddengue transmission for a number of years and, in this region at least, appeared to be sustainable[39,55,57]. Attempts should now be made to investigate the potential of this method in othercountries where vector-productive containers could sustain copepod populations, and wherecommunities might be willing to accept such a (depending on their experience) novel intervention.Furthermore, the efficacy of this method might be improved by combining it with other compatibletools, such as fish [46] or other methods (see next section).Bti toxinsThe endotoxin produced by the entomopathogenic bacteria Bacillus thuringiensis var. israelensis (Bti)has high larvicidal activity in mosquitoes, but is non-toxic to important beneficial organisms. Variousformulations (i.e. wettable powders, granules and briquettes) are effective, and newer slow-releaselong-lasting formulations may reduce the need for frequent reapplication. One recent field trial of slow-release long-lasting Bti products in Thailand demonstrated that the treatments could persist for 3months in utility water containers in rural villages (Wiwat et al., personal communication).Combination strategies have often yielded satisfactory results in terms of potency and long-termefficacy [22,60,70,83]. When a combination of M. longisetus and Bti, Bacillus sphaericus, ormethoprene was evaluated [83], the combined agents were better than either alone. The compatibilityof the commercial formulation Vectobac 12AS with certain chemical insecticides for controlling Aedeslarvae and adults was demonstrated in Malaysia [76]. A mixture of Vectobac 12AS and Actellic 50EC(pirimiphos-methyl) showed promise as a larvicide in the laboratory [19]. These combinations clearlywarrant follow-up. An experiment to integrate Bti with Mesocyclops and mosquito densovirus(AThDNV; see below), conducted in semi-natural conditions, demonstrated that this complexcombination might also be effective (Wiwat et al., personal communication).In Thailand it has been demonstrated that reductions of Ae. aegypti larvae of more than 90% could beachieved for 3-month periods with combined treatment of copepods and Bti, although supplementaryfood for the copepods (community-supplied products such as rice and leaves) was required [14,44]. Apilot community-based intervention using integrated physical and biological control, including acombination of copepods and Bti, in eastern Thailand was successful and showed potential forexpansion into other areas (Kittayapong et al., 2006) [42].Mosquito densonucleosis virusesDensonucleosis viruses or densoviruses (DNVs) are invertebrate viruses in the genus Brevidensovirusof the family Parvoviridae [6]. The virions of the DNVs contain a 4 kb single-stranded DNA genomewith terminal hairpins packed in a non-enveloped particle [3,7]. Five strains of Aedes densoviruseshave been identified to date [2,5,11,16,36,40]. Current experiments show that the efficiency in vectorcontrol could vary greatly depending on both viral strains and geographic origins of the mosquitovectors (Wiwat et al., personal communication). Application could involve either direct lethal effects ontreated populations, like a biological insecticide, or shortening of adult lifespan, much as describedbelow for Wolbachia. A recent finding has reported improved survival of Ae. aegypti larvae from 15%to 58% after infecting successive generations of mosquitoes with AThDNV, the Thai strain densovirus[71]. Future research to study interactions between the pathogenic viruses and their mosquito hosts,with respect to resistance and mode of action, will generate useful data. Field trials should beencouraged in due course.Vector control of adult mosquitoes
  • 4. In the past, control directed at adult mosquitoes has been limited to the use of ultra-low-volume (ULV)application of insecticides, usually by vehicle-mounted apparatus. There is controversy regarding theefficacy of this type of control, with a number of studies indicating that its effect is rarely, if ever,significant [65,66,68]. This is likely to be partly the result of a failure of outdoor sprayed insecticide toreach indoor populations of mosquitoes and failures of vertical programmes to deliver at communitylevel. Despite doubts about efficacy, such interventions remain the last resort in combating epidemics.However, new tools open the way to adult mosquito control at community level.Insecticide-treated materialsInsecticide-treated materials (ITMs; typically deployed as insecticide-treated bednets [ITNs]) haveproven highly effective in preventing diseases transmitted by nocturnally-active vectors. Their efficacyin controlling diurnally-active Ae. aegypti is now being evaluated. A cluster-randomized trial in LatinAmerica has demonstrated that insecticide-treated window curtains and/or insecticide-treateddomestic-water container covers can reduce dengue vector densities to low levels and potentially havean impact on dengue transmission [45]. ITMs, particularly curtains, were well accepted and theirefficacy reinforced by the sight of dead insects (cockroaches, houseflies and other pests, as well asmosquitoes) beneath the treated curtains. Importantly, a spill-over effect, whereby the interventionreduced vector populations in neighbouring control clusters, also occurred, such that houses withoutITMs that were located close to treated houses were less likely to have infestations than those furtheraway. Presumably, as with other vectors, the risk of a host-seeking mosquito contacting an ITM atsome point during its frequent visits to houses to blood-feed, means that its life expectancy isreduced; in effect, the age structure of the vector population is altered and few individuals are likely tolive long enough to become infective with dengue. This mass effect will reduce vectors throughout thecommunity [25,29] and is an excellent outcome, given that coverage with any intervention tool isalways less than 100%, sometimes markedly so. New trials are now underway in Venezuela andThailand to examine these interventions further and additional trials in yet more locations and contextsshould be encouraged.Indoor residual treatments are known to kill Ae. aegypti, although such methods have rarely beenused, nor are they recommended today [90]. Indeed, such is the strong endophagic/endophilictendency of this vector [17,64] that the use of insecticidal aerosol cans in the household can alsomarkedly affect dengue transmission [61]. Could other ‘indoor treatments’ also work? The question ofwhether ITNs might also affect Ae. aegypti has also been considered in a pilot study in Haiti (Wiwat etal., personal communication). Although not a fully controlled trial, results indicated that bednetsreduced peridomestic dengue vector breeding (as measured by standard indices), and may havehelped reduce seroconversion rates over 12 months. A community-wide effect was again observed, asdengue-vector breeding also appeared to be reduced in neighbouring control areas. As dengue vectorsbite during the day, how could ITNs exert an effect? Either the presence of the insecticide reducedentry into houses by repelling incoming mosquitoes or, most likely given the community-level effectobserved, the ITNs functioned as ‘residually-treated resting surfaces’ with which contact was maderesulting in killing; an effect that one might expect to be enhanced inside the smaller houses typical inpoorer districts. Effects on Ae. aegypti of ITNs deployed widely for malaria control have not beenrecorded despite the many trials that have been undertaken (presumably because routine sampling fornocturnal malaria vectors would not record Ae. aegypti), although low-level Ae. aegypti biting wasreduced to zero after introduction of ITNs in a village in the Democratic Republic of the Congo [37].Sustainability of many interventions against all mosquito vectors is a problem in many contexts.However, use of ITNs is invariably higher in urban areas [26,47], precisely where dengue is thegreatest problem. That such an appropriate and widespread intervention might also reduce denguetransmission should be evaluated.
  • 5. In considering ITM-based strategies for dengue control, new tools primarily developed for malariacontrol can also have applications for dengue control. In the case of long-lasting insecticide-treatednetting (LLIN), the netting is loaded with sufficient insecticide during manufacture to avoid the needfor re-impregnation. Both LLIN window curtains and water-container covers are effective (Kroeger etal., 2006). The long-lasting formulation ‘KO-Tab 1-2-3®’, which can be applied in the community toany material, renders it as wash-resistant as LLIN [93]. Treatment of the existing window curtains in ahouse might be possible and should be investigated, although loss in efficacy over time, resulting fromthe degradation of the insecticide by ultraviolet rays in sunlight may be a problem. Renewed interestfrom industry partners that perceive potential markets in this field, particularly for malaria control, islikely to result in new products to meet control needs in the coming years.The mode of action of ITMs should be investigated: do they repel Ae. aegypti (curtains, bednets or jarcovers), attract and kill them (during hostseeking or oviposition) or exert their effect in some ‘passive’or as yet unknown way? Finally, as is always the case with insecticide-based strategies, resistance toexisting insecticides is inevitable and the current global state of insecticide resistance in Ae. aegypti isworrying (see Hemingway, in the present report). This could be resolved by using alternatives toinsecticides, as described in this article, by using different or by rotating insecticides—a real possibility,as some of the ITMs that are proving effective in dengue control can be used with insecticides otherthan the pyrethroids, which, because of their low mammalian toxicity have been first choice in thepast. Eventually, new insecticides will be needed, an approach that is fundamental to the Gates-funded‘Innovative Vector Control Consortium’1 which aims to develop a portfolio of chemical and technologicaltools suitable for vector control [30].Lethal ovitrapsThe ovitrap or oviposition trap was first recommended by WHO for surveillance of Aedes vectors[87,88], then modified to render it lethal to adults or larvae of Ae. aegypti [12,13,42,65,66,81].Notably, they were used to eradicate Aedes vectors from Singapore International Airport [12]. Theautocidal ovitrap was designed and developed for the control of Aedes vectors in urban areas with ahigh density of Aedes and a high incidence of dengue haemorrhagic fever in Singapore [13]. Inprinciple, ovitraps could kill adult mosquitoes if the ovistrip was treated with insecticide [94] or destroyprogeny by using fine nylon netting for trapping the larvae [48]. In Brazil, lethal ovitraps withdeltamethrin-treated ovistrips killed 89% of Ae. aegypti adults and produced more than 99% larvalmortality during 1-month field trials [66]. The advantages of lethal ovitraps for controlling Aedesvectors include their simplicity, their specificity for and effectiveness against container breeders likeAe. aegypti and their potential for integration with other chemical or biological control methodologies.Studies are still at an early stage [66,81] and should be encouraged.The future: strategies based on genetic modificationIn the search for novel tools for vector control, genetic modification of Aedes to resist infection withdengue virus is one of the most seductive long-term approaches. Although some methodology hasalready been shown to be effective in the laboratory [43], the challenges here are technical (andpotentially independent of any kind of community participation in vector-control activities, althoughinitial acceptance of genetically-modified mosquitoes may not always be certain) requiringdevelopment of mosquito lines resistant to or unable to transmit dengue and replacement of thenatural populations with these non-vector lines.1 Innovative Vector Control Consortium:
  • 6. A major obstacle however, has been the slow development of strong driving systems to deliver denguevirus-resistant genes into natural vector populations [75], although much research has been devotedto identifying candidates such as transposable elements, meiotic drive or endosymbiotic Wolbachiabacteria [8,35,80]. Transposable elements have been shown to be efficient for transformation ofmosquitoes using an external transposase source, but further research is needed to investigate theautonomous transposable elements in which the effector gene is linked to the source of transposase[18]. The use of meiotic drive in genetic control also requires a greater understanding of the molecularmechanism, especially in mosquitoes. One of the proposed gene driving systems which has potential isthe use of maternally inherited Wolbachia endosymbionts [79]. An advantage is the possibility forrepeated spread and invasion of naturally Wolbachia-infected populations via superinfections ofdifferent Wolbachia strains. Much research is still needed.Development of strategies based on genetic modification ofAe. aegyptiOne of the global collaborative Grand Challenges in Global Health (GCGH)-funded projects aims to usegenetic-based strategies to prevent Ae. aegypti from transmitting dengue viruses either by reducingdensities of mosquito populations or by eliminating their ability to transmit dengue viruses (James,personal communication). The main challenges and objectives of this project are summarized in threetopics: first, the effector genes for population replacement and reduction will be optimized; secondly,safe and efficient drive systems for introgressing effector genes into mosquito populations will bedeveloped; and lastly, a field site for genetic control trials will be established in a suitable developingcountry. Different directions are being pursued. Two approaches aim to reduce or eliminate naturalpopulations of Aedes vectors: densoviruses could be developed as biological control agents of Ae.aegypti larvae [11], while release of insects carrying dominant lethal mutations (RIDL) are designed toreduce or eliminate mosquito populations, especially those that are infected with dengue viruses[31,33,84]. Other methods—synthetic transposable elements (TEs) [1], meiotic drive [53] andunderdominance [21]—aim to modify vector populations by introgressing genes that eliminate vectorcompetence. These methods are currently at various stages in development and readiness for field-testing.A different approach to is being taken via the development of a novel gene-based sterile insecttechnology (SIT) whereby genetically altered, rather than irradiated, males are released into theenvironment to mate with wild females, thereby reducing population numbers and ultimatelypreventing the transmission of disease [20]. This strategy is very well advanced and likely to lead tofield trials in the very near future (Alphey, personal communication).Development of Aedes vectors with a short lifespanAnother GCGH project aims to modify the age structure of the population of dengue vectors such thatlifespan is reduced and mosquitoes die before reaching the age when they could transmit dengue(O’Neill et al., personal communication). The strategy is based on introducing endosymbioticWolbachia bacteria into wild vector populations, these bacteria being capable of significantly shorteningthe adult mosquito lifespan [49,51]. These bacteria are present naturally in most insects andwidespread in mosquitoes [41,86]. Both single and double strains of Wolbachia, naturally found in Ae.albopictus, have already been successfully transferred into Ae. aegypti [72,92]. Dengue viruses needan extrinsic incubation period of about 12–14 days in the vector before being transmitted intohumans; the ‘Popcorn’ strain of Wolbachia could shorten the life of its insect hosts to about half thisperiod. Theoretical models with realistic parameter estimates suggest that an intervention usingrelease of Popcorn-transinfected vector lines could reduce dengue transmission by 90–100% [10,67].
  • 7. The primary objective of this project is to generate stable lines of Ae. aegypti and Ae. albopictus thatare infected with the Popcorn Wolbachia. Once established, these Wolbachia-transinfected lines couldbe characterized and tested in experimental cages to determine virulence, transovarial transmission,effect on host age and potential to spread in natural vector populations via cytoplasmic incompatibility.The project is ongoing and, if successful, a field trial in large, confined field cages will be attempted inan endemic country. Importantly, this strategy has the potential to be implemented without the needto release transgenic mosquitoes into the environment.Any studies on post-genomic relationships between mosquito hosts and their endosymbionts willbenefit further development of genetic strategies to control dengue vectors. Application of thepopulation-replacement approach in field situations will require detailed understanding of Wolbachia-transfected laboratory-generated strains compared with the naturally uninfected strains of denguevectors in term of their expressed physiological and behavioural parameters at the post-genomic level.The recently-completed sequencing of the Ae. aegypti genome should facilitate identification of neweffector genes, as well as potential gene-driving mechanisms.2 Future research should include studiesrelated to novel genetic markers to investigate gene flow and genetic diversity among differentgeographic populations, which will be crucial to the success of population replacement strategies. Alsoessential, in due course, will be the fostering of public understanding and support of such tools.Priorities and opportunities for researchA number of major initiatives have brought together scientists from many disciplines. Currentprogrammes include the WHO/TDR/International Development Research Centre (IDRC) ResearchInitiative on Eco-Bio-Social Research on Dengue in Asia, a research initiative aimed at improving theprevention of dengue by understanding its multifarious determinants and how they affect transmission(and therefore influence the likelihood of successful control) at community level. The European Unionis funding two major multidisciplinary studies on dengue, one of which, ‘DENCO’, includes two largecluster-randomized trials of ITMs and pyriproxyfen. The Bill & Melinda Gates Foundation have funded arange of initiatives in vector-borne diseases, three of which at least directly target dengue (seeabove).But many areas still require work. In addition to those directions already mentioned, further studiesare required to confirm the efficacy, acceptance, cost–effectiveness and sustainability of ITMs incontrolled trials; trials of slow-release formulations of Bti and pyriproxyfen; densovirus trials; theefficacy of tools against Ae. albopictus should be investigated wherever this is an important vector; thelong-term effects of interventions on mosquito populations and the long-term effects and benefits tocommunities should also be investigated.Ideal tools should be ‘user-friendly’, requiring little additional work or behaviour change byhouseholders. They should be affordable, safe and effective in reducing vector densities belowthreshold levels estimated by the ‘pupae per person index’; indeed, as might be the case withinsecticide-treated curtains in many societies, they could even be viewed as desirable by householders.The ideal situation that we must strive for is to have a suite of proven effective, safe andenvironmentally friendly tools available for intervention, from which the most appropriate tool orcombination of tools can be selected to suit the specific biological and cultural needs of eachcommunity.2 A special issue of Science will be devoted to the Aedes genome in early 2007.
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