REVIEWS VECTOR-BORNE DISEASES Beyond insecticides: new thinking on an ancient problem Elizabeth A. McGraw1 and Scott L. O’Neill1,2 Abstract | Vector-borne disease is one of the greatest contributors to human mortality and morbidity throughout the tropics. Mosquito-transmitted diseases such as malaria, dengue, yellow fever and filariasis are the main contributors to this burden. Although insecticides have historically been used to try to control vector populations, over the past 15 years, substantial progress has been made in developing alternative vector control strategies ranging from biocontrol methods through to genetic modification of wild insect populations. Here, we review recent advances concerning these strategies and consider the potential impediments to their deployment, including the challenges of obtaining regulatory approval and community acceptance. DALY Insect-transmitted diseases are present in more than stages of the parasite and our poor understanding of (Disability-adjusted life year). 100 countries worldwide, predominantly in developing the human immune response correlates. Ultimately, The number of years lost owing countries in the tropics (FIG. 1a). Although progress is multiple vaccines might be required to target differ- to morbidity or mortality of currently being made in combatting some of these dis- ent life stages as well as different parasite species5. The a disease. This measure is eases, including malaria, Chagas disease and filariasis, current antimalarial drugs of choice include a range of preferable to simple mortality 6 measures, as it better captures case burdens are still high, and for some diseases (for artemisinin-based combination therapies . These drugs the disease burden for example, dengue), the problem is worsening globally. function well to limit mortality and are fairly low risk debilitating but often One-sixth of the world’s infection-associated DALY for the development of resistance7. However, there is a self-limiting diseases like (disability-adjusted life year) estimate is attributed to need for drugs that can kill all stages of the parasite in dengue and malaria. vector-borne disease, and more than 90% of this fraction a single dose if this approach is to be effective in the is due to mosquito-transmitted agents; in fact, malaria push for malaria eradication8. By contrast, there are parasites contribute more to the burden than any other few, if any, drugs available for treatment of the major pathogen1 (FIG. 1b). Recent WHO estimates predict that arbovirus diseases9. Instead, greater progress has been there are 50–100 million cases of dengue per year — made with the preventative, vaccine-based approach, second only in the vector-borne diseases to malaria (for from the yellow fever vaccine developed in the 1930s10 which there are 216 million cases annually). But meas- through to the more recently developed vaccines for ures such as DALY, incidence or annual mortality rate Japanese encephalitis (reviewed in REF. 11). Several vac- for a disease greatly underestimate the importance of the cines are in development for dengue, the most advanced disease to communities. When the social and economic of which has just recently completed Phase IIb field impacts of diseases like dengue are also considered, then trials in Thailand, with mixed results12. Vaccine design the enormity of their effect on communities can be fully for dengue has been far more challenging than for appreciated2,3. other arbovirus diseases owing to the existence of For many years, much of the medical research com- multiple serotypes, the complexity of the human 1School of Biological Sciences, munity has been focused on the development of vaccines immune response to dengue virus and the propensity Monash University, Clayton, Victoria 3800, Australia. or drugs for mosquito-borne diseases. As yet, there is no for sequential infections to result in more severe forms 13 2Institute of Molecular effective vaccine for malaria, although Phase III trials of of the disease . Great strides have also been made in Bioscience, The University of the most advanced vaccine, RTS S/AS01 (which is being targeting lymphatic filariasis with mass drug adminis- Queensland, Brisbane, developed by GlaxoSmithKline, PATH and the Bill and tration of anthelmintics, chiefly ivermectin. However, Queensland 4072, Australia. Melinda Gates Foundation), are showing some promise, effective, long-term treatment of populations with Correspondence to S.L.O. e-mail: with up to a 50% reduction in disease rates in African anthelmintics has its challenges with respect to sus- 4 [email protected] children . The development of vaccines for malaria has tained delivery and coverage as well as potential resist- doi:10.1038/nrmicro2968 been slow owing to the complexity of the different life ance in the nematode14. For all these diseases, some of NATURE REVIEWS | MICROBIOLOGY VOLUME 11 | MARCH 2013 | 181 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS a b Onchocerciasis Chagas disease Dengue Japanese encephalitis Trypanosomiasis Leishmaniasis Lymphatic filariasis Malaria Total mosquito- vectored diseases Deaths per million Total insect- 0–1 200–500 vectored diseases 1–20 500–1,900 20–50 No data 5 6 7 8 50–200 10 10 10 10 Worldwide DALY estimate Figure 1 | Vector-borne diseases are a global problem. a | Heat map showing the worldwide incidence of deaths caused by vector-borne disease. b | Worldwide DALY (disability-adjusted life year) estimates for a rangeNature of reportable Reviews | vector-borneMicrobiology diseases. Data for parts a and b are taken from REF. 1. the most effective interventions have targeted the mos- focused on either reducing mosquito abundance or quito instead of the pathogen through the use of insec- preventing the transmission of pathogens by the mos- ticides (see extensive reviews15,16). Although insecticides quito (see TABLE 1 for a summary of the vector species have been shown to be effective in many contexts, the and the diseases that they transmit). Together with the financial cost of their application can be prohibitively more traditional approaches for vector control, there are high, their widespread application logistically difficult now four major classes of interventions that have had in both very urban and remote areas, and their efficacy demonstrated success (TABLE 2). None of these methods unstable owing to the evolution of resistance in their is a panacea, and often a combination of approaches target insects. Despite the successes, the ongoing case provides the best outcome17. burden demonstrates that insecticides, as they are cur- The first class of intervention, environmental man- rently being deployed, are not sufficient to bring these agement, includes both modification of the natural diseases under control. environ­ment to reduce the breeding habitat of mosqui- toes and modification of human habitats or behaviours Alternative vector control strategies to reduce biting incidence (TABLE 2). As mosquitoes During the past 15 years, researchers have been develop- vary in their larval habitats of choice (man-made water ing a range of alternative vector control strategies that sources, natural brackish or fresh water, and so on) and in do not rely on the use of insecticides or the creation of their biting behaviour (time of day, indoors or outdoors, new vaccines or drugs. These approaches are typically and so on), some of the interventions are better suited to Table 1 | Vector species and the diseases that they spread Vector Geographical Primary vectors for Natural Genetically tractable? spread Wolbachia infection? Aedes aegypti Tropics worldwide Chikungunya disease, No Yes 128 dengue and yellow fever Aedes albopictus Tropics and Dengue, West Nile virus Yes Yes 129 subtropics worldwide disease and various types of encephalitis Anopheles gambiae Sub-Saharan Africa Malaria No Yes 130 Other The Middle East, Malaria No Yes for Anopheles stephensi131, Anopheles spp. North Africa, the Anopheles albimanus132 and (>28) Mediterranean, the Anopheles arabiensis133; Far East, Australasia, theoretically possible for South America and others Central America Culex Tropics and Lymphatic filariasis Yes Yes 134 Brackish quinquefasciatus subtropics worldwide Slightly salty; pertaining to The distribution of mosquito species around the world is variable, and so is the ability of particular species to serve as pathogen water such as that present in vectors. The table summarizes some of the major vectors of diseases across different world regions135,136. In each of the genera estuaries. listed, other species exist that also serve as vectors. 182 | MARCH 2013 | VOLUME 11 www.nature.com/reviews/micro © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Table 2 | Past approaches that have demonstrated effectiveness for mosquito vector control Approach Disease targeted Effectiveness Environmental modification Draining wetlands and ditches Malaria137–139 Field trials showed reductions in both vector numbers and malaria transmission rates Community clean‑up campaigns for Filariasis140and dengue141 Field trials showed reductions in numbers of adult mosquito breeding habitats mosquitoes Screening windows Dengue142, filariasis and Epidemiological studies indicated a lack of window malaria143 screens is a risk factor for dengue transmission, and field trials and commercial application of window screening reduced vector abundance Biological control Larvivorous fish Dengue144 and malaria145 Field trials in water storage and