PerspectiveEcology

Mosquito Trials

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Science  11 Nov 2011:
Vol. 334, Issue 6057, pp. 771-772
DOI: 10.1126/science.1213798

After two decades of research at the bench, strategies based on biologic or genetic modification of mosquitoes to control vector-borne diseases are now advancing to field testing. Such strategies seek either to reduce the overall number of target mosquitoes to levels unable to support pathogen transmission (population suppression) or to introduce into the local mosquito population a genetic modification that renders them unable to transmit the pathogen (population replacement). Dengue represents a good target for such interventions. The disease is caused by a flavivirus transmitted primarily by the mosquito Aedes aegypti (see the figure) and is a major problem in tropical and subtropical regions. Conventional methods (insecticide fogging, larvaciding, manual elimination of breeding sites) are difficult to sustain at effective levels and largely have failed to control dengue. Small experimental trials of genetically engineered (1) or Wolbachia-infected (2) Ae. aegypti are showing promising results in meeting their respective entomological goals of population suppression and population replacement (infection with Wolbachia bacteria inhibits growth of dengue virus in the mosquitoes). What indications of success are required for these technologies to be accepted as public health tools? A recent meeting to consider this question brought together vector biologists, epidemiologists, infectious disease and clinical trial experts, and others interested in dengue control (3).

Most vector biologists agree that success is reflected ultimately in reduced morbidity and mortality. Some consider entomological endpoints, such as local elimination of the principal vector species or complete introgression of a gene or symbiotic species that causes pathogen refractoriness, as surrogate markers for impact on infection and disease. However, those familiar with trials of conventional interventions (vaccines, drugs, and insecticides) maintain that sustained epidemiological and clinical impact should be the primary efficacy endpoint. Observations that dengue transmission can sometimes continue even with low mosquito population densities (4) are cited as a reason for vector biologists to conduct trials to measure the incidence of infection and/or disease.

Although cluster-randomized trials have been adopted for studying the impact of insecticide-treated nets on the vector-borne disease malaria (5), similar trials of modified mosquitoes for dengue control present a number of complications. Dengue transmission can be endemic, epidemic, multiyear episodic, and unpredictable, so that trials may have to continue for years. Trials also must encompass large geographic areas to ensure that there is sufficient human infection to detect differences between control and treated populations. For a drug or vaccine, it is possible to randomize individuals with a similar risk of infection into control or treatment groups and follow them over time to measure the direct effect of the intervention. However, mosquito trials involve area-wide, rather than individual, intervention. Thus, the effect must be measured at community (cluster) levels. Clusters must be large enough and sufficiently replicated to detect an indirect effect and overcome confounding factors such as access to a health facility, propensity for travel into and out of the cluster, level of local vector control efforts, or presence of insecticide resistance. In urban environments, there may be many such confounders. Furthermore, should the modified mosquitoes prove efficacious within treatment clusters, it is likely that new dengue outbreaks will occur disproportionately in control clusters because transmission would be higher. If local government policy is to react to these outbreaks by insecticide application, this would occur more frequently in control clusters and potentially bias results.

Modified for release.

Aedes aegypti (Higgs strain shown) can be modified genetically so that they are unable to support transmission of dengue viruses. Their potential value as a means to control disease spread requires field trials with appropriate indicators of success.

CREDIT: O. MARINOTTI AND P. J. BRYANT

Blind treatments could be important components in cluster-randomized trials. The release of mosquitoes at some sites but not others is likely to be obvious to the specific communities, and human behavioral changes may complicate trials. For example, people living in treatment clusters may become more conscientious about removing mosquito breeding sites around their homes because of regular visits from the trial team, which could decrease the incidence of infection. Participants in control sites may perceive that they are not receiving the same level of care and decide to withdraw from the trial. Release of some type of “placebo,” most likely unaltered male mosquitoes (males do not bite humans and therefore are harmless), could improve the robustness of trials but would increase considerably their complexity and expense.

Lengthy trials of modified mosquitoes may increase the possibility of “contamination” of the treatment or control clusters as people and mosquitoes migrate into and out of the selected areas. Moreover, some of the new technologies are designed to spread modifications into the native mosquito populations by mating, so as to introduce long-lasting protection against transmission (6). These modifications may be disseminated into mosquito populations in the control clusters. Methods must be included to detect these events so that adjustment can be made in the trial analysis. One way to avoid this contamination is for the control and trial sites to be separated widely, but geographic distance may hamper the ability to equally match control and experimental sites for other factors that influence transmission, such as proximity to mosquito breeding sites or health care.

There currently is no pharmaceutical or agrochemical industry investment for modified mosquitoes, as new biological products presumably have low profit potential. Philanthropies or small biotech companies may be unable to make the major financial commitments required for large trials or may not be willing to fund such efforts in countries that could support them on their own. Large-scale trials of these technologies will be costly, and thus the type of evidence required to prove their utility should be carefully considered in the context of potential availability of support. Showing that mosquito-based technologies produce the desired biological effect on local mosquitoes under various conditions will be a crucial first step. In 2009, a transgenic strain of Ae. aegypti that does not produce fertile offspring was released on a small scale in the Cayman Islands and demonstrated that transgenic males could survive and mate with wild females (generating sterile larvae) (1). A larger-scale trial was subsequently launched there and has reportedly achieved an 80% reduction in mosquito numbers (7). Moreover, Wolbachia has been shown to spread into local mosquito populations (2). But is this confirmation enough?

Demonstrating decreased incidence of infection in a cluster-randomized trial, based on seroconversion (the production of antibodies against the flavivirus) within a subset of individuals residing in treatment clusters, may provide a relatively feasible epidemiologic endpoint with respect to trial size and cost. Must we assume a need to prove a reduction in actual cases of dengue, which will require very large trials? This ultimately will be determined by policy-makers, who will decide whether these technologies are taken up as public health interventions. Much will depend on estimated cost-effectiveness and whether the threat posed by dengue continues to expand. The recent history of cluster-randomized trials of insecticide-treated nets for malaria prevention, where broad uptake followed convincing proof of efficacy, demonstrates the value of generating evidence to inform policy and attract donor funding for roll-out of the intervention.

The challenges raised by large field trials of modified mosquitoes are manageable, and some precedents exist from trials of other types of interventions. However, researchers must understand the level of evidence required by policy-makers, which will allow the appropriate studies to be designed and the challenges to be addressed systematically. In the meantime, additional smaller-scale pilot studies will help to elucidate the potential value of modified mosquito technologies.

References and Notes

  1. We thank T. W. Scott, J. Farrar, and S. O'Neill for helpful comments and the meeting attendees (3) for discussions. Support was provided by the Foundation for the NIH through the Vector-Based Control of Transmission: Discovery Research Program of the Grand Challenges in Global Health Initiative.

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