Optimal trial design for a confined release of malaria-refractory transgenic mosquitoes

Malaria is an infectious disease caused by a parasite spread between people by mosquitoes. In sub-Saharan Africa, it causes an estimated 800,000 deaths per year, most of whom are children under the age of five. The disease is proving very difficult to control in many parts of Africa using tools that are currently available. These include bed nets, insecticides and antimalarial drugs. It is thought that, even if these tools are widespread, elimination may not be possible in some areas. Consequently, new strategies are being considered that will complement existing ones. One such strategy is the use of genetically modified (GM) mosquitoes.

Strategies using GM mosquitoes can be grouped into two categories - those aiming to reduce mosquito population size, and those aiming to replace mosquito populations with varieties unable to transmit diseases. The former strategy has been tested in the Cayman Islands, Malaysia and Brazil to control dengue fever. The latter strategy is being considered for malaria control because it is more promising on a wider scale. Here, mosquitoes would be engineered with a gene that prevents them from transmitting malaria. This would be linked to a gene that favors its inheritance across generations. Mosquitoes have a short generation time - just a few weeks - and so the antimalarial gene could quickly increase in frequency, spreading into one population and then into another. This is promising for wide-scale malaria control, but draws into question the ability to conduct a confined field trial.

In this project, Dr John Marshall, a researcher in the Department of Infectious Disease Epidemiology at Imperial College London, will develop a computer simulation to determine the optimal strategy for conducting a field trial of GM mosquitoes for malaria control. One major requirement for a field trial is that transgenes remain confined to their release site while also causing a significant reduction in local malaria transmission. Field trials are being considered on islands off the coast of Africa, including the Comoros Islands, Bioko Island, and Sao Tome and Principe. Dr Marshall will tailor his models to these locations using available mosquito and malaria prevalence data. He will then use his model to determine whether transgenes can be confined to these field sites, and under what release scenarios they will cause a maximal reduction in malaria transmission.

If a confined field trial is eventually successful, this will provide an important mandate for more invasive GM mosquito strategies with the potential to control malaria on a much wider scale. The malaria modelling group at Imperial College London, led by Professor Azra Ghani, has developed a model of malaria transmission covering the African continent. Dr Marshall will use this model to explore the role that GM mosquitoes could play as part of a combined, Africa-wide malaria control program. GM mosquitoes hold great promise for malaria control because they can spread beyond their release site and reduce disease transmission without requiring human compliance. This modelling work will allow the public health impact of GM mosquitoes to be predicted and compared against other combinations of malaria interventions.

Research into genetically modified (GM) mosquitoes is quickly progressing. The first release of sterile male GM mosquitoes to control dengue fever took place in the Cayman Islands in 2009, and enthusiasm is growing for future releases to control malaria in Africa. Malaria is proving particularly difficult to control in highly-endemic areas where it is predicted that elimination may not be possible with currently-available tools. The use of selfish genetic elements capable of spreading malaria-refractory transgenes from one mosquito population to another is appealing for wide-scale control, but also draws into question the ability to conduct a confined field trial. The aim of this project is to compare proposed strategies for a field trial of malaria-refractory mosquitoes in terms of their potential for confinement and their ability to significantly reduce malaria prevalence.

The first objective is to develop models of mosquito population dynamics based on ecological data from potential field sites such as the Comoros Islands and Bioko Island. Mosquito populations are structured spatially and temporally, and important features include seasonal fluctuations in population size, relative abundances of different vector species, and rates of gene flow between populations. The second objective is to link these models to a model of malaria transmission. Parameters for this model will be fitted using parasite prevalence data. Proposed strategies for introducing malaria-refractory genes will then be contrasted. Possibilities include releasing large numbers of malaria-refractory males, and releasing males engineered with selfish genetic elements that only spread if they exceed a critical frequency in the population. These models will be of great use in designing field trials that are both spatially limited and effective as a means of malaria control and, if successful, could lead the way to more ambitious projects with the potential to control malaria on a much wider scale.

The proposed research consists of two major aims - to determine optimal strategies for conducting field trials of GM mosquitoes on islands off the coast of Africa; and to compare strategies for spreading malaria-refractory genes through mosquito populations on a wider scale.

In terms of planning confined field trials of GM mosquitoes, potential beneficiaries include governmental organizations and local decision-makers in countries and communities where trials are being considered. People hold a variety of opinions about GM organisms, and their release will require careful thought by local authorities. Relevant governmental organizations for potential field sites include the Ministry of Health and Social Welfare for Equatorial Guinea (Bioko Island), the Ministry of Health for Sao Tome and Principe, the Ministry of Public Health for Guinea-Bissau (Bissagos archipelago), and the Ministry of Health, Solidarity and Promotion for the Comoros Islands. My collaborators, who will provide me with epidemiological and entomological data from these islands, have links to several of these ministries. If field trials look promising, then model outputs from this project will contribute to an evidence-based decision-making process on whether to proceed.

In terms of a wide-scale release of GM mosquitoes, potential beneficiaries include stakeholders with an interest in knowing the potential role that GM mosquitoes could play as part of a global integrated malaria control program. These include the World Health Organization, the Bill and Melinda Gates Foundation and the Centers for Disease Control. As a member of the Imperial College malaria modelling group, led by Professor Azra Ghani, I will benefit from already-established links to many of these stakeholders. Currently-available tools for malaria control - long-lasting insecticidal nets, indoor residual spraying and antimalarial drugs - have shown some degree of success in reducing transmission; however, it is thought that additional control methods will be required to eliminate the disease from highly-endemic areas. Model outputs will therefore be of interest in assessing the cost-effectiveness of alternative control strategies and will assist stakeholders in making evidence-based policy decisions on the degree of funding for these technologies.

One potential beneficiary related to both aims is the Sub-Working Group on Living Modified (LM) Mosquitoes which has been assigned by the Ad Hoc Technical Expert Group on Risk Assessment and Risk Management to prepare guidance documents on the safe transfer, handling and use of GM mosquitoes for the Cartagena Protocol on Biosafety. The Cartagena Protocol is the fundamental document of the United Nations governing the international movement of GM organisms. GM mosquitoes are particularly contentious due to the ability of some varieties to spread across international borders in the absence of an agreement. The Sub-Working Group will therefore be interested in model outputs concerning the ability to confine transgenes to isolated locations during field trials of malaria-refractory mosquitoes. That said; the Parties to the Protocol also recognize the potential for modern biotechnology to improve human well-being, and the Sub-Working Group will be interested in the potential implications that a wide-scale release of malaria-refractory genes could have for reducing the global malaria burden.

Finally, over the course of the next few decades, it is hoped that the wider public will benefit from the proposed research. Malaria is one of the world's most deadly infectious diseases and is in need of all the tools available for its control. It is hoped that the proposed research will help to move this technology forward. Given recent advances in the release of GM sterile and Wolbachia-infected mosquitoes, a release of malaria-refractory mosquitoes may be as little as a decade away.