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

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Gatton ML (2013) The importance of mosquito behavioural adaptations to malaria control in Africa. in Evolution; international journal of organic evolution

 
Description Expert advisor to Cartagena Protocol on Biodiversity
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Improved regulation of genetically modified mosquitoes for disease control. Paving the way for the use of genetically modified mosquitoes to be released and to assist in disease reduction.
 
Description WHO/TDR Biosafety Manual for Genetically Modified Mosquitoes
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Book chapters inform researchers on biosafety issues related to genetically modified mosquitoes for disease control.
 
Description Attractive toxic sugar baits for mosquito control 
Organisation Hebrew University of Jerusalem
Department Faculty of Medicine
Country Israel 
Sector Academic/University 
PI Contribution Myself and others at the MRC Centre for Outbreak Analysis and Modelling, Imperial College London have been developing mathematical models for the impact toxic sugar baits could have on malaria control.
Collaborator Contribution Prof Beier of the University of Miami and Dr Gunter Muller of the Hebrew University of Jerusalem have been contributing experimental data to inform this project.
Impact Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2013 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control. Malar. J. 12: 291. Zhu, L., Qualls, W. A., Marshall, J. M., Arheart, K. L., DeAngelis, D. L., McManus, J. W., Traore, S. F., Doumbia, S., Schlein, Y., Müller, G. C., Beier, J. C., 2014 A spatial individual-based model predicting a great impact of copious sugar sources and resting sites on survival of Anopheles gambiae and malaria parasite transmission. Under review.
Start Year 2012
 
Description Attractive toxic sugar baits for mosquito control 
Organisation University of Miami
Department Department of Public Health Sciences
Country United States 
Sector Academic/University 
PI Contribution Myself and others at the MRC Centre for Outbreak Analysis and Modelling, Imperial College London have been developing mathematical models for the impact toxic sugar baits could have on malaria control.
Collaborator Contribution Prof Beier of the University of Miami and Dr Gunter Muller of the Hebrew University of Jerusalem have been contributing experimental data to inform this project.
Impact Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2013 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control. Malar. J. 12: 291. Zhu, L., Qualls, W. A., Marshall, J. M., Arheart, K. L., DeAngelis, D. L., McManus, J. W., Traore, S. F., Doumbia, S., Schlein, Y., Müller, G. C., Beier, J. C., 2014 A spatial individual-based model predicting a great impact of copious sugar sources and resting sites on survival of Anopheles gambiae and malaria parasite transmission. Under review.
Start Year 2012
 
Description Gene drive systems in mosquitoes 
Organisation California Institute of Technology
Department Division of Biology and Biological Engineering (BBE)
Country United States 
Sector Academic/University 
PI Contribution I am developing mathematical models of gene drive systems in mosquitoes.
Collaborator Contribution Prof Bruce Hay's lab at CalTech are developing these gene drive systems in mosquitoes using genetic engineering techniques.
Impact Akbari*, O., K. D. Matzen*, J. M. Marshall*, H. Huang, C. M. Ward, and B. A. Hay, 2013 A synthetic gene drive system for local, reversible modification and suppression of insect populations. Curr. Biol. 23: 671-677. *Equal contribution Marshall, J. M., and O. Akbari, 2015 Gene Drive Strategies for Population Replacement. In: Adelman ZN, editor. Genetic Control of Malaria and Dengue. Elselvier. Marshall, J. M., and B. A. Hay, 2014 Medusa: A novel gene drive system for confined suppression of mosquito populations. PLoS ONE 9: e102694. Akbari*, O., C. H. Chen*, J. M. Marshall*, H. Huang, I. Antoshechkin, and B. A. Hay, 2012 Novel synthetic Medea selfish genetic elements drive population replacement in Drosophila; a theoretical exploration of Medea-dependent population suppression. ACS Synth. Biol. doi: 10.1021/sb300079h. *Equal contribution
Start Year 2009
 
Description Modelling malaria epidemiology 
Organisation Imperial College London
Department Department of Infectious Disease & Epidemiology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been developing models of the contributions transgenic mosquitoes may make to malaria control in sub-Saharan Africa. I have also been conducting surveys of human movement patterns of relevance to malaria transmission in Mali, Burkina Faso, Zambia and Tanzania.
Collaborator Contribution The malaria modelling group at Imperial College led by Prof Azra Ghani is a large interdisciplinary group studying the epidemiology of malaria. Group members all contribute to different aspects of the model, including the human, vector and parasite dimensions of malaria transmission.
Impact Gatton, M. L., N. Chitnis, T. Churcher, M. J. Donnelly, A. C. Ghani, H. C. J. Godfray, F. Gould, I. Hastings, J. M. Marshall, H. Ranson, M. Rowland, J. Shaman, and S. W. Lindsay, 2013 The importance of mosquito behavioral adaptations to malaria control in Africa. Evolution 67: 1218-1230. Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2013 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control. Malar. J. 12: 291. White, M. T., D. Lwetoijera, J. M. Marshall, G. Caron-Lormier, D. A. Bohan, I. Denholm, and G. J. Devine, 2014 Negative cross resistance mediated by co-treated bed nets: A potential means of restoring pyrethroid-susceptibility to malaria vectors. PLoS ONE 9: e95640. Marshall, J. M., Touré, M. B., Ouédraogo, A. L., Ndhlovu, M., Kiware, S. S., Rezai, A., Nkhama, E., Griffin, J. T., Hollingsworth, T. D., Doumbia, S., Govella, N. J., Ferguson, N. M., Ghani, A. C., 2014 Contributions of Women with Children and Youth Workers to Spatial Malaria Transmission in Sub-Saharan Africa. Under review. Completed surveys of human movement patterns of relevance to malaria transmission in Mali, Burkina Faso, Zambia and Tanzan
Start Year 2010
 
Description Modelling malaria transmission in elimination settings 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution I have contributed towards models of malaria transmission in elimination settings, incorporating the role of travels in malaria importation.
Collaborator Contribution Researchers in the Global Health Group at UCSF have conducted field work in malaria elimination settings and developed novel strategies for delivering combinations of interventions to eliminate transmission in these areas.
Impact This is a multi-disciplinary collaboration involving public health and mathematics.
Start Year 2014
 
Description Population structure of mosquitoes in West Africa 
Organisation University of California, Berkeley
Department Department of Integrative Biology
Country United States 
Sector Academic/University 
PI Contribution I am analyzing the population structure of mosquito populations in West Africa of relevance to transgenic mosquito projects based on genetic data.
Collaborator Contribution Prof Greg Lanzaro at the University of California, Davis is contributing mosquito genetic data, and Prof Montgomery Slatkin at the University of California, Berkeley is advising on population genetic analysis methods.
Impact I was a visiting scholar at the University of California, Berkeley in the lab of Prof Montgomery Slatkin, working on this project and am continuing to work towards this goal.
Start Year 2013
 
Description Population structure of mosquitoes in West Africa 
Organisation University of California, Davis
Department School of Veterinary Medicine Davis
Country United States 
Sector Academic/University 
PI Contribution I am analyzing the population structure of mosquito populations in West Africa of relevance to transgenic mosquito projects based on genetic data.
Collaborator Contribution Prof Greg Lanzaro at the University of California, Davis is contributing mosquito genetic data, and Prof Montgomery Slatkin at the University of California, Berkeley is advising on population genetic analysis methods.
Impact I was a visiting scholar at the University of California, Berkeley in the lab of Prof Montgomery Slatkin, working on this project and am continuing to work towards this goal.
Start Year 2013
 
Description Temperature-controlled gene drive systems 
Organisation National Health Research Institutes (NHRI) Taiwan
Department Institute of Molecular and Genomic Medicine
Country Taiwan, Province of China 
Sector Charity/Non Profit 
PI Contribution I have written and submitted an application for a Royal Society travel grant with Dr Chen entitled "A temperature-controlled gene drive system for mosquito-borne disease control"
Collaborator Contribution Dr Chen and I have written and submitted an application for a Royal Society travel grant entitled "A temperature-controlled gene drive system for mosquito-borne disease control"
Impact Application for a travel award under the Royal Society International Exchanges Scheme. This was a multi-disciplinary application with Dr Chen contributing molecular biological knowledge and myself contributing mathematical modeling expertise.
Start Year 2013
 
Description Plenary lecture (India 2013) 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Marshall, J. M., 2013 What role should mathematical models and transgenic mosquitoes play in dengue control programs in India? Contributed talk at Brain Storming Conference on Dengue Scenario in India: Disease Burden, Surveillance and Control, Madurai, India.

Several members of public health institutes in India asked how the methods we use to model malaria transmission in Africa could be applied to dengue transmission in India.
Year(s) Of Engagement Activity 2013
 
Description Public lecture (Los Angeles 2012, London 2013) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Several hundreds attended the TEDx talk in Los Angeles. Around 50 attended the talk at University College London, which sparked questions and discussions afterwards.

Marshall, J. M., 2013 If Mother Teresa was a genetic engineer: From golden rice to GM mosquitoes for malaria control. Contributed talk at University College London, London, England.

Marshall, J. M., 2012 If Mother Teresa was a Genetic Engineer. Contributed talk at TEDx LA Miracle Mile, Los Angeles, California.

Agent suggest a book along these lines - "If Mother Teresa was a genetic engineer..."
Year(s) Of Engagement Activity 2012,2013
URL http://www.youtube.com/watch?v=BzpkWXfUL6o
 
Description Scientific presentation (New Orleans 2014) 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Presentation sparked discussion with several conference attendees.

After the presentation, opportunities arose to publish further research in the subject area.
Year(s) Of Engagement Activity 2014
 
Description Scientific talk (Greece 2013) 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2012 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits for vector control. Contributed talk at the 6th International Meeting on Molecular and Population Biology of Mosquitoes and Other Disease Vectors, Kolymbari, Greece.

Communication of results. Discussions with colleagues following the talk.
Year(s) Of Engagement Activity 2013
 
Description Scientific talks (Atlanta 2012) 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2012 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits for vector control. Contributed talk at the 61st Annual Meeting of the American Society for Tropical Medicine and Hygiene, Atlanta, Georgia

Marshall, J. M., and B. A. Hay, 2012 Medusa: A novel gene drive system for confined suppression of mosquito populations. Contributed talk at the 61st Annual Meeting of the American Society for Tropical Medicine and Hygiene, Atlanta, Georgia.

Large audience. Discussions with colleagues following the talks.
Year(s) Of Engagement Activity 2012
 
Description Scientific talks (Berkeley 2014) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talks sparked questions and discussion.

Talks led to subsequent collaborations.
Year(s) Of Engagement Activity 2013,2014
 
Description Scientific talks (London 2013) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Marshall, J. M., M. T. White, A. C. Ghani, Y. Schlein, G. C. Muller, and J. C. Beier, 2012 Quantifying the mosquito's sweet tooth: Modelling the effectiveness of attractive toxic sugar baits for vector control. Contributed talk at the Malaria Centre, Imperial College London, London, England.

Marshall, J. M., and B. A. Hay, 2012 Medusa: A novel gene drive system for confined suppression of mosquito populations. Contributed talk at the Malaria Centre, Imperial College London, London, England.

Communication of results. Discussions with colleagues following the talk.
Year(s) Of Engagement Activity 2013