Research Article: Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group†

Date Published: June 07, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Stephanie James, Frank H. Collins, Philip A. Welkhoff, Claudia Emerson, H. Charles J. Godfray, Michael Gottlieb, Brian Greenwood, Steve W. Lindsay, Charles M. Mbogo, Fredros O. Okumu, Hector Quemada, Moussa Savadogo, Jerome A. Singh, Karen H. Tountas, Yeya T. Touré.


Gene drive technology offers the promise for a high-impact, cost-effective, and durable method to control malaria transmission that would make a significant contribution to elimination. Gene drive systems, such as those based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein, have the potential to spread beneficial traits through interbreeding populations of malaria mosquitoes. However, the characteristics of this technology have raised concerns that necessitate careful consideration of the product development pathway. A multidisciplinary working group considered the implications of low-threshold gene drive systems on the development pathway described in the World Health Organization Guidance Framework for testing genetically modified (GM) mosquitoes, focusing on reduction of malaria transmission by Anopheles gambiae s.l. mosquitoes in Africa as a case study. The group developed recommendations for the safe and ethical testing of gene drive mosquitoes, drawing on prior experience with other vector control tools, GM organisms, and biocontrol agents. These recommendations are organized according to a testing plan that seeks to maximize safety by incrementally increasing the degree of human and environmental exposure to the investigational product. As with biocontrol agents, emphasis is placed on safety evaluation at the end of physically confined laboratory testing as a major decision point for whether to enter field testing. Progression through the testing pathway is based on fulfillment of safety and efficacy criteria, and is subject to regulatory and ethical approvals, as well as social acceptance. The working group identified several resources that were considered important to support responsible field testing of gene drive mosquitoes.

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Mosquitoes modified with gene drive systems are being proposed as new tools that will complement current practices aimed at reducing or preventing transmission of vector-borne diseases such as malaria. Gene drive systems have the potential to spread new genetic traits through interbreeding populations of malaria mosquitoes from low initial introductions (Figure 1), and the transgenic construct could persist in those mosquitoes indefinitely or until the target mosquito population is locally eliminated. Having observed naturally occurring drive mechanisms in insects and other organisms, scientists speculated for decades about how these mechanisms could be harnessed to insert beneficial traits into a population of vector mosquitoes to create a high-impact, low-cost, sustainable tool for controlling disease transmission.1 With the advent of new molecular tools for modifying mosquitoes,2 a mechanism was envisioned to use synthetic genes with the capability of spreading in populations, even if they confer a fitness cost (driving transgenes). The envisioned goal for applying this technology is to reduce or eliminate vector mosquito populations or, alternatively, to render them less competent to transmit pathogens. Either of these outcomes should contribute to disease reduction. However, the characteristics that make gene drive technology so attractive as a cost-effective and durable vector control tool raise questions about possible adverse effects on human or animal health or the environment that must be seriously considered in product development.

As defined in the WHO Guidance Framework, gene drive approaches that are “self-sustaining” (sometimes termed “self-propagating”) are intended to spread through the target mosquito population.15 The drive mechanism must be capable of overcoming any fitness costs and capable of increasing in frequency from low initial levels to fixation, or near fixation, in the population into which it was introduced within a time frame that will be meaningful for malaria elimination. Although other, more limited, approaches are now being considered (see Self-limiting alternatives), this definition remains valid for low-threshold gene drive strategies that are the subject of these recommendations.

Many of the issues that must be considered for field-testing an investigational product will be common to all low-threshold gene drive strategies and all along the continuum of the development pathway. Product development will be more efficient if planning for these issues begins early in the project (see Box 3).

As described in the WHO Guidance Framework, testing of new investigational gene drive products begins with small-scale laboratory studies for efficacy and safety testing under appropriate containment conditions and operating procedures.15 This phase may proceed through testing in larger population cages within the laboratory setting, including large environmentally controlled indoor spaces that aim to simulate a field setting.#

Although making no assumptions about where gene drive constructs might be created, working group members recognized the critical importance of site selection and preparation for field testing gene drive mosquitoes. For those projects originating outside a disease-endemic country, this will begin by establishing a partnership with an institution with which to pursue research and product development within a country where further testing will be conducted.

The intent of a phased development pathway is to test a new technology incrementally, adding complexity at each new step. For other GMO, limited environmental exposure traditionally has been accomplished by two means: physical or ecological confinement. These methods may likewise be applied to gene drive mosquitoes. Thus, the first step beyond contained laboratory testing for GMM may be conduct of physically confined semi-field, or caged, testing. Semi-field testing is intended to allow for observation under a more natural setting, but under conditions that limit release of gene drive mosquitoes into the environment.

As defined in the WHO Guidance Framework, the next testing phase would be small-scale ecologically confined testing with a primary goal of measuring entomological efficacy.15 The working group debated whether ecological confinement is applicable to gene drive mosquitoes released into an existing wild population. As described under the Site selection and containment requirements, efforts can be made to identify a geographically isolated site for the initial field release where ecological characteristics minimize the possibility of outward migration of gene drive mosquitoes and inward migration of wild-type mosquitoes. Thus, the working group determined that although in the case of low-threshold gene drive ecological confinement cannot be assured, the intent in the initial field trial should be to minimize environmental exposure to the extent possible while confirming efficacy and safety observations from prior stages of testing.

The ultimate measure of the efficacy of a gene drive intervention is its ability to reduce or eliminate morbidity and mortality due to malaria parasites, without significant long-term costs to the socioeconomic system in which it is deployed. How epidemiological efficacy can be evaluated may differ depending on whether researchers are working in a malaria control setting (where there is still appreciable malaria transmission) or a malaria elimination setting (where disease burden and transmission levels will be low).129 It will be important to anticipate what the malaria situation will be at field sites at the time the investigational gene drive product is ready for field-testing, as more countries move toward elimination.

Because of the characteristics of potential persistence and spread, implementation of gene drive mosquitoes as a public health tool within national malaria control programs likely will build onto prior large-scale releases for testing epidemiological efficacy, moving to broader and more systematic regional distributions. Observations from prior releases of the behavior of the investigational product under different geographic and ecological conditions, in combination with modeling, will inform the design of deployment plans (see Box 8).

After a decision is made to deploy gene drive mosquitoes as a public health tool, there will be a need for ongoing surveillance, monitoring, and evaluation. In this regard, the working group re-emphasized the following three important points:1.The requirements for post-implementation monitoring and evaluation of gene drive mosquitoes must be considered on the background of current activities routinely conducted by national programs to monitor malaria cases and the efficacy of vector and other control methods, as well as activities that must be put in place in the context of malaria elimination efforts. Malaria surveillance is identified as a core intervention in the Global Technical Strategy for Malaria 2016–2030.312.The loss of efficacy due to genetic selection is a general challenge for malaria control tools, including insecticides, drugs, and diagnostics.28,1533.Reduction in the number of malaria vectors is a generally accepted public health goal and the aim of all existing insecticide-based control methods. Commonly used insecticides are known to have effects on a broad range of nontarget species,154 and gene drive mosquitoes must be considered in the context of their relative risk and benefit versus other forms of vector control.

These recommendations describe the development pathway for a new and potentially powerful tool, based on gene drive technology, to prevent transmission of vector-borne diseases. New synthetic gene drive applications, such as those using the CRISPR/Cas system, have the potential to introduce a beneficial modification rapidly into the local population of vector mosquitoes allowing it to become established, spread, and persist. Two applications of gene drive, leading to either a reduction in numbers of vector mosquitoes or a reduction in their ability to transmit pathogens, currently are being considered. Because of the present uncertainties around gene drive technology, the complexity of anticipating the development pathway was such that this working group chose to simplify discussions by focusing on a relatively narrow use, namely a tool for controlling malaria transmission by An. gambiae s.l. mosquitoes in Africa. However, it is expected that these recommendations will stimulate similar thinking about other possible uses of gene drive technology.

ACL: Arthropod Containment LevelCDISC: Clinical Data Interchange Standards ConsortiumCRISPR: Clustered regularly-interspaced short palindromic repeatsCRT: Cluster randomized controlled trialDNA: Deoxyribonucleic acidDSMB: Data and safety monitoring boardGLP: Good Laboratory PracticeGM: Genetically modifiedGMM: Genetically modified mosquitoesGMO: Genetically modified organismIVM: Integrated vector managementNASEM: National Academies of Science, Engineering and MedicineNBA: National Biosafety AuthorityNEPAD: New Partnership for Africa’s DevelopmentPCR: Polymerase chain reactionRNA: Ribonucleic acidSOPs: Standard operating proceduresTPP: Target Product ProfileVCAG: Vector Control Advisory GroupWHO: World Health Organization




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