Q&A: WHO updates guidance on testing genetically modified mosquitoes
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Researchers have been exploring the use of genetically modified mosquitos as a potential control method for vector-borne diseases.
Just last month, Oxitec began releasing its genetically modified (GM), self-limiting male Aedes aegypti mosquitoes in the Florida Keys in the hope of reducing the mosquito population.
Source: Adobe Stock.
This month, WHO released the second edition of its guidance for testing GM mosquitos (GMMs), updating guidelines that were originally released in 2014. We spoke with Jan Kolaczinski, PhD, MSc, head of the vector control and insecticide resistance unit in WHO’s Global Malaria Program, about the new guidance and what it means for researchers.
Healio: What are the major issues addressed by the guidance?
Kolaczinski: There have been major research advances that increase the feasibility of GMM interventions, with lots of different possibilities of using this approach being explored. The characteristics of different GM strategies must be taken into account in how they would be tested and how they might be used. The updated guidance describes best practices for safety and efficacy testing, ethical and engagement obligations and regulatory oversight for different types of GMMs at each phase of the testing pathway for different types of GMMs.
Healio: What has changed in the world of GMM research since the guidance was first written in 2014, and how did the guidance change to reflect that?
Kolaczinski: The first two papers using CRISPR/Cas for gene drive in mosquitoes came out in late 2015 and early 2016 after the guidance was published. Before that, people were trying to harness naturally occurring drive mechanisms with limited success. Progress on gene drive became very rapid with the advent of CRISPR/Cas, and now many types are envisioned, including those that are designed to be self-limiting and those that are self-sustaining. Examples of these various types of modifications are provided in the guidance. In addition to substantial technical advances, there has been much more attention placed on risk assessment as well as ethical and governance issues for these new types of technologies. We have become much more sophisticated in our thinking about stakeholder engagement generally and perhaps particularly in the context of risk assessment. All of these changes are reflected in the updated guidance.
Healio: Which technologies are already being tested in the wild, and what other technologies are furthest along in development?
Kolaczinski: Self-limiting mosquitoes produced by Oxitec are the furthest along in terms of being evaluated in the field. The first version of the Oxitec nonviable GMM for population suppression was tested in small-scale releases by 2014. Now there have been larger scale tests, and Oxitec has moved on to a more efficient second-generation product that is fertile and that is intended to make the suppression effect last slightly longer in the local mosquito population but eventually disappear. Releases of fertile male Aedes aegypti are currently being evaluated in Florida. No construct of an anopheline mosquito is as yet available for field evaluation.
Target Malaria conducted a very small single-field release of a male sterile version of their technology in Burkina Faso as part of their local capacity strengthening activities in preparation for future trials.
No gene drive-containing GMM has so far been released in the field. Developers have made a lot of progress in creating candidates for gene drive approaches and demonstrating efficacy in the lab or insectary, but it is recognized that much additional groundwork must be laid before these are tested in the field, as described in the guidance.
Wolbachia work is much further advanced and has provided a lot of real-world experience that has been informative.
A population suppression strategy using irradiation rather than genetic manipulation to sterilize mosquitoes has been field tested.
Healio: What does the guidance say specifically about gene drive-modified mosquitoes?
Kolaczinski: The updated guidance includes a much-expanded consideration of the advances made and challenges faced by gene drive-modified mosquitoes. It discusses the implications of different types of gene drive on the phased testing pathway proposed in 2014. For example, it talks about how the spreading characteristics of gene drive must be taken into account in the design of field trials. It discusses how characteristics of spread and persistence in the environment must be considered in risk assessment, reviews existing guidance and recommendations from other sources on this issue and recommends how risk assessment and management should be addressed at each testing phase. It also reviews relevant precedents for regulatory oversight of gene drive mosquitoes. These include not only biosafety regulation stemming from the Cartagena Protocol but regulation of biological control agents, which also persist and spread in the environment, and of course, health regulatory pathways that are applicable for public health tools. As mentioned earlier, the updated guidance describes best practices for safety and efficacy testing, ethical and engagement obligations and regulatory oversight for different types of GMMs, including different types of gene drive-modified mosquitoes at each phase of the testing pathway.
Healio: Can GMMs end mosquito-borne disease?
Kolaczinski: We have learned from experience that vector-borne diseases are very resilient, which is why we need as many interventions as possible to combat them in the form of intervention packages tailored to specific contexts. At this point, no one is expecting GMMs to be a silver bullet to end malaria or arboviral infections. But they do have certain theoretical advantages that make them very attractive as a complement to existing or other envisioned interventions. For example, they offer areawide protection that is independent of socioeconomic status or proximity to medical facilities; they don’t require people to change their behavior in order to be effective; they can reach hard-to-find mosquito breeding sites and should be effective against outdoor and day-biting vectors that aren’t targeted by long-lasting insecticidal nets and indoor residual spraying; and they are appropriate for both urban and rural disease transmission settings. Those that are self-sustaining should offer durable protection that would lower delivery costs, allow them to function under conditions where other interventions are difficult to maintain (such as during civil unrest or the COVID-19 pandemic) and contribute to disease eradication efforts by providing ongoing protection against resurgence in regions where the disease has been cleared. Given these potential benefits and the fact that GMM technologies now appear to be technically feasible, but understanding the need for any possible risks to be thoroughly assessed on a case-by-case basis, WHO has taken the position that these technologies deserve further investigation.
References:
Diabaté A. Results from months of monitoring following the first release of non gene drive genetically modified mosquitoes in Africa. https://targetmalaria.org/results-from-months-of-monitoring-following-the-first-release-of-non-gene-drive-genetically-modified-mosquitoes-in-africa/#:~:text=Target%20Malaria%20Burkina%20Faso%20is,release%20over%202019%20and%202020. Accessed May 24, 2021.
Gantz VM, et al. Proc Natl Acad Sci U S A. 2015;doi:10.1073/pnas.1521077112.
Hammond A, et al. Nat Biotechnol. 2016;doi:10.1038/nbt.3439.
Oxitec. Landmark project to control disease carrying mosquitos kicks off in the Florida Keys. https://www.oxitec.com/en/news/landmark-project-to-control-disease-carrying-mosquitoes-kicks-off-in-the-florida-keys. Accessed May 24, 2021.
WHO. Evaluation of genetically modified mosquitoes for the control of vector-borne diseases. https://www.who.int/publications/i/item/9789240013155. Accessed May 24, 2021.
Perspective
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This guidance provides a prudent path forward for safely developing and testing innovative genetic technologies for the control of mosquitoes. As the WHO statement articulates — vector borne diseases result in significant morbidity and mortality, which are disproportionally high among poorer populations. Current approaches are not sufficient; therefore, there exists a pressing demand for testing new technologies to combat these diseases. Presently there are many innovative genetic technologies that are under development — many of which can potentially provide long-lasting lifesaving solutions. This WHO guidance will provide a necessary framework to inform future research and development for which these technologies can safely and cautiously progress forward, taking into consideration potential risks and benefits, safety, ethics, affordability and effectiveness.
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WHO. Guidance framework for testing of genetically modified mosquitoes, second edition. https://www.who.int/publications/i/item/9789240025233. Accessed May 24, 2021.
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