Before a new vector control product is brought to market, it is standardly tested in a series of expanding clinical or field trials. This phased testing pathway allows developers and regulators to learn whether the new product works and is safe to use. Research on new products begins with extensive testing in the laboratory. Developers will submit laboratory results to regulatory authorities, who will determine whether and how the product can move to clinical or field testing. Upon regulatory approval, testing will begin at a very small scale under conditions that minimize risk to people or the environment. If results from such small-scale testing look promising, regulators may approve moving to larger scale trials of safety and efficacy. Based on those results, regulators will decide whether and under what conditions the product can be made publicly available. If at any phase of the pathway the product fails to demonstrate agreed upon safety and efficacy characteristics it should not move forward, and developers will need to decide whether and how it might be improved to restart the testing process.

For more information:

https://www.fda.gov/patients/drug-development-process/step-3-clinical-research

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials

https://apps.who.int/iris/bitstream/handle/10665/259688/WHO-HTM-NTD-VEM-2017.03-eng.pdf

https://nap.nationalacademies.org/catalog/23405/gene-drives-on-the-horizon-advancing-science-navigating-uncertainty-and

The recommended pathway involves four phases.

• Phase 1 involves initial studies on safety and efficacy, conducted in the laboratory and in cages that contain a small number of mosquitoes. All of these studies are conducted indoors under appropriate containment to prevent escape of the modified mosquitoes into the environment. If the modified mosquitoes demonstrate the desired biological and functional characteristics, testing may move forward.
• Phase 2 expands contained testing under conditions of physical or ecological confinement, intended to limit outward migration of the modified mosquitoes by studying them in large outdoor cages or under geographic/spatial/climatic isolation. This will examine whether the modified mosquitoes continue to show expected characteristics that predict an ability to reduce disease transmission. Depending on Phase 2 results, testing may proceed to Phase 3 of revert to conduct additional studies.
• Phase 3 includes open release trials to assess performance under various disease transmission conditions. In this phase, the ability of the modified mosquitoes to reduce the incidence or prevalence of infection or disease can be directly measured. If Phase 3 testing demonstrates sufficient efficacy and safety, regulators and policy makers may consider wider implementation of the product as a public health tool.
• Phase 4 entails ongoing monitoring of the product’s effectiveness and safety under operational conditions.

Phases 1 through 3 may need to be repeated to improve the technology and refine the procedures until the requirements for moving to the next phase are met. If the genetic modification is a self-sustaining gene drive that is expected to persist in the environment, the phased testing pathway may be more realistically conceived as a continuum of expanding releases.

Decisions to move forward from one testing phase to the next will require appropriate regulatory authorization and the agreement of the communities hosting the trials.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083

The American Committee of Medical Entomology has issued guidance for the safe handling of arthropod vectors of human and animal disease agents, including mosquitoes. These describe the facilities and training required to guard against unauthorized release from containment. They include considerations for vectors that contain recombinant DNA molecules, and those that have been modified with transgenes capable of gene drive. These recommendations take a risk-based approach, with containment requirements varying according to the potential consequences of premature releases.

For more information:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396570/
https://www.liebertpub.com/doi/10.1089/vbz.2021.0035

Phased testing will include examination of safety as well as efficacy characteristics. As recommended by the World Health Organization and the Convention on Biological Diversity, this would involve examination of possible adverse effects on human or animal health or the environment, including protection of biodiversity. Health hazards that have been identified as priorities for consideration include: the potential for the modification to cause increased abundance of mosquito species that carry the pathogen of interest; alteration that would result in an increased ability of mosquitoes to transmit the targeted pathogen or other pathogens; alterations that would reduce the ability to control the mosquitoes with conventional methods; increased allergenicity or toxicity of mosquitoes for humans or other organisms; or increased virulence of pathogens carried by the mosquito. Environmental hazards that have been identified as priorities include the potential for: spread of the modification to other species that would cause harm to the ecosystem; indirect harm to other species that depend on the modified mosquitoes for some essential service; increase in a harmful competitor species; or harmful higher order effects to the ecological community.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083
https://www.youtube.com/playlist?list=PLbopRNGowKJ_z1k9Sqxt26ONibFCjlgKe
https://www.youtube.com/playlist?list=PLbopRNGowKJ-UO7zxtZ3YoCKfuLKKExLv

Yes, depending upon the type of gene drive and extent of release. Gene drive does not cause or increase insecticide resistance. Care is being taken not to introduce modifications that might increase insecticide resistance in the local mosquito population. For example, the gene drive construct can be introgressed into the genetic background of the local target species so that their other characteristics remain unchanged. Additional methods for controlling gene drive-modified mosquitoes, including genetic mechanisms and small molecule approaches, also are being explored.

For more information:

https://www.ajtmh.org/view/journals/tpmd/98/6_Suppl/article-p1.xml

This is a question that will be addressed in risk assessment (see How to manage risks?). Risk assessment will take into account what other diseases that can be transmitted by the target mosquito species are present in the region where the gene drive-modified mosquitoes will be released. If necessary to support risk assessment, experiments can be conducted in the laboratory to measure the ability of the gene drive-modified mosquitoes to transmit different pathogens. Such experiments involve artificial feeding on blood containing the pathogen, using a membrane feeding device, and then examining the ability of the pathogen to grow in the mosquito and/or to be ejected in the mosquito’s saliva as might happen when it bites.

For more information:

https://www.youtube.com/watch?v=nfZrSH7uQ08

https://www.who.int/publications/i/item/9789240025233;

https://www.beiresources.org/AnophelesProgram/TrainingMethods.aspx

Phase 1 studies can be conducted in appropriately contained laboratory and cage facilities anywhere, as long as the mosquito species of interest can be maintained there. All field studies and trials will necessarily have to be conducted in environments where the target mosquito species exists naturally. Phase 3 testing, which measures safety and efficacy for reducing disease, must be conducted in areas where the disease of interest is actively transmitted.

We do not yet know the answer to this question as it is dependent upon many variables, including clarification of the regulatory pathway and collection of information needed to support risk assessment for different gene drive systems and in different venues.

Genetically modified mosquitoes are developed using genetic engineering. Gene drive-modified mosquitoes are a type of genetically modified-mosquitoes. In both cases, mosquitoes of the targeted species are modified to exhibit one or more different traits from wild type (non-modified) mosquitoes of the same species. An example of a desirable new trait would be a decreased ability of the modified mosquitoes to transmit diseases such as malaria or dengue. Modifications might involve altering the sequence of existing genes, disabling or excising of existing genes, or introducing new genes or other genetic elements within the mosquito genome.

Several genetic modification approaches are being explored, from those that will have no lasting effect on the targeted vector population after release to those that are intended to introduce a more persistent change. When not coupled to a gene drive, a gene (including any introduced genetic modification) is typically transmitted to the progeny from mating of modified with wild type mosquitoes according to the standard (Mendelian) pattern of inheritance, where each gene has a 50% chance of being passed from the parent to the next generation. If the gene or genetic modification is associated with a fitness cost (reduced competitive ability), the related trait is expected to disappear from the population over time. If the fitness cost is severe, the introduced gene(s) can disappear rapidly; this would be the case, for example, if the modification caused reduced fertility in those mosquitoes that carried it.

When coupled with a gene drive, the genetic modification is inherited preferentially. The related new trait will eventually become dominant in the population because more than 50% (sometimes almost 100%) of the progeny from matings between gene drive-modified mosquitoes and their wild-type counterparts inherit the modification.

For more information: https://www.geneconvenevi.org/gene-drive-defined/