How can gene drives control insect-borne diseases?
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Vaccines are important tools against many infectious diseases. Several potential dengue vaccines are being studied and one has been recommended for use under limited circumstances. Likewise, research on malaria vaccines has been ongoing for decades and one vaccine recently received WHO recommendation for children living in regions of high disease transmission, where it has demonstrated a partial reduction in severe disease.
Malaria and dengue have proven to be very challenging diseases to control. There is little doubt that successful control and/or elimination will require multiple different tools. Vector control is expected to remain important with or without available vaccines. WHO has taken the position that new tools are urgently needed for vector-borne diseases, and that the potential contribution of genetically modified-mosquitoes should continue to be explored.
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Mosquitoes transmit many deadly and debilitating human and animal diseases. Those performing the research on gene drive technologies in mosquitoes envision several possible uses, such as: 1) to prevent transmission of malaria parasites in high incidence areas; 2) to prevent transmission of disease-causing arboviruses such as dengue or Zika in regions where they are prominent; or 3) to control transmission of avian malaria that is threatening fragile native bird populations in island habitats.
Gene drive technologies if successfully deployed in mosquitoes might be used to reduce the risk of these diseases by depleting populations of disease-carrying mosquitoes (population suppression) or reducing the ability of the mosquitoes to harbor the pathogen (population replacement or modification).
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What need might gene drive-modified mosquitoes address that more conventional vector control cannot?
Conventional vector control has proven successful in reducing and in some cases eliminating vector-borne diseases. Environmental engineering (e.g., draining swamps) and insecticides (principally DDT) were important in eliminating malaria from North America and Western Europe. In Africa, insecticide-treated bed nets and indoor spraying of insecticides have substantially reduced the burden of malaria. However, insecticide-based control methods are costly, subject to development of resistance in the mosquito, and apt to miss important populations of disease-transmitting mosquitoes. Progress against malaria has plateaued in recent years, and the problem remains especially severe in Africa. Theoretical advantages of genetically modified mosquitoes are that they could do the following:
- Provide protection that benefits all people in the treated area regardless of socioeconomic status or access to healthcare facilities and without imposing additional burdens or requiring people to modify their behaviors.
- Affect only the target species directly, unlike the case with some insecticide-based methods, and thus have fewer effects on biodiversity.
- Reach mosquito populations and breeding sites that traditionally have been the hardest and most expensive to target using conventional vector control strategies, by exploiting the natural seeking behavior of the mosquitoes to find each other and oviposition sites.
- Be useful in both urban and rural environments and whether the vector is present at high or low density.
- Provide ongoing protection in situations where delivery of other malaria control tools has been disrupted.
Some gene drive technologies could be highly sustainable, requiring only a few releases of gene drive-containing mosquitoes to make large and lasting impacts on a target species. Some gene drive technologies could spread over large geographic areas that are challenging to cover using conventional technologies such as insecticides. These characteristics are expected to make their use highly cost effective. Moreover, ongoing protection provided by mosquitoes carrying self-sustaining gene drive could prevent re-introduction of a disease in regions where it has been eliminated, or protect regions from introduction of new mosquito-borne diseases.
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What might be the potential benefits associated with using gene drive technologies as public health tools?
Gene drive technologies could potentially enhance and enable reduced incidence of mosquito-borne diseases such as malaria in Africa and dengue fever in many parts of the world, resulting in healthier human populations. Gene drive technologies are being developed to complement other disease control tools, and may actually help the other tools to be more effective. In addition to direct public health benefits that might be gained through the use of gene drive technologies, those adopting the technologies could benefit from the technologies’ expected ease of delivery and low cost, which would contribute to sustainability of their protective effects.
Gene drive-modified mosquito technologies are intended to be used in integrated vector management programs, in conjunction with other control methods. Many of these activities may be incorporated into ongoing disease control plans, in which case national vector and disease control programs could play a central role in operationalizing these plans. Implementation of genetically modified mosquito technologies will involve preparatory analysis, site-specific product development, application/delivery, and post-implementation monitoring and evaluation work. Many of these functions are part of, or can build upon, current national vector control activities.
Aren’t mosquito-borne diseases like malaria and dengue transmitted by many different mosquito species, and wouldn’t one have to release genetically modified versions of all of them?
Many different species of mosquito have been reported to transmit malaria worldwide, but they are all not equally good as vectors, resulting in some being much more impactful to control than others. For example, one of the reasons why Anopheles gambiae s.s. is such a dangerous vector of human malaria in Africa is because of its almost exclusive preference for biting humans whereas other vectors tend to also bite non-human animals in order to obtain the blood needed for their reproduction. Other members of the Anopheles gambiae family (sibling species) also transmit malaria, and it should be relatively straightforward to adapt the same gene drive approaches to them as well. Control of this powerful family of vectors in Africa is expected to have a large impact on malaria transmission. Similar technology could be applied to other malaria vectors.
Dengue and several other important arboviral diseases are primarily transmitted by Aedes aegypti mosquitoes, so targeting just these mosquitoes could dramatically reduce disease transmission.
There at least three reasons why gene drive systems might be considered in lieu of other genetic biocontrol techniques:
- Those that have the potential to persist and spread within and between interbreeding populations of the target organism will be better suited for control needs that extend over large areas (country or regional level).
- Genetic biocontrol methods such as the Sterile Insect Technique and related techniques require continuous rearing, transport, and release of large numbers of insects to sustain control of the target organism. Maintaining such programs over time can be challenging and resource intensive. The ability of gene drive technologies to persist and spread could make them easier to deliver and maintain, contributing to their sustained impact.
- Gene drive technologies can be designed either to reduce or eliminate the target organism from the local environment or to leave the target species in the environment but to alter it genetically in such a way that it is no longer a threat. This is flexibility is an important feature of gene drive technologies.
Mosquitoes and certain other organisms are potentially good targets for gene drive technologies because they have a short generation time and many offspring, which will allow the gene drive-associated traits to spread quickly enough to yield the desired public health effect within an observable time-frame. The generation time of mosquitoes is only a few weeks.
Molecular biology techniques are used to make the genetic construct which is to be introduced into the mosquito. The construct is then micro-injected into a mosquito egg to become incorporated into the mosquito’s DNA.
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Malaria in Africa is found from northern South Africa to the southern edge of the Sahara Desert, an enormous area. Malaria elimination from Africa has involved and will continue to involve the use of many tools. Gene drive technologies hold promise to provide a new and highly effective set of complementary tools that can contribute to malaria elimination.
The Sterile Insect Technique and related genetic biocontrol programs require continuously rearing and release large numbers of insects to sustain control of the pest. While it is quite possible that these programs could contribute to malaria elimination in urban areas, they are much less suited to deal with malaria control across the abundant, remote, and highly dispersed towns and rural villages across the continent. The potential for the effects of gene drive technologies to persist for longer periods, and, in some cases to spread within and through specific malaria-transmitting mosquito species, make them attractive tools for eliminating malaria transmission over the broad region affected.
Oxitec pioneered a variation on Sterile Insect Technique using genetically engineered Aedes aegypti mosquitoes that contained genes lethal to the next generation. When the male mosquitoes were released in large numbers, local female mosquitoes which mated with them were unable to produce viable progeny and the overall numbers of Aedes aegypti mosquitoes were reduced. With this first generation product, there was no intention that the modification remain in the environment beyond the initial release. Oxitec has now moved to a second generation technology in which the introduced gene acts only against female progeny. When these modified mosquitoes are released, only male offspring survive to reproduce and these males can pass the modification to half of their offspring.
There is sometimes confusion about whether this genetic biocontrol method uses gene drive, but the answer is that it does not. This second generation technology depends on Mendelian inheritance, in which the genes from either parent usually are passed to about half of offspring in each subsequent generation. In this way, the modification will persist in the local mosquito population for some time but the numbers of modified mosquitoes will continue to decline. In contrast, the intention of gene drive is to increase the numbers of modified mosquitoes within the targeted population over time for greater sustainability and cost-effectiveness.
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The World Mosquito Program developed a unique strain of Aedes aegypti mosquito that is infected with the intracellular bacterium Wolbachia and this infection is transmitted from parent to progeny. Wolbachia-containing mosquitoes are much less capable of transmitting dengue and other mosquito-borne viruses. The World Mosquito Program product demonstrated significant reduction of dengue transmission in an extensive clinical trial conducted in Indonesia.
Research is underway to understand whether naturally-occurring microbes, including Wolbachia, in Anopheles mosquitoes could cause refractoriness to malaria parasites that would prevent disease transmission. Importantly, however, Wolbachia-based technologies would require larger numbers and more releases of Wolbachia-infected mosquitoes than self-sustaining and some self-limiting gene drive technologies. This might present operational and logistic limitations for the use of technologies based on Wolbachia or other symbionts against malaria across the range of conditions found in Africa.
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How can scientists know whether a genetically modified-mosquito product successfully prevents disease?
An important aspect of the phased testing pathway is assessing efficacy (the ability to produce the desired effect). Efficacy testing begins with measurement of entomological characteristics, such as whether the modification is stable, adversely affects the survival or mating competitiveness of the mosquitoes, and reduces either the mosquitoes’ ability to reproduce or carry the pathogen of interest. These characteristics can help predict the product’s future efficacy for preventing disease. However, the ability of the product to reduce the incidence or prevalence of infection or disease can only be assessed in subsequent large-scale field trials. These will be conducted similarly to other types of clinical trials, according to internationally agreed upon ethical standards as well as applicable national and local regulatory requirements. Pre-determined performance milestones will determine whether efficacy results justify continued testing at each phase.
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Conventional control methods include drugs to prevent or treat human infection and disease, vector control tools based on chemical pesticides such as spatial application of insecticides and use of insecticide-impregnated nets, as well as environmental management efforts to decrease the habitat where vectors breed and housing improvement to reduce human exposure.
These methods are all important, but they have not been able to fully solve the public health problem posed by vector borne diseases. Conventional vector control methods can be extremely costly to maintain and insecticide resistance is a problem in the mosquitoes that transmit either malaria or common arboviral diseases. It is widely recognized that current tools likely will be insufficient to eradicate malaria. For example, the World Health Organization reports that progress against malaria has plateaued in recent years and the situation remains precarious, especially in sub-Saharan Africa. They also report that global incidence of dengue has grown dramatically, with about half the world’s population at risk from dengue and other viral diseases carried by the same mosquito species.
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https://www.who.int/news-room/fact-sheets/detail/malaria; https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021; https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
Most research has been conducted in Anopheles gambiae (Anopheles gambiae s.s. and Anophleles coluzzii) mosquitoes thus far, which are important vectors of malaria in Africa. Aedes aegypti mosquitoes, which are important vectors of arboviral infections, have not proven to be as amenable to CRISPR/Cas-mediated homing gene drive systems as Anopheles. However, CRISPR-based drive systems have recently shown success in the laboratory and antiviral effector genes for population replacement have been identified. Work to apply gene drive technology to Culex mosquitoes, which transmit a number of human and animal diseases, is at an even earlier stage but tools to support genome editing have been developed.
For more information: https://elifesciences.org/articles/51701; https://www.mdpi.com/2075-4450/11/1/52; https://www.biorxiv.org/content/10.1101/2021.12.08.471839v1; https://www.nature.com/articles/s41467-021-23239-0
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;