BioEd Online

Any long-term programme for disease control that relies on one type of intervention has a high probability of failure owing to the development of treatment resistance. Efforts to limit malaria by using insecticides to kill female mosquitoes, which transmit the disease-causing Plasmodium parasite, are no exception: mosquito resistance to insecticides is on the increase. Writing in Nature, Paton et al. report a non-insecticidal intervention that stops mosquitoes from transmitting malaria and that might offer a way to reduce the reliance on insecticides alone as a means of malaria prevention.

It is estimated that mosquito control using bed nets impregnated with long-lasting insecticides called pyrethroids, and indoor insecticide spraying, resulted in 1.3 billion fewer malaria cases and 6.8 million fewer deaths between 2000 and 2015. However, despite these intensive efforts, a 2018 report by the World Health Organization (WHO) states that, between 2015 and 2017, global efforts to reduce the burden of malaria stalled.

The report highlights a funding gap that has resulted in a failure to achieve universal coverage of bed nets, where needed, and an increase in resistance to antimalarial drugs and insecticides. It also mentions the limited data available on insecticide resistance, and states that the impact of pyrethroid resistance on the effectiveness of current pyrethroid-based interventions is poorly understood. Although the report says that such increasing resistance will probably reduce the efficacy of current interventions, it downplays the potential impact on the use of pyrethroid-treated bed nets, stating that the nets, which have been responsible for approximately 68% of the estimated reduction in malarial transmission since 2000, continue to be effective. Sadly, this optimism seems misplaced, given the evidence that the increased insecticide resistance is affecting the level of disease transmission.

Models had already predicted that insecticide resistance would affect malaria transmission. Even low levels of insecticide resistance would increase the incidence of malaria because of the effect of reduced mosquito mortality and lower overall community protection during the projected three-year lifespan of a bed net. A type of bed net called a PBO net that contains pyrethroid and piperonyl butoxide, a compound that enhances pyrethroid’s effectiveness, would be substantially more effective than pyrethroid-only nets5. It is estimated that switching from pyrethroid-only bed nets to PBO nets would prevent up to 0.5 clinical cases of malaria per person per year in some scenarios5. Trials have demonstrated that, in insecticide-resistant areas, PBO nets are more effective at reducing the transmission of malaria than are pyrethroid-only nets.

Given the urgent need to expand the range of effective interventions, Paton et al. suggest a way forward for the development of next-generation antimalarial bed nets. They tested whether Plasmodium falciparum, the major malaria-causing parasite in Africa, could be killed by exposing mosquitoes to the parasite-killing drugs that are used to prevent people from getting malaria. These work by targeting mitochondria — energy-generating organelles.

The authors found that the antimalarial drug atovaquone, which inhibits the mitochondrial protein cytochrome b — as well as other types of cytochrome b inhibitor drug — could kill parasites in a mosquito host. Exposing mosquitoes for six minutes to a glass surface coated with low doses of the drug was enough to have an effect. This is within the time frame for which wild mosquitoes rest on bed nets. The finding is important because, after more than a century of research, and small-scale projects involving biological or environmental control, it is evident that non-insecticidal interventions do not contribute substantially to efforts to reduce malaria transmission.

Paton and colleagues suggest that antimalarial drugs could be incorporated into bed nets alongside insecticides. Their modelling predicts that this would reduce the prevalence of malaria, with the size of the impact being affected by the levels of disease transmission, the number of people using nets and the degree of insecticide resistance. The increased effect of adding the antimalarial drug to insecticide-treated nets is most striking in the authors’ models when bed-net usage is 70–100%, underscoring the need to strive for high levels of net usage even if the compounds used to treat the nets change in the future.

Malaria cannot be sustainably controlled or eliminated without effective mosquito control. Paton and colleagues’ approach fits well with the WHO’s global plan for managing insecticide resistance. This suggests that a multifaceted approach should be used, and progress will rely on efforts to reduce the cost of bringing new drugs to market and streamlining the associated development, policy and implementation steps.

Although Paton and colleagues’ approach holds promise, substantial hurdles must be overcome before a product is generated that is recommended and universally accepted by funders, countries and communities for use in control programmes. Extensive work will be needed to optimize drug development, and so produce long-lasting formulations. Moreover, assessments of the drug-manufacturing process should be undertaken, together with a drug’s resistance potential and the cost and public acceptability of the approach.

The WHO has a system called prequalification, in which a product for tackling a health problem must meet certain specifications before it can be placed on a list for selection by donor organizations. In addition, countries have product-recommendation systems that consider proposed interventions and establish the burden of proof for whether a WHO recommendation is warranted for use there. Completing these steps is a difficult and lengthy process. For example, the first PBO nets were a market-ready product bearing a WHO interim recommendation ten years before the first WHO guidance was issued on where and when this type of net should be used. The combined developmental, regulatory and other processes involved can create a 20-year hiatus before a new technology enters the marketplace and is used at scale. Substantial effort and funding will therefore be needed to ensure a rapid evaluation of whether Paton and colleagues’ suggested approach could have a role in reversing the current trend of rising malaria transmission.