Ivermectin as a complementary strategy to kill mosquitoes and stop malaria transmission?

Abstract

Vector control/killing has been a long and durable strategy for malaria control across the globe. Current efforts to kill or dramatically shorten the life span of female Anopheles mosquitoes have honed the use of insecticides to specifically meet the biology of mosquito biting and resting behaviors, including putting insecticide on long-lasting insecticidal nets (LLINs) where the mosquito lands when trying to reach the person sleeping under thenet and indoor residual spraying (IRS) of insecticide on house walls where a blood-fed mosquito often lands and rests before flying off to lay her eggs. There is now much attention focused on methods to kill the mosquitoes that escape these interventions because they bite when people are not yet under LLINs or because they rest or feed outside the sprayed house—but they all must bite to get their blood meals to support egg development and mosquito reproduction. Thus, a systemic endectocidal drug like ivermectin, which can be given to both humans and animals and is toxic to Anopheles mosquitoes when they take a blood meal from a host that has recently received it, provides an intriguing opportunity to kill the remaining mosquitoes that avoid or survive our existing vector control interventions [1, 2]. The results from the randomized controlled trial from Burkina Faso by Ouedraogo et al, reported in this issue of Clinical Infectious Diseases [3], build on a growing body of evidence that demonstrates the safety and efficacy of ivermectin in killing malaria mosquitoes—in this case, Anopheles gambiae and Anopheles funestus, 2 of the most important malaria vectors in Africa—when used as adjunct therapy in patients with uncomplicated falciparum malaria treated with a standard 3-day course of the antimalarial drug artemether-lumefantrine. Of particular note, they used a standard dose (200 μg/kg) of ivermectin that has been used widely for mass drug administration (MDA) in onchocerciasis and lymphatic filariasis control and elimination [4], and they confirmed its safety when used singly or as repeated dosing (2 × 200 μg/kg) in a short 3-day interval. They demonstrated partial but substantial mosquitocidal efficacy during the week following ivermectin and showed that the killing effect was strongly associated with ivermectin plasma concentrations, which were affected by body mass index and sex (higher in females, possibly due to generally higher body fat content and fat storage of the drug). And, they suggest that the 2-dose ivermectin regimen given during a standard 3-day artemisinin combination therapy (ACTs) could reduce malaria transmission in the protected laboratory setting by approximately 35% during the first week when gametocyte concentrations are highest and onward transmission is most likely [3]. Finally, they demonstrate that a small number of mosquitoes (approximately ≤1%) surviving the ivermectin exposure can become malaria infected and infective after membrane feeding on malaria-infected blood, suggesting that the transmission-blocking properties of ivermectin may be predominantly resulting from its mosquitocidal