A six-months, long acting, one-shot injectable formulation of Ivermectin as a complementary malaria vector control tool to target zoophagic Anopheles : laboratory and model-based proofs of concept.

Abstract

ContextIn the current context of residual plasmodium transmission where zoophagic proclivities of Anopheles intervene, we propose to treat peridomestic animals using the endectocide Ivermectin as a complementary approach to bednets. As Ivermectin remanence with classic veterinary compounds is insufficient to induce a significant decrease in vectors populations, we developed a long-lasting injectable formulation of ivermectin from the BEPO(R) technology designed to release insecticidal concentrations of the molecule for 6 months. The work reported here is a proof of concept that using this new technology could help decrease field Anopheles populations. MethodsEight calves were injected with Ivermectin therapeutic doses of 1.2 mg/kg body weight using 2 long lasting formulations (A and B). Efficacy of the product at killing wild derived An. coluzzii has been evaluated by direct-skin feeding assays from 1 to 210 days after injection (DAI). Efficacy on survival was estimated with Cox proportional hazards mixed models and Kaplan meier estimates. To predict efficacy in field-based scenarii, we used a transmission model fed with an entomological model considering different levels for the Anopheles zoophagic preference, calves vs humans ratios, and bed net use variables. ResultsThe release at mosquitocidal plasmatic concentrations of Ivermectin during 6 months is confirmed for both formulations (Hazard ratios > 1 for both formulations against their vehicle for 210 days). The Ivermectin concentration allowing to kill 90% of the mosquitoes before the extrinsic incubation period of the parasite is achieved (10 days) are 11 and 9 ng/ml for formulations A and B if the blood meal is taken before the infectious one, and 15 and 13 ng/ml if it was taken after. Modeling showed that Ivermectin treatment of calves using BEPO(R) technology would reduce infectious vector populations, from at least 35% for most anthropophagic Anopheles in villages where cattle to human ratio is the lowest, to more than 75% if vectors were zoophagic and calves numbers superior to humans. ConclusionOur study gives the proof of concept that a long-lasting formulation of Ivermectin administered to calves could help decrease field malaria vectors populations, which may, ultimately, have an impact at the epidemiological level.