Proof-of-concept study for a long-acting formulation of ivermectin injected in cattle as a complementary malaria vector control tool

Abstract

Background Domesticated animals play a role in maintaining residual transmission of Plasmodium parasites of humans, by offering alternative blood meal sources for malaria vectors to survive on. However, the blood of animals treated with veterinary formulations of the anti-helminthic drug ivermectin can have an insecticidal effect on adult malaria vector mosquitoes. This study therefore assessed the effects of treating cattle with long-acting injectable formulations of ivermectin on the survival of an important malaria vector species, to determine whether it has potential as a complementary vector control measure. Methods Eight head of a local breed of cattle were randomly assigned to either one of two treatment arms (2 × 2 cattle injected with one of two long-acting formulations of ivermectin with the BEPO® technology at the therapeutic dose of 1.2 mg/kg), or one of two control arms (2 × 2 cattle injected with the vehicles of the formulations). The lethality of the formulations was evaluated on 3–5-day-old Anopheles coluzzii mosquitoes through direct skin-feeding assays, from 1 to 210 days after treatment. The efficacy of each formulation was evaluated and compared using Cox proportional hazards survival models, Kaplan–Meier survival estimates, and log-logistic regression on cumulative mortality. Results Both formulations released mosquitocidal concentrations of ivermectin until 210 days post-treatment (hazard ratio > 1). The treatments significantly reduced mosquito survival, with average median survival time of 4–5 days post-feeding. The lethal concentrations to kill 50% of the Anopheles (LC50) before they became infectious (10 days after an infectious blood meal) were maintained for 210 days post-injection for both formulations. Conclusions This long-lasting formulation of ivermectin injected in cattle could complement insecticide-treated nets by suppressing field populations of zoophagic mosquitoes that are responsible, at least in part, for residual malaria transmission. The impact of this approach will of course depend on the field epidemiological context. Complementary studies will be necessary to characterize ivermectin withdrawal times and potential environmental toxicity. Graphical Abstract

Impact of blood meals taken on ivermectin-treated livestock on survival and fecundity of the malaria vectorAnopheles coluzziiunder laboratory conditions

“…To improve the efficacy of ITL using ivermectin as a complementary malaria vector control tool, it will be necessary to identify the suitable ivermectin dose to inject for each species, and to improve the persistence of its effect through the use of long-lasting technologies, as already discussed [33, 54]. Increasing efficacy of the approach also resides in timely interventions, notably at the start of the rainy season when mosquito populations are only starting to build up [52].…”

“…Mosquito blood-feeding bioassays were performed as previously described [32,33]. Briefly, three to five-day-old female An.…”

Preferences of Patients and Providers in High-Burden Malaria Settings for Long-Acting Malaria Chemoprevention

“… 19 For small molecule drugs, the predominant focus has been on the development of injectable formulations analogous to those recently approved for HIV treatment and prevention, which provide long periods of drug exposure by reducing the absorption rate to extend the half-life. This has included the development of novel drugs optimized for low solubility and high metabolic stability, 20 but new drug development and approval can take more than a decade for products to reach patients, if they do at all. The repurposing of an existing drug from an oral to an injectable format faces fewer regulatory barriers because the existing drug safety is already well understood.…”