Modelling the impact of ivermectin-based optimal strategies on malaria control: the role of formulation, coverage, and mosquitocidal efficacy timing

BACKGROUND: Despite wide use of insecticidal nets and indoor spraying, residual malaria transmission persists due to insecticide resistance and mosquito behaviours like early and outdoor biting. Ivermectin (IVM) can kill mosquitoes after blood feeding, regardless of the timing or location of the bite. However, oral IVM's short efficacy duration and required frequent dosing limits epidemiological impact. Using mosquitocidal efficacy data from a long-acting injectable IVM formulation (BEPO® technology), we modelled its effect on malaria transmission, comparing it with oral regimens evaluated in the fields. METHODS: We developed a mathematical model incorporating IVM's pharmacodynamic persistence and stratifying humans by age and sex. Three regimens were evaluated: (i) monthly oral IVM at 3 × 300 μg/kg for 4 months, (ii) monthly oral IVM at 1 × 400 μg/kg for 3 months, and (iii) long-acting BEPO® injection at 0.6 or 1.0 mg/kg. The model includes post-exposure effects on mosquitoes and the target population excludes women of childbearing age or pregnant women, and children under 15 kg. Mosquitocidal efficacy data were derived from published human oral studies and from preclinical studies in livestock (cattle) for injectable formulations. FINDINGS: Campaigns delivering ivermectin are projected to lower clinical prevalence, with slightly greater benefits in Burkina Faso-like seasonal settings when aligned with the transmission peak. Under perennial transmission and 50-90% target population coverage, oral regimens reduced total cases (all ages) by 7-11%, 9-14%, and 24-38% over one year, depending on the regimen and the data source. A single long-acting injectable IVM campaign achieved 16-29%, rising to 33-57%, 48-74%, and 59-78% with two, three, and four campaigns, respectively. INTERPRETATION: Long-acting injectable ivermectin offers increased and sustained efficacy and simpler delivery to tackle residual malaria transmission. Phase 1 trials are timely and warranted. FUNDING: The African Consortium in Modelling for Effective Vector Control (ACoMVeC) project INV-047049, IMPACT (Unitaid) and Institut de Recherche pour le Développement (IRD).