Abstract
<jats:p>Background: Ivermectin, a widely used endectocide with activity against Anopheles (An) mosquitoes, has emerged as a promising complementary tool for malaria vector control. However, currently approved oral formulations provide only short-lived plasma concentrations at mosquitocidal levels, thereby limiting their operational impact. To overcome this limitation, a long-acting injectable formulation based on ivermectin and BEPO technology (mdc-STM-001) was selected through laboratory screening using mosquito colonies. This formulation demonstrated mosquitocidal efficacy meeting WHO criteria, with a hazard ratio (HR) >4 maintained for at least two months. The present study aims to further characterize the efficacy of ivermectin under robust field conditions and to expand susceptibility assessments to wild Anopheles populations representing different species and vectorial status. Ivermectin was tested in cattle at two doses under field conditions using experimental huts and tent traps. Plasma drug levels were also monitored to characterize the pharmacokinetic profile of ivermectin. Methods: Thirty-six calves were involved in the study and allocated to three groups (n = 12 per group). The mdc-STM-1.0 group received a single subcutaneous injection of the long-acting ivermectin formulation mdc-STM-001 at a dose of 1.0 mg/kg; the mdc-STM-1.5 group received the same formulation at 1.5 mg/kg and the third group served as controls. Using a three-arm design, cattle from each treatment group were simultaneously exposed to mosquitoes in experimental huts and tent traps, following a Greco-Latin Square rotation to minimize positional confounding factors. Pharmacokinetic data were collected to assess ivermectin release from the subcutaneous depot. Correlations between plasma ivermectin concentrations and mosquito mortality were explored, and survival analysis including Kaplan-Meier and cox proportional hazards models were performed to assess the effect of treatment on mosquito survival. Results: The mdc-STM-001 formulation was well tolerated and produced sustained, dose-dependent plasma ivermectin concentrations, with detectable levels maintained for more than 90 days after a single administration. Both doses induced strong mosquitocidal activity against wild Anopheles, with hazard ratios reaching 8.03 and 16.47 for the 1.0 and 1.5 mg/kg doses, respectively. An. funestus and An. rufipes were the most susceptible species (LC50: 5.1-6.9 ng/mL) exhibiting prolonged LC50 coverage (>75 days), whereas An. coustani was less susceptible (LC50: 12.4-19.2 ng/mL) resulting in a shorter duration of effective coverage (17-41 days). Conclusions: Taken together, our results revealed the potential of the mdc-STM-001 long-acting ivermectin formulation as an effective endectocide against residual malaria transmission by primary and secondary vectors and establish evidence basis to support its progression to early-phase clinical trials in humans. Keywords: Ivermectin, long-acting formulation, Anopheles, primary and secondary vectors, mortality, residual malaria, Burkina Faso</jats:p>