Parasitological efficacy of sulfadoxine-pyrimethamine and amodiaquine for Seasonal Malaria Chemoprevention (SMC) in Africa

Abstract Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) is given to millions of African children to prevent malaria during the peak transmission season, yet the contribution of the individual drugs to preventive efficacy remains unclear. We pooled individual-level data on drug concentrations and qPCR positivity from 934 children under 5 years from three prospective studies in Uganda, Mozambique, and Burkina Faso. We used natural variation in drug exposures to estimate the concentration-protection relationships against malaria infection over one month. The concentration of desethylamodiaquine, the active amodiaquine metabolite, was the primary determinant of malaria infection (odds ratio [OR] 0.55, 95% CI 0.44–0.68 per standard deviation increase in log concentration). Children with low day 28 desethylamodiaquine exposure (<24 ng/mL) had nearly twice the risk of malaria infection compared to those with high exposure (risk ratio 1.9, 95% CI 1.5-2.4). Only weak associations were observed with sulfadoxine and pyrimethamine concentrations. Concentration-protection relationships were consistent across countries despite marked differences in parasite resistance markers. These findings suggest that the preventive efficacy of SPAQ is primarily driven by amodiaquine, highlighting the importance of adherence to the 3-day amodiaquine regimen. The contribution of single-dose sulfadoxine–pyrimethamine appears modest and merits further evaluation in randomised trials.