Abstract

The role of humoral immunity on the efficacy of artemisinin combination therapy (ACT) has not been investigated, yet naturally acquired immunity is key determinant of antimalarial therapeutic response. We conducted a therapeutic efficacy study in high transmission settings of western Kenya, which showed artesunate-mefloquine (ASMQ) and dihydroartemisinin-piperaquine (DP) were more efficacious than artemether-lumefantrine (AL). To investigate the underlying prophylactic mechanism, we compared a broad range of humoral immune responses in cohort I study participants treated with ASMQ or AL, and applied machine-learning (ML) models using immunoprofile data to analyze individual participants treatment outcome. We showed ML models could predict treatment outcome for ASMQ but no AL with high (72-92%) accuracy. Simulated PK profiling provided evidence demonstrating specific humoral immunity confers protection in the presence of sub-therapeutic residual mefloquine concentration. We concluded patient humoral immunity and partner drug interact to provide long prophylactic effect of ASMQ.