Quantitative and Clinical Pharmacology Perspectives on Next-Generation Malaria Prevention Using Vaccines and...

Malaria remains a significant global health burden, particularly among pediatric populations in endemic regions. Recent advances in preventive interventions highlight the complementary roles of vaccines and long-acting monoclonal antibodies (mAbs) in reducing infection risk. Vaccines such as RTS,S/AS01 and R21/Matrix-M induce active immunity through polyclonal antibody and CD4⁺ T-cell responses against the circumsporozoite protein (CSP), providing durable, population-level protection. In contrast, mAbs including CIS43LS and L9LS confer immediate, passive immunity, with protection directly linked to systemic exposure and duration above protective thresholds. Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling and physiologically based pharmacokinetic (PBPK) approaches are central to optimizing these interventions. Population PK models, combined with controlled human malaria infection (CHMI) studies, enable model-informed selection of dose, route, and timing to achieve efficacious exposures, while PBPK models facilitate extrapolation to pediatric and special populations by incorporating developmental physiology, protein turnover, and FcRn-mediated recycling. Clinical studies demonstrate robust protection from both vaccines and mAbs, supporting complementary combination strategies. Forward-looking approaches integrate vaccines and long-acting mAbs to leverage broad, durable immunity from vaccines and immediate, predictable protection from antibodies, particularly during seasonal peaks or in high-risk groups. This review emphasizes how quantitative PK/PD and PBPK modeling provide a framework to optimize dosing, predict durability of protection, and guide clinical development across diverse populations. These strategies underscore the value of model-informed translational pharmacology in accelerating development of next-generation malaria preventive interventions against malaria.