Quantitative and Clinical Pharmacology Perspectives on Next‐Generation Malaria Prevention Using Vaccines and Long‐Acting Monoclonal Antibodies

ABSTRACT

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.