Current therapies and advances in the development pipeline of pre-erythrocytic preventive drugs

Abstract

Malaria prevention remains a cornerstone strategy for reducing global mortality and morbidity. Although the two World Health Organization (WHO)-recommended pre-erythrocytic malaria vaccines, RTS,S/AS01 and R21/Matrix-M, demonstrate substantial reductions in disease burden, they exhibit only partial efficacy and fail to provide sterilizing immunity against clinical malaria. As a result, chemotherapies targeting the pre-erythrocytic stage are critical for comprehensive prevention. However, compared to erythrocytic-stage interventions, the availability of prophylactic drugs against exoerythrocytic forms (EEFs), particularly hypnozoites, is limited. Existing agents also face significant challenges from drug-resistant Plasmodium strains, which compromise clinical efficacy. Therefore, there is an urgent need for pre-erythrocytic prophylactics to complement or replace current preventive chemotherapy regimens. In this review, we comprehensively summarize recent advances in the development of pre-erythrocytic prophylactic drugs and outline target product profiles for next-generation agents. We also discuss strategies to expand the repertoire of preventive chemotherapy and describe successful discovery paradigms for compounds targeting the pre-erythrocytic stage.