Chemovaccination with a late-liver-stage antimalarial induces durable immunity against malaria

Plasmodium falciparum sporozoite vaccines, in which parasites are attenuated at the liver stage, provide high efficacy but require complex manufacture and intravenous administration of high sporozoite doses. We found that a single low-dose P. berghei sporozoite exposure (intravenous or mosquito bite) and treatment with a plasmepsin IX and X (PMIX/X) inhibitor, either WM382 or MK-7602, that produced "chemo-attenuated liver merozoites" (CALM) induced sterile immunity in mice for up to 21 months. Protection involved anti-circumsporozoite protein (CSP) antibodies and CD8⁺ T cells, including liver-resident memory subsets that recognized diverse antigens (SERA1, RPL6, GAP50, RNT, PHIST, S20, and RBP). WM382 also attenuated P. falciparum liver merozoites, and conservation of PMIX/X active sites supports pan-Plasmodium potential for preventing malaria. CALM vaccination merits clinical evaluation, including by natural mosquito exposure if long-acting injectable PMIX/X inhibitor formulations prove feasible.