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

Abstract

<i>Plasmodium falciparum</i> 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 <i>P. berghei</i> 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 <i>P. falciparum</i> liver merozoites, and conservation of PMIX/X active sites supports pan-<i>Plasmodium</i> potential for preventing malaria. CALM vaccination merits clinical evaluation, including by natural mosquito exposure if long-acting injectable PMIX/X inhibitor formulations prove feasible.