Chemovaccination with a late-liver-stage antimalarial induces durable immunity against malaria
- Ryan W. J. Steel
- Yu Cheng Chua
- Waail A. I. Abdalla
- Robyn McConville
- Amelia Ford
- Sabrina Caiazzo
- Eva Hesping
- Daniel Fernandez-Ruiz
- Lauren E. Holz
- William R. Heath
- John A. McCauley
- David B. Olsen
- Justin A. Boddey
2026-08-13
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.