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

Steel, RWJ; Chua, YC; Abdalla, WAI; McConville, R; Ford, A; Caiazzo, S; Hesping, E; Fernandez-Ruiz, D; Holz, LE; Heath, WR; McCauley, JA; Olsen, DB; Boddey, JA

Author(s): Steel, RWJ; Chua, YC; Abdalla, WAI; McConville, R; Ford, A; Caiazzo, S; Hesping, E; Fernandez-Ruiz, D; Holz, LE; Heath, WR; McCauley, JA; Olsen, DB; Boddey, JA;
Details: Publication Year 2026-08-13,Volume 393,Issue #6812,Page eaea7605
Journal Title: Science
Publication Type: Aug 13
Abstract: 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.
Publisher: AAAS
Keywords: Animals; *Malaria Vaccines/immunology/administration & dosage; *Liver/parasitology/immunology; Mice; *Plasmodium falciparum/immunology; *Plasmodium berghei/immunology; Sporozoites/immunology; Sterilizing Immunity; *Malaria/prevention & control/immunology; Female; *Malaria, Falciparum/prevention & control/immunology; Aspartic Acid Endopeptidases/antagonists & inhibitors; CD8-Positive T-Lymphocytes/immunology; Antibodies, Protozoan/immunology/blood; Merozoites/immunology; Immunologic Memory
Research Division(s): Infection and Global Health
PubMed ID: 42594189
Publisher's Version: https://doi.org/10.1126/science.aea7605
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-08-28 10:52:08

Last Modified: 2026-08-28 10:56:27