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

• 成果类型: Article
• 署名作者: Steel, Ryan W. J.; Chua, Yu Cheng; Abdalla, Waail A. I.; McConville, Robyn; Ford, Amelia; Caiazzo, Sabrina; Hesping, Eva; Fernandez-Ruiz, Daniel; Holz, Lauren E.; Heath, William R.; McCauley, John A.; Olsen, David B.; Boddey, Justin A.
• 署名单位: Walter & Eliza Hall Institute; University of Melbourne; University of Melbourne; Peter Doherty Institute; University of New South Wales Sydney; Merck & Company; Merck & Company USA; Flinders University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aea7605
• 发表日期: 2026-08-13
• 页码: eaea7605
• 关键词: PLASMODIUM-FALCIPARUM PARASITE; t-cells; PROTECTIVE IMMUNITY; HOST HEPATOCYTES; PLASMEPSINS IX; vaccination; immunization; SPOROZOITES; efficacy; protein

摘要

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.