The high protection of a novel chemo-attenuated sporozoite vaccine requires IL-15-mediated liver CD8 ⁺ tissue-resident memory T-cell responses

Chemo-attenuated sporozoite vaccines (SPZ-CVacs) are considered promising for malaria prevention, but safety concerns persist regarding antimalarial drugs targeting either liver- or blood-stage parasites. In this study, we found that nitroquine (CI-679), used to eliminate malaria blood-stage parasites, effectively rendered sporozoites attenuated by arresting late liver-stage development. A single vaccination with CI-679-attenuated Plasmodium berghei ( P. berghei ) sporozoites conferred robust protection against sporozoite challenge in BALB/c mice. Using mouse models with distinct genetic backgrounds, we demonstrated that the robust protection conferred by the CI-679-attenuated vaccine was primarily associated with the frequency of parasite-specific CD8 ⁺ tissue-resident memory (Trm) cells mediated by IL-15. Notably, the supplement of IL-15/IL-15Ra sushi complex remarkably increased Trm frequency and improved the protective efficacy of CI-679-attenuated vaccine. Our findings characterize a novel SPZ-CVac and provide mechanistic evidence supporting IL-15 as an adjuvant to enhance the efficacy of pre-erythrocytic stage vaccines.