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.IMPORTANCEMalaria remains a devastating global disease. Chemo-attenuated sporozoite vaccines show promise, yet safety concerns persist as current drugs target only liver- or blood-stage parasites. Here, we found nitroquine (CI-679) has a potentially favorable safety profile because of its dual liver- and blood-stage activity, and a single vaccination with CI-679-attenuated P. berghei sporozoites conferred robust protection against sporozoite challenge in BALB/c mice. Mechanistically, protection was associated with IL-15-mediated parasite-specific CD8+ tissue-resident memory (Trm) cells. Notably, the supplement of IL-15/IL-15Ra sushi complex remarkably increased Trm frequency and enhanced protective efficacy. Therefore, we characterize a novel chemo-attenuated sporozoite vaccine and provide mechanistic evidence supporting IL-15 as an adjuvant for pre-erythrocytic stage vaccines.