Genetically-attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Though CVac with WT sporozoites confers better immunity, the overhanging threat of drug resistance limits its use as a vaccine. Here, we demonstrate that a liver stage-specific mutant of Plasmodium berghei when used as a vaccine under a CVac regimen provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+T-cell response through an IFN-gamma;-independent mechanism and is associated with a stable population of antigen-experienced CD8+T cells. Jointly, our findings support the benefit of liver stage mutants as vaccines over WT, under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.

中文翻译：

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疟原虫肝阶段自噬突变体的化学预防接种可提供增强的持久保护

减毒的子孢子基因疫苗可以引起对疟疾的长期保护，但具有突破性感染的风险。化学预防接种（CVac）已被证明是最有效的抗疟疾疫苗策略。尽管带有WT子孢子的CVac具有更好的免疫力，但耐药性的突出威胁限制了其作为疫苗的用途。在这里，我们证明了当在CVac方案下用作疫苗时，伯氏疟原虫的肝阶段特异性突变体与WT-CVac相比，在近交和近交小鼠中均提供了卓越的长期保护。独特地，由该突变体引起的保护主要依赖于通过IFN-γ独立机制的CD8 + T细胞应答，并且与稳定的抗原经历的CD8 + T细胞群体有关。共同，我们的发现支持在CVac协议下，肝阶段突变体作为疫苗的优势优于WT。这种疫苗接种策略也是研究保护性免疫机制并发现新的保护性抗原的有力模型。