Multi-epitope mRNA Malaria Vaccine for Liver-Stage Specific CD8+ T Cells 3136

Description Plasmodium sporozoites progress through a short obligate liver-stage, representing a critical period for vaccine targeting, prior to blood-stage infection. Malaria-specific liver tissue resident memory CD8 T cells (Trm) are critical for sterilizing immunity in mouse models of vaccination. However, the generation of liver Trm in humans remains a substantial challenge. In malaria naïve humans, multiple IV doses of radiation attenuated sporozoites (RAS) result in long-lasting sterilizing immunity. Recently, we showed that a single dose of RAS can serve as the initial priming step in a single epitope-specific prime-boost strategy of murine vaccination. The literature also suggests that CD4-derived IL-21 can contribute to the differentiation of CD8 T cells into liver-Trm. Here, we apply priming of CB6F1 mice with a low dose of RAS and boosting with recombinant Listeria monocytogenes expressing multiple malaria epitopes to generate CD8 T cell responses that can reduce liver parasite burden. To address a translationally relevant approach, RAS-primed mice were boosted with a multi-epitope malaria LNP mRNA vaccine both intravenously and intramuscularly to induce immunity. We also investigated how the addition of unconjugated aGC or a synthetic analogue 7DW8-5 to the mRNA vaccine can significantly reduce liver parasite burden and impact CD8 T cell responses. These results describe modifications of conventional RAS vaccination that address limitations of these vaccines.