A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver TRM Cell-Mediated Immunity against Malaria in Mice

Liver-resident memory CD8+ T (TRM) cells remain in and constantly patrol the liver to elicit rapid immunity upon antigen encounter and can mediate efficient protection against liver-stage Plasmodium infection. This finding has prompted the development of immunization strategies where T cells are activated in the spleen and then trapped in the liver to form TRM cells. Here, we identify PbRPL6120-127, a H2-Kb-restricted epitope from the putative 60S ribosomal protein L6 (RPL6) of Plasmodium berghei ANKA, as an optimal antigen for endogenous liver TRM cell generation and protection against malaria. A single dose vaccination targeting RPL6 provided effective and prolonged sterilizing immunity against high dose sporozoite challenges. Expressed throughout the parasite life cycle, across Plasmodium species, and highly conserved, RPL6 exhibits strong translation potential as a vaccine candidate. This is further advocated by the identification of a broadly conserved, immunogenic HLA-A∗02:01-restricted epitope in P. falciparum RPL6. [Display omitted] •The Plasmodium ribosomal protein RPL6 is expressed during liver-stage infection•RPL6 can be targeted by specific liver TRM cells for efficient parasite elimination•Prime-and-trap vaccination targeting RPL6 induces effective protection against malaria•RPL6 is highly conserved across global P. falciparum clinical isolates Valencia-Hernandez et al. identify the ribosomal protein RPL6 as a liver-stage Plasmodium antigen that can be targeted by tissue-resident memory T cell-based vaccines for efficient protection against malaria. RPL6 is highly conserved across global isolates of P. falciparum, and is thus an ideal candidate for subunit vaccination against malaria.