A major limitation on the development of a malaria vaccine is the lack of validated T cell epitope targets. Plasmodium falciparum is the most prevalent malaria parasite affecting humans in Africa, whereas Plasmodium vivax is more widespread and is the main species that causes malaria in the Americas and Asia¹. P. vivax exclusively infects peripheral-blood reticulocytes, which retain RNA and the capacity for host protein synthesis². We previously reported that reticulocytes infected with P. vivax express human leukocyte antigen class I (HLA-I), which enables recognition and killing of the parasite by CD8⁺ T cells³. Here we use immunopeptidomics to identify Plasmodium-antigen-derived peptides presented by HLA-I on infected reticulocytes. We identified 453 unique peptides, mapping to 166 proteins. Seventy-five antigens were housekeeping proteins that are constitutively expressed at multiple stages of the parasite’s life cycle and are highly conserved between Plasmodium species. Identical peptides were presented in different individuals by the same or distinct HLA-A, HLA-B and HLA-C alleles, as well as by the non-classical HLA-E allele. The antigenicity of the newly identified epitopes was validated in samples from both P. vivax-infected and P. falciparum-infected individuals. Furthermore, T cell responses to several of these antigens were observed in the blood and liver of non-human primates after infection with Plasmodium or immunization with attenuated parasites. Two antigens also induced protective CD8⁺ T cell-mediated immunity in rodents. Thus, these antigens have the potential for use in a cross-stage and cross-species malaria vaccine.

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