Decoding the human CD4+ T cell epitope repertoire for Lassa fever virus reveals T cell-based pan-mammarenavirus vaccine candidates

Mammarenaviruses are classified into Old World and New World viruses (Old World arenaviruses [OWAs] and New World arenaviruses [NWAs]). Characterization of antigens recognized by human T cells is essential for identifying immunodominant targets, informing vaccine design, and performing immunological assessments. Here, we select the Lassa virus (LASV) as a prototype OWA to map the human CD4 T cell epitope repertoire. We then calculate conservation in different LASV lineages and other representative OWAs and NWAs and define conserved T cell epitope regions (CTERs) using Lassa as the OWA prototype and Junin as the NWA prototype. We show that these CTERs are able to broadly cross-recognize other OWA or NWA sequences. We validate our findings in humans immunized with an experimental glycoprotein complex (GPC) LASV vaccine or infected with lymphocytic choriomeningitis mammarenavirus (LCMV), as well as in the mouse model immunized with a stabilized GPC vaccine candidate. Our results on mammarenavirus-specific T cell immunity contribute to guiding the development of next-generation mammarenavirus vaccines.