biostudies-literatureAbt ERHHS | NIH | National Cancer InstituteNCI NIH HHSHHS | NIH | National Cancer Institute (NCI)California HIV/AIDS Research ProgramCalifornia HIV/AIDS Research Program (CHRP)e2406332121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11626164biostudies-literatureUnknown121(49)Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cProceedings of the National Academy of Sciences of the United States of AmericaStaggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire.PMC11626164H22BD4466R01 CA2505291R01CA250529-01A1T32 CA009120Cheng DArumugaswami VJeyachandran AVBurton Sojo GTran WLam AKNoguchi MComai LRashid KTeng PLMcLaughlin JTam YKNesterenko PACreech ALHenley JEPardi NWitte ONWu TTAbt ERMao ZRadu CGfalseStaggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire.Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T c2024-01-01T00:00:00Z2024 Dec2026-06-02T04:38:14.244Z2025-04-19T14:36:30.213ZS-EPMC116261643958986910.1073/pnas.2406332121