{"doi":"10.1073/pnas.2406332121","title":"Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire","abstract":"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 cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":458865,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":511627,"name":"Alex K. Lam","orcid":"0000-0003-2879-719X","position":1,"is_corresponding":false},{"id":928255,"name":"Miyako Noguchi","orcid":null,"position":2,"is_corresponding":false},{"id":724666,"name":"Khalid Rashid","orcid":"0000-0002-5070-8010","position":3,"is_corresponding":false},{"id":745427,"name":"Jami McLaughlin","orcid":null,"position":4,"is_corresponding":false},{"id":1114934,"name":"Pu-Lin Teng","orcid":null,"position":5,"is_corresponding":false},{"id":927761,"name":"Wendy Tran","orcid":"0000-0002-7851-4859","position":6,"is_corresponding":false},{"id":306324,"name":"Donghui Cheng","orcid":null,"position":7,"is_corresponding":false},{"id":744765,"name":"Pavlo A. Nesterenko","orcid":"0000-0001-9841-8170","position":8,"is_corresponding":false},{"id":744767,"name":"Zhiyuan Mao","orcid":"0000-0003-1817-5469","position":9,"is_corresponding":false},{"id":75576,"name":"Amanda L. Creech","orcid":"0000-0002-8341-1213","position":10,"is_corresponding":false},{"id":745428,"name":"Giselle Burton Sojo","orcid":null,"position":11,"is_corresponding":false},{"id":869247,"name":"Arjit Vijey Jeyachandran","orcid":null,"position":12,"is_corresponding":false},{"id":54908,"name":"Ying K. Tam","orcid":"0000-0002-4083-5251","position":13,"is_corresponding":false},{"id":631179,"name":"Jill Henley","orcid":null,"position":14,"is_corresponding":false},{"id":432453,"name":"Lucio Comai","orcid":"0000-0003-3109-1841","position":15,"is_corresponding":false},{"id":54904,"name":"Norbert Pardi","orcid":"0000-0003-1008-6242","position":16,"is_corresponding":false},{"id":232372,"name":"Vaithilingaraja Arumugaswami","orcid":"0000-0002-6872-5118","position":17,"is_corresponding":false},{"id":304228,"name":"Owen N. Witte","orcid":"0000-0003-4461-4533","position":18,"is_corresponding":false},{"id":419512,"name":"Caius G. Radu","orcid":"0000-0002-9338-5397","position":19,"is_corresponding":false},{"id":711508,"name":"Ting Wu","orcid":"0000-0002-1806-3056","position":20,"is_corresponding":false},{"id":419504,"name":"Evan R. Abt","orcid":"0000-0002-3160-7134","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39589869","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}