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Adv."],"published-print":{"date-parts":[[2025,11,21]]},"abstract":"<jats:p>The emergence of SARS-CoV-2 variants has challenged the current spike protein\u2013focused COVID-19 vaccine strategy due to neutralizing antibody escape and waning antibody-mediated immunity. In contrast, T cell\u2013mediated immunity targeting conserved epitopes may offer broad and long-lasting protection. However, whether T cells alone can provide sufficient protection remains unclear. Here, we identified both Omicron BA.1\u2013specific and ancestral (Wuhan)\u2013conserved CD8 T cell epitopes in the SARS-CoV-2 spike protein and evaluated them as carrier-protein fusion vaccines in mouse models. Subcutaneous immunizations with two CD8 epitope peptides substantially lowered lung viral load and conferred protection against low-dose viral challenge, but not against high-dose challenge. Notably, intranasal boosting\u2014with or without adjuvant\u2014enhanced lung resident memory T cell responses and conferred potent, durable protection against high-dose infection. These findings emphasize the importance of mucosal vaccination to boost protective T cell immunity against SARS-CoV-2 and support the potential of T cell\u2013based vaccines targeting conserved epitopes for broad immunity against SARS-CoV-2 and other respiratory viral threats.<\/jats:p>","DOI":"10.1126\/sciadv.adx0037","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T18:59:23Z","timestamp":1763751563000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Conserved CD8 T cell vaccines without B cell epitopes drive robust protection against SARS-CoV-2 that is enhanced by intranasal boost"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-9943","authenticated-orcid":true,"given":"Genghao","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0338-6053","authenticated-orcid":true,"given":"Thao","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA."},{"name":"Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0369-9067","authenticated-orcid":true,"given":"Lindsay G. 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