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These limitations highlight the importance of developing next\u2010generation vaccines that can induce strong tissue\u2010specific and systemic immune responses. Cytomegalovirus (CMV) represents a promising vaccine vector due to its ability to elicit robust and durable immunity. In this study, we generated murine CMV (MCMV)\u2010based vaccine vectors expressing the SARS\u2010CoV\u20102 spike (S) protein using either a wild\u2010type or immunologically attenuated viral strain. By comparing intraperitoneal (IP) and intranasal (IN) immunization with both MCMV vectors, we show that IP administration induced higher, long\u2010lasting S\u2010specific antibody levels in serum. Both routes elicited strong systemic S\u2010specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses; however, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses induced by different immunization routes differed notably in their kinetics and phenotype. Importantly, IN immunization with recombinant MCMV vector expressing NKG2D ligand, RAE\u20101\u03b3, resulted in a robust accumulation of lung\u2010resident S\u2010specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, surpassing even the levels induced by licensed COVID\u201019 vaccines. Overall, we demonstrate the potential of CMV\u2010based vector vaccines to fine\u2010tune immune responses by combining vector design with the route of delivery. By leveraging these variables, it is possible to influence both the magnitude and the quality of the immunity induced.\n                  <\/jats:p>","DOI":"10.1002\/eji.70146","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T09:28:32Z","timestamp":1770370112000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytomegalovirus\u2010Based Viral Vectors Elicit Robust Systemic and Tissue\u2010Resident Immune Response Against SARS\u2010CoV\u20102 Antigens"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9335-8700","authenticated-orcid":false,"given":"Maja","family":"Cokari\u0107 Brdov\u010dak","sequence":"first","affiliation":[{"name":"Center For Proteomics, Faculty of Medicine University of Rijeka  Rijeka Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"Materljan 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Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-8426","authenticated-orcid":false,"given":"Magdalena","family":"Medved","sequence":"additional","affiliation":[{"name":"Center For Proteomics, Faculty of Medicine University of Rijeka  Rijeka Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Ga\u0107ina","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine University of Rijeka  Rijeka Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina","family":"Ru\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Center For Proteomics, Faculty of Medicine University of Rijeka  Rijeka 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