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We evaluated humoral and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike\u2013specific T-cell responses in 41 adults\u2014stratified by age (&amp;lt;50 vs. \u226560\u2009years), sex, prior SARS-CoV-2 infection, and cytomegalovirus (CMV) serostatus\u2014before and after a fourth dose of the bivalent BNT162b2 vaccine. Anti-RBD IgG titers increased in nearly all participants, with no measurable impact of age, sex, infection history, or CMV status, and baseline titers predicted post-booster antibody levels. In contrast, cellular immunity showed clear heterogeneity across aging-related variables. Although the booster enhanced IFN-\u03b3 production and reduced TNF-\u03b1-associated inflammatory activity at the cohort level, older adults and males exhibited significantly lower post-boost frequencies of IFN-\u03b3\u2013producing CD4+ T cells. Prior SARS-CoV-2 infection was associated with attenuated CD4+ recall responses, whereas infection-na\u00efve and female participants showed the strongest functional gains. Immunosenescence markers were associated with reduced cellular responsiveness. CMV-related immune remodeling\u2014including higher anti-CMV IgG levels and expansions of differentiated CD8+ subsets\u2014correlated with diminished IFN-\u03b3 responses in CD4+ and CD8+ T cells after boosting, suggesting that chronic CMV imprinting constrains heterologous antiviral immunity even in mid-adult life. Humoral and cellular changes were largely uncoupled, supporting the need to evaluate both arms of adaptive immunity. These findings indicate that while a fourth bivalent BNT162b2 dose reliably reinforces humoral immunity across ages, the magnitude and quality of cellular responses are shaped by age, sex, infection history, and CMV-associated immunosenescence. Incorporating immune-aging markers into vaccination strategies may improve booster efficacy in older populations.<\/jats:p>","DOI":"10.1093\/gerona\/glag095","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:38:26Z","timestamp":1776339506000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2 booster responses"],"prefix":"10.1093","volume":"81","author":[{"given":"Irene","family":"Reina-Alfonso","sequence":"first","affiliation":[{"name":"University of C\u00f3rdoba Molecular Immunology Group (CTS-208), Department of Cell Biology, Physiology and Immunology, , C\u00f3rdoba,","place":["Spain"]},{"name":"Maim\u00f3nides Biomedical Research Institute of C\u00f3rdoba (IMIBIC), University of C\u00f3rdoba, Reina Sofia University Hospital Immunology and Allergy Group (GC01), , C\u00f3rdoba,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"\u00c1lvarez-Heredia","sequence":"additional","affiliation":[{"name":"Maim\u00f3nides Biomedical Research Institute of C\u00f3rdoba (IMIBIC), University of C\u00f3rdoba, Reina Sofia University Hospital Immunology and Allergy Group (GC01), , C\u00f3rdoba,","place":["Spain"]},{"name":"Anatomy Pathology Service, Hospital Nostra Senyora de Meritxell , Andorra"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel M","family":"Vallejo-Berm\u00fadez","sequence":"additional","affiliation":[{"name":"University of C\u00f3rdoba Molecular Immunology Group (CTS-208), Department of Cell Biology, Physiology and Immunology, , C\u00f3rdoba,","place":["Spain"]},{"name":"Maim\u00f3nides Biomedical Research Institute of C\u00f3rdoba (IMIBIC), University of C\u00f3rdoba, Reina Sofia University Hospital Immunology and Allergy Group (GC01), , 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