Immunosenescence and cytomegalovirus-associated immune signatures on severe acute respiratory syndrome coronavirus 2...

Aging remodels antiviral immunity, yet its influence on responses to repeated mRNA vaccination is not fully defined. We evaluated humoral and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific T-cell responses in 41 adults-stratified by age (<50 vs. ≥60 years), sex, prior SARS-CoV-2 infection, and cytomegalovirus (CMV) serostatus-before 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-γ production and reduced TNF-α-associated inflammatory activity at the cohort level, older adults and males exhibited significantly lower post-boost frequencies of IFN-γ-producing CD4+ T cells. Prior SARS-CoV-2 infection was associated with attenuated CD4+ recall responses, whereas infection-naïve and female participants showed the strongest functional gains. Immunosenescence markers were associated with reduced cellular responsiveness. CMV-related immune remodeling-including higher anti-CMV IgG levels and expansions of differentiated CD8+ subsets-correlated with diminished IFN-γ 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.