Influenza vaccine-specific CD4⁺ T cell responses are impaired in older adults

Immune defenses decline with age, increasing susceptibility to influenza. Vaccination remains the most effective strategy to prevent severe disease and death, but its efficacy is reduced in older adults, particularly against influenza A(H3N2). The mechanisms underlying this age-related decline in vaccine-specific antibody responses remain unclear. We investigated the magnitude and quality of influenza-specific T-cell responses following quadrivalent inactivated influenza vaccination in adults aged under (n = 100) or over (n = 120) 65 years. Frequencies of T cells specific to influenza A (H1N1, H3N2) and influenza B (Victoria, Yamagata) strains were measured before and after vaccination. Polyfunctionality of vaccine-induced CD4⁺ and CD8⁺ T cells and immune ageing markers were assessed in a subset of responders (n = 34). Older adults exhibited significantly reduced H3N2-specific CD4⁺ T-cell frequencies (P = 0.01) and polyfunctionality (P = 0.04), which correlated with lower H3N2 hemagglutination inhibition antibody titers (r = 0.42, P = 0.008). Cytomegalovirus seropositivity was associated with diminished influenza-specific CD8⁺ T-cell responses in the older age group (P = 0.01). These findings demonstrate quantitative and qualitative deficiencies in influenza-specific memory T cells with ageing, which may contribute to impaired humoral responses, particularly against H3N2. This highlights the need for vaccines that more effectively enhance cellular immunity in older adults, potentially through improved H3N2 antigen design or alternative vaccine platforms.