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

Immune defences decline with age, rendering older adults vulnerable to infectious diseases such as influenza. Vaccination remains the most effective means of preventing severe illness and death caused by influenza, although its efficacy is diminished in older adults. Vaccine-specific antibody responses and effectiveness are generally lowest against the influenza A(H3N2) strain, and particularly in individuals over 65 years of age. The mechanisms underlying this age-related decline in vaccine responsiveness remains unclear, prompting the present investigation into the quantity and quality of influenza specific T-cell responses upon vaccination. Frequencies of T cells specific to two influenza A strains H1N1 and H3N2, and two influenza B strains Victoria and Yamagata were measured in adults before and after quadrivalent inactivated influenza vaccination, stratified by age, under (n = 100) or over (n = 120) 65 years. Polyfunctionality of vaccine induced CD4 ⁺ and CD8 ⁺ T cells and immune ageing markers were also assessed in a selection of responders (n = 34). Older individuals showed significantly reduced H3N2-specific CD4⁺ T cell frequencies ( P  = 0.003) 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 highlight both quantitative and qualitative deficiencies of influenza-specific memory T cells in older vaccinees, which could explain suboptimal humoral responses with advanced age, notably against H3N2. This underscores the need for vaccines designed to boost cellular immunity in this vulnerable population, potentially through improved H3N2 antigen design or alternative vaccine platforms promoting stronger T cell induction.EU Clinical Trials Registration2019–000836–24