Cross-reactive antibody and T-cell responses after influenza virus infection in community-dwelling older adults.

Seasonal influenza virus infection is one of the main causes of morbidity and mortality in older adults. The high mutation rate of influenza virus gives rise to new variants that are antigenically different, thereby evading pre-existing immune responses. In addition, due to aging of the immune system, older adults have diminished responses to infections with novel antigens. Here, we investigated longitudinal influenza virus-specific humoral and cellular responses in a cohort of community-dwelling older adults after influenza virus infection in the 2014/15 flu season in the Netherlands, a season hallmarked by vaccine mismatch. Moreover, we assessed the effect of vaccination on these responses and potential cross-reactivity. Hemagglutination inhibition assays revealed that antibodies against both vaccine and circulating strains increased 2 weeks after infection, regardless of vaccination status, indicating cross-reactivity. Although infection alone was capable of inducing antibodies, prior vaccination further increased titers. Peripheral blood mononuclear cell (PBMC) stimulation with hemagglutinin-peptide pools of circulating and vaccine strains showed induction of strain-specific T-cell responses after infection in IFN-γ ELISpots. At each timepoint, T-cell responses were similar between individuals vaccinated prior to infection and unvaccinated individuals. However, the increase in influenza virus-specific T-cell responses from 72 h to 2 weeks post-infection seemed stronger in individuals vaccinated before infection. Moreover, despite mismatch between vaccine and circulating strains, T-cell cross-reactivity was observed, albeit less pronounced than the antibody response. Overall, our study shows that community-dwelling older adults with influenza virus infection are capable of inducing virus-specific immune responses with cross-reactive potential, and vaccination further enhances these responses. IMPORTANCE: The older population is at increased risk for severe influenza virus infection due to age-related impaired immune responses to novel antigens. Consequently, older adults rely more on previously formed cross-reactive memory responses compared to younger adults. In this study, we longitudinally investigated the influenza virus-specific antibody response as well as the virus-specific T-cell response in community-dwelling older adults after influenza virus infection. We demonstrate that, despite higher age, this group of older adults was capable of inducing influenza virus-specific antibody and T-cell responses. Moreover, receiving vaccination prior to infection further increased these immune responses. Importantly, individuals mounted antibody and T-cell responses to several different influenza virus strains, indicating cross-reactivity at both levels, despite mismatch between vaccine and infection strains. Unraveling the immune responses to influenza virus infection in older adults could inform new vaccine developments and strategies that may better protect the vulnerable older population from infection.