Life course exposures continually shape antibody profile and risk of seroconversion to influenza

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest variation. Higher pre-existing, homologous titers reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion among those with higher immunity to older previously exposed strains. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza.