Historic 1994 influenza vaccine cohorts define breadth of antibody and B cell responses toward future influenza A and B viruses

Vaccination is the best way to combat annual influenza epidemics, yet the breadth of vaccine-induced humoral immunity toward decades of future differentially evolving influenza A (IAV) and influenza B (IBV) viruses is unclear. Using historic 1994 influenza vaccination cohorts of young and older adults, we defined antibody responses elicited by 1994 vaccination against future influenza strains spanning three decades of differentially evolving IAV and IBV strains. Quality of antibody responses and vaccine-induced and cross-reactive B cell memory responses were investigated. Vaccination increased antibody titers against all 1994 vaccine components in younger and older adults. Antibodies to future H1N1 strains were also detected across younger and older adults, including nonneutralizing hemagglutinin (HA) stem responses. Prominent boosting against earlier B/Yamagata/16/1988 and future Yamagata lineage strains was also observed, but antibody responses toward future rapidly evolving H3N2 strains were minimal. Systems serology revealed divergent antibody signatures between younger and older adults against future antigens. However, postvaccination responses were of high quality in both age groups. Cross-reactive HA-specific memory B cells induced by 1994 vaccination bound to vaccine and future H1 and IBV strains but exhibited minimal responses against H3. Group 1 cross-reactive H1/H5 stalk-specific responses also contributed to the overall H1 future response, whereas cross-reactive H3/H7 stalk-specific B cells were not detected. Our study provides insights into the breadth of vaccine-induced humoral immunity toward future influenza viruses over 30 years of influenza virus evolution, including newly emerging pandemic strains, and highlights the unmet need to optimize future vaccines strategies, especially for H3N2.