Historic 1994 influenza vaccine cohorts reveal breadth of antibody and B cell responses towards three decades of future influenza A and B viruses

Influenza vaccination is the best way to combat annual influenza epidemics, yet the breadth of vaccine-induced humoral immunity towards decades of future differentially-evolving influenza A and B 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 influenza A (FLUAV) and B (FLUBV) viruses. Quality of antibody responses together with vaccine-induced and cross-reactive B-cell memory responses were investigated. Vaccination increased antibody titers against all 1994 vaccine components (H1N1 A/Texas/36/1991, H3N2 A/Beijing/32/1992, Yamagata B/Panama/45/1990) in young adults, but not B/Panama/45/90 in older adults. Antibodies towards future H1N1 strains were detected across younger and older adults. Older adults, additionally displayed boosted responses towards A/Michigan/45/2015, related to the 2009 pandemic strain known to induce cross-reactive antibodies with 1918-like H1N1 viruses. Antibody responses towards future rapidly-evolving H3N2 strains were minimal. Prominent boosting against earlier B/Yamagata/16/1988 and future Yamagata-lineage strains were found across younger and older adults. Individuals who responded strongly to B/Panama/45/1990 also responded to future FLUBV strains from Yamagata and Victorian lineages. Systems serology revealed qualitative differences in antigen-antibody signatures between younger and older adults at baseline before 1994 vaccination, with serological features towards vaccine antigens overlapping post-vaccination. Older adults, however, comprised divergent antibody signatures against future antigens featuring mature IgA1 responses, while younger adults featured more naive IgM responses. To define cross-reactive B-cell responses, fluorescently-labelled recombinant HA-probes were generated for vaccine and future influenza strains. 1994 vaccination induced cross-reactive memory B-cells towards vaccine and future H1 and FLUBV strains, but minimal responses for H3. Our study provides key insights into the breadth of vaccine-induced humoral immunity towards future influenza viruses over 30-years of FLUAV and FLUBV evolution, including newly-emerging pandemic strains, and the need to optimize future vaccine strategies, especially for the rapidly-evolving H3N2.