Abstract Background Pre-existing immunity to emerging influenza viruses informs pandemic risk assessment. We compared cross-reactive neuraminidase (NA) antibody levels against avian influenza A(H5N1) by age and birth (imprinting) cohorts defined by periods of human influenza A subtype (H1N1, H2N2 or H3N2) circulation over the past century. Methods We used anonymized, residual sera collected from ten age groups spanning one to 80 years during an August 2024 cross-sectional serosurvey conducted in British Columbia, Canada. We assessed NA inhibition antibody titres by enzyme-linked lectin assay against clade 2.3.4.4b H5N1, and 2009 H1N1pdm09 and 1968 H3N2 pandemic strains Results Among 575 participants with median age 32 (IQR: 15-62) years, 404 (70%) had detectable anti-N1 titres 10 against H5N1, with 260 (45%), 182 (32%) and 98 (17%) having titres 40, 80 and 160, respectively. Anti-N1 titres against 2009 H1N1pdm09 and H5N1 were strongly correlated (r=0.86; 95%CI: 0.82-0.89), with both highest among young adults born 1997-2003 who were school-aged children during the 2009 H1N1 pandemic (427.9, 100.8), lowest among the youngest and least influenza-experienced pediatric cohorts born 2015-2023 (20.7, 6.8) and middle-aged adults born during the 1957-1967 H2N2 era (25.1, 10.7), thereafter increasing toward a similar secondary peak among the oldest cohorts born during the pre-1947 H1N1 era (387.3, 81.0). Conclusions A substantial proportion of the population has pre-existing anti-N1 against H5N1, with age-related variation reflecting H1N1 imprinting and exposure opportunities. Through heightened attack rates and shifts in immunological hierarchies, historic pandemics shape and expand the immune repertoire with implications for pre-immunity to emerging zoonotic threats.
Skowronski et al. (2026) studied this question.