Cross-reactive H5N1 Neuraminidase Antibodies by Age and Influenza A Imprinting Cohorts of the Past Century: Population-Based Serosurvey, British Columbia, Canada.

BACKGROUND: Preexisting immunity to emerging influenza viruses informs pandemic risk assessment. We compared cross-reactive neuraminidase 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 10 age groups spanning 1 to >80 years during an August 2024 cross-sectional serosurvey conducted in British Columbia, Canada. We assessed neuraminidase inhibition antibody titers 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 a median age of 32 years (IQR, 15-62), 404 (70%) had detectable anti-N1 titers ≥10 against H5N1, with 260 (45%), 182 (32%), and 98 (17%) having titers ≥40, ≥80, and ≥160, respectively. Anti-N1 titers against 2009-H1N1pdm09 and H5N1 were strongly correlated (r = 0.86; 95% CI, .82-.89): highest among young adults born 1997 to 2003 who were school-aged children during the 2009 H1N1 pandemic (427.9, 100.8); lowest among the least influenza-experienced pediatric cohorts born 2015 to 2023 (20.7, 6.8) and middle-aged adults born during the 1957-1967 H2N2 era (25.1, 10.7); 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 preexisting anti-N1 against H5N1, with age-related variation reflecting H1N1 imprinting and exposure opportunities. Through heightened attack rates and shifts in immunologic hierarchies, historical pandemics shape and expand the immune repertoire influencing potential preimmunity to emerging zoonotic threats.