Cross-reactive neuraminidase inhibition antibodies against H5N1 by consecutive influenza A imprinting cohorts of the past century: population-based serosurvey, British Columbia, Canada

BackgroundAvian influenza of the H5N1 subtype shares substantial relatedness in its neuraminidase (NA) surface protein with human influenza A H1N1 viruses of the past century. Understanding variation in pre-existing anti-N1 antibodies against H5N1 is critical to pandemic risk assessment and preparedness. MethodsWe used anonymized, residual sera collected equally from ten age groups spanning one to >80 years during an August 2024 cross-sectional serosurvey in British Columbia, Canada. We assessed NA inhibition antibody titres by enzyme-linked lectin assay against H5N1 (N=575), H1N1pdm09 (N=250) and H3N2 (N=205). We compared anti-NA titres by birth (imprinting) cohorts defined in relation to historic N1 and/or N2 exposure opportunities. ResultsAmong participants with median age 32 (IQR: 15-62) years, 404 (70%) had cross-reactive anti-N1 titre >10 against H5N1, with 260 (45%), 182 (32%) and 98 (17%), having titres >40, >80 and >160, respectively. H5N1 titres were consistently lower but strongly associated with H1N1pdm09 (r=0.86; 95%CI:0.82-0.89). Geometric mean titres against H1N1pdm09 and H5N1 peaked among young adults born 1997-2003 (427.9, 100.8), declining to lows among young children born 2015-2023 (20.7, 6.8) and middle-aged adults born 1957-1967 (25.1, 10.7), increasing to similar secondary peak among older adults born pre-1947 (387.3, 81.0). ConclusionsA substantial proportion of the population has pre-existing, cross-reactive anti-N1 antibodies against H5N1. We interpret variation by age and imprinting cohorts within a unifying hypothesis, emphasizing the role of historic influenza pandemics in expanding and refining the immune repertoire through heightened attack rates and shifts in immunological hierarchies. Our findings have implications for H5N1 and other zoonotic influenza risk assessment.