Background: For antigenically variable pathogens such as influenza, strain fitness is partly determined by the relative availability of hosts susceptible to infection with that strain compared with others. Antibodies to the hemagglutinin (HA) and neuraminidase (NA) confer substantial protection against influenza infection. We asked if a cross-sectional antibody-derived estimate of population susceptibility to different clades of influenza A (H3N2) could predict the success of clades in the following season.

Methods: We collected sera from 483 healthy individuals aged 1 to 90 years in the summer of 2017 and analyzed neutralizing responses to the HA and NA of representative strains using focus reduction neutralization tests (FNRT) and enzyme-linked lectin assays (ELLA). We estimated relative population-average and age-specific susceptibilities to circulating viral clades and compared those estimates to changes in clade frequencies in the following 2017-2018 season.

Results: The clade to which neutralizing antibody titers were lowest, indicating greater population susceptibility, dominated the next season. Titer correlations between viral strains varied by age, suggesting age-associated differences in epitope targeting driven by shared past exposures. Yet substantial unexplained variation remains within age groups.

Conclusions: This study indicates how representative measures of population immunity might improve evolutionary forecasts and inform selective pressures on influenza.