A(H3N2)
influenza vaccine effectiveness (VE) was low during the 2016-19 seasons and varied by age. We analyzed
neutralizing antibody responses to egg- and cell-propagated A(H3N2)
vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all
vaccine-eligible age groups in 3
influenza seasons. Antibody responses to cell- versus egg-propagated
vaccine viruses were significantly reduced due to the egg-adapted changes T160K, D225G, and L194P in the
vaccine hemagglutinins.
Vaccine egg adaptation had a differential impact on antibody responses across the different age groups. Immunologically naive children immunized with egg-adapted
vaccines mostly mounted
antibodies targeting egg-adapted
epitopes, whereas those previously primed with
infection produced broader responses even when vaccinated with egg-based
vaccines. In the elderly, repeated boosts of
vaccine egg-adapted
epitopes significantly reduced antibody responses to the WT cell-grown viruses. Analysis with reverse genetic viruses suggested that the response to each egg-adapted substitution varied by age. No differences in antibody responses were observed between male and female vaccinees. Here, the combination of age-specific responses to
vaccine egg-adapted substitutions, diverse host immune priming histories, and virus antigenic drift affected antibody responses following vaccination and may have led to the low and variable VE against A(H3N2) viruses across different age groups.