Background: Antibody responses to influenza A viruses are strongly focused on immunodominant antigenic sites within the haemagglutinin (HA) head domain. Although immunodominance hierarchies have been described for H1 and H3 subtypes in adults, it remains unclear whether these patterns are shaped by first early-life exposure or by cumulative influenza infections or vaccinations over time.

Methods: We evaluated HA antigenic site immunodominance using haemagglutination inhibition (HI) assays with panels of H1 and H3 mutant viruses lacking individual classical antigenic sites. Sera from two human cohorts with different exposure histories were analysed: adults from New York City with mixed exposures through vaccination and infection, as well as children and adults living in rural Zambia exposed only through infection. Analyses of children with presumed first exposure were conducted to assess how initial influenza exposure shapes immunodominance hierarchies.

Findings: Across both cohorts, H1-specific antibody responses were consistently dominated by antigenic sites Sb and Ca2, regardless of age, geography, or exposure history. For H3, sites A and B shared immunodominance. The first influenza A infection in children was associated with the establishment of these hierarchies. Importantly, influenza B infection did not alter the immunodominance profiles of influenza A H1 or H3 haemagglutinin.

Interpretation: Immunodominance hierarchies of influenza A haemagglutinin antigenic sites are established early in life following first exposure and appear not to be substantially affected by diverse exposure histories.