Sex differences in antibody responses to influenza A/H3N2 across the life course

Sex differences in both innate and adaptive immunity are increasingly recognized as shaping responses to a range of pathogens. For antigenically variable pathogens that infect people many times over their lifetime, like influenza, sex differences may accumulate or be obscured by the interplay of immunity derived from each infection and future risk. However, sex-specific lifetime trajectories of influenza immunity are poorly characterized. Here, we analyzed hemagglutination inhibition antibody titers to multiple strains of influenza A/H3N2, measured in individuals spanning a wide age range to disentangle strain-specific and cross-reactive antibody responses by sex. To account for potential differences in exposure, we separately analyzed antibody titers to: (1) viruses circulating during an individual's lifetime, and (2) viruses isolated before birth (pre-birth) or after sampling, with responses to the latter interpreted as exclusively cross-reactive, given the absence of possible exposure to these strains. We found that females aged 15 to 40 generally have higher antibody titers than males against pre-birth and post-sampling strains, consistent with greater cross-reactivity. Conversely, older males have stronger responses to strains that they could have encountered during their lives, suggesting that they mount stronger responses upon infection.