Modifiers of Influenza Vaccine Immunity from over Ten Years of Serological Data

Annual influenza vaccination is the cornerstone for seasonal protection, yet antibody responses are highly variable across individuals and over time. To systematically assess the determinants of this heterogeneity, we compiled 20,449 hemagglutination inhibition and neutralization titers from 4,540 participants enrolled in 14 new vaccine studies we conducted and 50 prior studies that collectively span 2010-2023. Seasonal effects dominated, with pre- and post-vaccination titers declining steadily from 2017 onwards, outweighing the influence of age, sex, or repeated vaccination. Titers to B Yamagata remained steady throughout all years examined, suggesting unique durability and offering a reason for lineage extinction. Vaccine timing emerged as a strong and previously underappreciated determinant of immunity, with individuals vaccinated later in the season exhibiting larger post-vaccination titers. Not being vaccinated or receiving the live-attenuated FluMist vaccine in one year significantly enhanced the response to inactivated vaccines in 45% or 68% of cohorts, respectively, whereas antigen dose and adjuvants had modest impact. These findings identify vaccine timing and seasonal context as underrecognized drivers of immunogenicity and provide actionable insights for optimizing influenza vaccination strategies.