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 21,373 hemagglutination inhibition and neutralization titers from 4,453 participants enrolled in 14 new vaccine studies we conducted and 50 prior studies that collectively span 2010-2023. Seasonality, age, vaccine brand, and pre-vaccination antibody titers were the largest and most consistent modifier of post-vaccination titers, outweighing the influence of sex, passaging, or vaccination history. Titers to B Yamagata remained steady throughout all years examined, suggesting unique durability and a potential 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 significantly enhanced the response to inactivated vaccines during the following season in 53% or 67% of cohorts, respectively, whereas high-dose vaccines increased post-vaccination titers after adjusting for age and seasonality. These findings quantify how age shapes the influenza antibody responses in unprecedented resolution, identify vaccine timing and seasonal context as underrecognized drivers of immunogenicity, and provide actionable insights for optimizing influenza vaccination strategies.