High-resolution antibody dynamics following influenza vaccination reveal predominantly weak responses as well as infrequent but durable immunity across the 2014-2022 seasons.

Most influenza vaccine studies evaluate acute antibody responses 1 month post-vaccination, yet the finer details of immune kinetics remain poorly understood. Here, we conducted two new vaccine studies and analyzed 12 prior vaccine studies to map antibody responses against H3N2 and H1N1 influenza in high resolution from the day of vaccine administration out to 1 year post-vaccination. Antibody kinetics corresponded to three major phenotypes, namely, weak (<4x fold-change at 1 month and 1 year), transient (≥4x at 1 month, <4x at 1 year), or durable (≥4x at 1 month and 1 year). Surprisingly, ≥50 % of vaccine recipients were weak across nearly all seasons, age groups, sexes, pre-vaccination titers, and high or standard vaccine doses examined. Peak fold-change at 1 month post-vaccination was strongly associated with the long-term response, with transient responders often achieving a peak fold-change of 4x and then decaying back to baseline, while durable responders reached ≥16x fold-change and maintained comparable titers out to 1 year. Using the weak, transient, and durable trajectories, a single time point early in the response (days 7-8 or 21) predicted an individual's response out to 1 year post-vaccination. These results highlight the stark heterogeneity that is consistently seen across influenza seasons, where the vaccine elicits little-to-no response in some but strong and long-lasting antibody immunity in others.