Faster waning of immunity to influenza vaccine strains reintroduced into subsequent seasons: A human cohort study

BACKGROUND: Seasonal influenza vaccines are updated annually, and some seasons reuse strains from prior formulations. Although repeated vaccination has been associated with lower-than-expected post-vaccination titers, whether it alters immune durability remains unclear. We compared strain-specific waning rates across seasons in which vaccine formulations shared one or more strains. METHODS: We analyzed hemagglutination inhibition (HAI) titers from a longitudinal vaccine cohort (2016-2023). For strains reused across seasons, we compared waning rate from season i to i + 1 (initial waning period) with waning from i + 1 to i + 2 (second waning period). Mixed-effects models estimated differences in strain-specific waning between periods, adjusting for age, BMI, previous vaccination in season i - 1, and other covariates. RESULTS: Seven vaccine strains were reused across seasons (768 strain-specific measurements from 275 participants). The B lineage strain Phu/13 appeared in all seasons. Across repeatedly used subtype A and lineage B viruses, antibody levels waned significantly faster after subsequent vaccination. Among adults, the average increase in waning rate during the second period was 0.011 (H1N1), 0.108 (H3N2), 0.056 (Yamagata), and 0.049 (Victoria) log2 titer per month. Age modified these relationships, with slower waning in older adults for H1N1 and in teenagers for Yamagata. Waning also varied by strains, with BR08 waning faster than WA19. Higher pre-vaccination titers were associated with slower waning for H1N1 and H3N2, whereas larger post-vaccination boosts predicted faster waning for all virus strains. CONCLUSIONS: We found that the waning rates of certain vaccine strains may differ between initial and subsequent waning periods. Further investigation is warranted to optimize annual influenza vaccine composition updates.