(1) Background: The influenza virus continues to cause significant annual morbidity and mortality. The overall efficacy of seasonal
influenza vaccination is suboptimal, which is partly due to host
immune factors. The effects of imprinting and repeated seasonal
influenza vaccination were investigated to assess for
immune factors and mechanisms that impact
influenza vaccine responses. (2) Methods: Twenty participants were enrolled into a prospective pilot study based on birth cohort and seasonal
influenza immunization history. Immunologic parameters were assessed over a six-month period after the seasonal
influenza vaccine was administered. (3) Results: There was no significant imprinting effect, as measured by hemagglutination inhibition (HAI) fold change, HAI geometric mean titer (GMT) for Day 29 or Day 180 post-vaccination and
antigen- specific antibody-secreting cells (ASC) for Day 8 post-vaccination. Individuals who had minimal prior seasonal
influenza vaccination had a higher magnitude ASC response and a higher HAI fold change post-vaccination than individuals who were repeatedly vaccinated. (4) Conclusions: Repeated seasonal
influenza vaccination resulted in a decreased fold change of the immune response, although individuals in this cohort tended to have high HAI titers at baseline that persisted after vaccination. Imprinting effects were not observed in this cohort. These host
immune factors should be considered in the development of
universal influenza vaccines. ClinicalTrials.gov Identifier: NCT03686514.