Immunogenicity of High-Dose Egg-Based, Recombinant, and Cell Culture-Based Influenza Vaccines Compared to Standard-Dose Egg-Based Influenza Vaccine among Healthcare Personnel Aged 18-65 Years in 2019-2020

Background Emerging data suggest second-generation influenza vaccines with higher hemagglutinin (HA) antigen content and/or different production methods may induce stronger antibody responses to HA than standard-dose egg-based influenza vaccines in adults. We compared antibody responses to high-dose egg-based inactivated (HD-IIV3), recombinant (RIV4), and cell-culture based (ccIIV4), versus standard-dose egg-based inactivated influenza vaccine (SD-IIV4) among healthcare personnel (HCP) aged 18-65 years in two influenza seasons (2018-19, 2019-20). Methods In the second trial season, newly and re-enrolled HCPs who received SD-IIV4 in season one were randomized to receive RIV4, ccIIV4, or SD-IIV4 or were enrolled in an off-label, non-randomized arm to receive HD-IIV3. Pre-vaccination and one month post-vaccination sera were tested by hemagglutination inhibition (HI) assay against four cell-culture propagated vaccine reference viruses. Primary outcomes, adjusted for study site and baseline HI titer, were seroconversion rate (SCR), geometric mean titers (GMTs), mean fold rise (MFR), and GMT ratios that compared vaccine groups to SD-IIV4. Results Among 390 HCP in the per protocol population, 79 received HD-IIV3, 103 RIV4, 106 ccIIV4, and 102 SD-IIV4. HD-IIV3 recipients had similar post-vaccination antibody titers compared with SD-IIV4 recipients, whereas RIV4 recipients had significantly higher one month post-vaccination antibody titers against vaccine reference viruses for all outcomes. Conclusions HD-IIV3 did not induce higher antibody responses than SD-IIV4, but consistent with previous studies, RIV4 was associated with higher post-vaccination antibody titers. These findings suggest that recombinant vaccines rather than vaccines with higher egg-based antigen dose may provide improved antibody responses in highly vaccinated populations.