Randomized Pragmatic Trial of the Comparative Effectiveness of Chicken Egg-Based Inactivated, Mammalian Cell Culture-Based Inactivated, and Recombinant Protein Quadrivalent Seasonal Influenza Vaccines in United States Military Health System Beneficiaries

BACKGROUND: Influenza is a major cause of morbidity and mortality worldwide. The Pragmatic Assessment of Influenza Vaccine Effectiveness (VE) in the Department of Defense (PAIVED) study compared the relative VE (rVE) of 2 licensed influenza vaccines (cell culture-based inactivated influenza vaccine [ccIIV] and recombinant influenza vaccine [RIV]) to egg-based inactivated influenza vaccine (eIIV). METHODS: Between 2018 and 2021, PAIVED randomized (1:1:1) eligible Military Health System beneficiaries to receive eIIV, ccIIV, or RIV during an influenza season. Participants received weekly surveys querying influenza-like illness (ILI); those reporting ILI completed an online symptom diary, were interviewed by research staff, and underwent nasal swab collection. Laboratory-confirmed influenza was the primary outcome. Immunogenicity assessment was conducted in a subset of participants. RESULTS: Among 15 432 participants, influenza was identified in 87/5130 (1.7%) ccIIV recipients, 79/5154 (1.5%) RIV recipients, and 69/5148 (1.3%) eIIV recipients during their season of enrollment. rVE of ccIIV compared to eIIV was -27% (95% confidence interval [CI], -73%, 8%), and rVE of RIV compared to eIIV was -14% (95% CI -58%, 17%). RIV (N = 375) recipients were more likely to seroconvert (4-fold increase) than those who received eIIV (N = 355) (A/H1N1: 49.1% vs 29.0%; A/H3N2: 71.2% vs 30.4%; B/Victoria 24.5% vs 13.8%; B/Yamagata 17.1% vs 5.4%; P < .001 for all). ccIIV (N = 357) recipients were more likely to seroconvert only against A/H3N2 compared with eIIV recipients (44.0% vs 30.4%) (P < .001). CONCLUSIONS: Significant differences in VE were not detected comparing egg-based to non-egg-based influenza vaccines, although immunogenicity differences were observed; low influenza case numbers impacted VE estimate precision. TRIAL REGISTRATION: ClinicalTrials.gov NCT03734237.