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 two licensed influenza vaccines (cell-culture-based inactivated influenza vaccine (ccIIV) and recombinant influenza vaccine (RIV)) to egg-based inactivated influenza vaccine (eIIV).

Methods: Between 2018-2021, PAIVED randomized (1:1:1) eligible Military Health System (MHS) 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<0.001 for all). ccIIV (N=357) recipients were more likely to seroconvert only against A/H3N2 compared to eIIV recipients (44.0% vs 30.4%) (p<0.001).

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.