Effect of Previous-Year Vaccination on the Efficacy, Immunogenicity, and Safety of High-Dose Inactivated Influenza Vaccine in Older Adults

High-dose inactivated influenza vaccine (IIV-HD) is an alternative to the standard-dose inactivated influenza vaccine (IIV-SD) in the United States for influenza prevention in older adults. IIV-HD improved efficacy relative to IIV-SD in a randomized controlled trial. Recent observational studies suggest that previous influenza vaccination may influence the immunogenicity and effectiveness of current-season vaccination. Methods. The original study was a double-blind, randomized trial comparing IIV-HD to IIV-SD in adults aged ≥65 years over 2 influenza seasons. A subset of year 1 (Y1) participants reenrolled in year 2 (Y2), receiving vaccine by random assignment in both years. We evaluated the effect of Y1 vaccination on Y2 relative vaccine efficacy (VE), immunogenicity (hemagglutination inhibition [HAI] titers), and safety among reenrolled participants. Results. Of 14 500 Y1 participants, 7643 reenrolled in Y2. Relative to participants who received IIV-SD both seasons, VE was higher for IIV-HD vaccinees in Y2 (28.3% overall; 25.1% for Y1 IIV-HD, Y2 IIV-HD; and 31.6% for Y1 IIV-SD, Y2 IIV-HD). In multivariate logistic regression models, Y1 vaccine was not a significant modifier of Y2 VE (P =. 43), whereas Y2 IIV-HD remained significantly associated with lower influenza risk (P =. 043). Compared to administration of IIV-SD in both years, postvaccination HAI titers were significantly higher for patterns that included IIV-HD in Y2. No safety concerns were raised with IIV-HD revaccination. Conclusions. IIV-HD is likely to provide clinical benefit over IIV-SD irrespective of previous-season vaccination with IIV-HD or IIV-SD. IIV-HD consistently improved immune responses, and no safety concerns emerged in the context of IIV-HD revaccination.