Effect of Repeat Vaccination on Immunogenicity of Quadrivalent Cell-Culture and Recombinant Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized, Open-Label Trial

Clin Infect Dis. 2023 Feb 8;76(3):e1168-e1176. doi: 10.1093/cid/ciac683.


Background: Antibody responses to non-egg-based standard-dose cell-culture influenza vaccine (containing 15 µg hemagglutinin [HA]/component) and recombinant vaccine (containing 45 µg HA/component) during consecutive seasons have not been studied in the United States.

Methods: In a randomized trial of immunogenicity of quadrivalent influenza vaccines among healthcare personnel (HCP) aged 18-64 years over 2 consecutive seasons, HCP who received recombinant-HA influenza vaccine (RIV) or cell culture-based inactivated influenza vaccine (ccIIV) during the first season (year 1) were re-randomized the second season of 2019-2020 (year 2 [Y2]) to receive ccIIV or RIV, resulting in 4 ccIIV/RIV combinations. In Y2, hemagglutination inhibition antibody titers against reference cell-grown vaccine viruses were compared in each ccIIV/RIV group with titers among HCP randomized both seasons to receive egg-based, standard-dose inactivated influenza vaccine (IIV) using geometric mean titer (GMT) ratios of Y2 post-vaccination titers.

Results: Y2 data from 414 HCP were analyzed per protocol. Compared with 60 IIV/IIV recipients, 74 RIV/RIV and 106 ccIIV/RIV recipients showed significantly elevated GMT ratios (Bonferroni corrected P < .007) against all components except A(H3N2). Post-vaccination GMT ratios for ccIIV/ccIIV and RIV/ccIIV were not significantly elevated compared with IIV/IIV except for RIV/ccIIV against A(H1N1)pdm09.

Conclusions: In adult HCP, receipt of RIV in 2 consecutive seasons or the second season was more immunogenic than consecutive egg-based IIV for 3 of the 4 components of quadrivalent vaccine. Immunogenicity of ccIIV/ccIIV was similar to that of IIV/IIV. Differences in HA antigen content may play a role in immunogenicity of influenza vaccination in consecutive seasons.

Clinical trials registration: NCT03722589.

Keywords: Flublok Quadrivalent; Flucelvax Quadrivalent; healthcare personnel; immunogenicity; influenza vaccines.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antibodies, Viral
  • Cell Culture Techniques
  • Delivery of Health Care
  • Hemagglutination Inhibition Tests
  • Humans
  • Influenza A Virus, H1N1 Subtype*
  • Influenza A Virus, H3N2 Subtype
  • Influenza Vaccines*
  • Influenza, Human*
  • Smallpox Vaccine*
  • United States
  • Vaccination
  • Vaccines, Combined
  • Vaccines, Inactivated
  • Vaccines, Synthetic


  • Antibodies, Viral
  • Influenza Vaccines
  • Smallpox Vaccine
  • Vaccines, Combined
  • Vaccines, Inactivated
  • Vaccines, Synthetic

Associated data

  • ClinicalTrials.gov/NCT03722589