Immunogenicity Trial of Egg- Versus Non-Egg-Based Influenza Vaccines Among HCP
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 4

Summary: 
      This randomized, open-label trial will assess humoral and cell-mediated immune responses to
      cell culture-based and recombinant unadjuvanted quadrivalent influenza vaccines compared to
      conventional egg-based unadjuvanted quadrivalent standard dose (15µg of HA per strain)
      influenza vaccines among persons aged 18-64 years. The trial will be conducted at two sites
      in the United States during two influenza seasons (2018-19 and 2019-20). Stratified
      enrollment procedures will be used to enroll a mix of participants based on age.
    

Detailed description: 
      In year 1 of the trial (the 2018-19 Northern Hemisphere influenza season), eligible
      participants at each site will be randomized 2:2:1:1 to receive a single dose of cell
      culture-based vaccine (Flucelvax™ Quadrivalent by Seqirus, Inc., 15µg of HA per strain)
      versus recombinant vaccine (Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain)
      versus one of two standard dose egg-based vaccines (Fluzone® Quadrivalent by Sanofi Pasteur,
      15µg of HA per strain and Fluarix® Quadrivalent by GlaxoSmithKlein, 15µg of HA per strain)
      during August-September of 2018. All study vaccines are licensed for use in adults aged >18
      years in the United States. Participants will have blood collected just prior to vaccination
      and at approximately 28 days and 6 months post-vaccination (or at the end of influenza virus
      circulation as determined by available surveillance data) to evaluate humoral immune
      responses to vaccination. Additional blood will be collected from a subset of participants
      pre-vaccination and at approximately 7 days, 28 days and 6 months post-vaccination (or at the
      end of influenza virus circulation) to evaluate cell-mediated immune responses to
      vaccination. Active surveillance with mid-turbinate nasal swab collection for influenza-like
      illness (ILI) defined as new onset of cough or worsening of chronic cough within the
      preceding 7 days will be conducted during the period of influenza circulation at each study
      site. Additional blood will also be collected at 6 months post-vaccination (or at the end of
      influenza virus circulation) from participants with reverse-transcription polymerase chain
      reaction (RT-PCR)-confirmed ILI during the influenza season to evaluate cell-mediated immune
      responses to natural influenza virus infection.

      In year 1, sites will aim to enroll 864 participants (432 per site) at the start of the
      2018-19 season, including up to 200 participants (up to 100 per site) who will contribute
      additional blood at all study visits to evaluate cell-mediated immune responses to
      vaccination. Efforts will be made to retain participants enrolled in the first year of the
      study for both years of the study. Sites will also enroll additional participants at the
      start of the 2019-20 season to make up for participants who withdraw or are lost to follow-up
      prior to the start of the 2019-20 season. Both participants and study investigators will be
      aware of study arm assignments with the exception of laboratory investigators who will be
      blinded to study arm assignment until testing is completed, as appropriate.

      In year 1 , relative efficacy of single doses of study vaccines will be assessed by comparing
      immunologic responses to vaccination among participants between study arms using Fluzone®
      Quadrivalent and Fluarix® Quadrivalent as the comparator groups for participants in the
      Flucelvax™ Quadrivalent or Flublok® Quadrivalent arms. In addition, the effect of frequency
      of prior vaccination during the preceding five years on immunologic responses to vaccine will
      be evaluated in subgroup analysis. Both humoral (influenza antibody) and cell-mediated
      (influenza- specific CD4 and CD8 T cell) immune responses will be evaluated.

      In year 2 of the trial, (the 2019-20 Northern Hemisphere influenza season), participants from
      the first year of the trial who received Flucelvax™ Quadrivalent or Flublok® Quadrivalent
      will be randomized 1:1 to receive Flucelvax™ Quadrivalent or Flublok® Quadrivalent, and
      participants who received an egg-based standard-dose vaccine in year one (Fluzone®
      Quadrivalent or Fluarix Quadrivalent) will be randomized 1:1:1 to receive Flucelvax™
      Quadrivalent , Flublok® Quadrivalent , or Fluzone® Quadrivalent. In addition, both sites will
      enroll additional participants in year 2 to achieve a total of 150 participants per site
      (including participants who continue from year one plus additional newly enrolled
      participants) who received egg-based standard dose influenza vaccine during the 2018-2019
      influenza season and who will be randomized 1:1:1 to receive Flucelvax™ Quadrivalent,
      Flublok® Quadrivalent, or Fluzone® Quadrivalent in year two. The Kaiser Permanente Northwest
      site site will also enroll up to 80 new participants for a non-randomized study arm that will
      receive Fluzone® High-Dose. All study vaccines except Fluzone High-Dose are licensed for use
      in adults aged >=18 years in the United States. Fluzone High-Dose is licensed for use in
      adults aged >=64 years in the United States and will be used off-label in this trial.
      Participants will have blood collected just prior to vaccination and at approximately 28 days
      post-vaccination (or at the end of influenza virus circulation as determined by available
      surveillance data) to evaluate humoral immune responses to vaccination. Additional blood will
      be collected from a subset of participants pre-vaccination and at approximately 7 and 28 days
      post-vaccination to evaluate cell-mediated immune responses to vaccination.

      In year 2, sites will aim to retain from year 1 or newly enroll 750 participants.
    

Intervention name(s): Flublok; Flucelvax; Fluarix; Fluzone; Fluzone High-Dose
Intervention type(s): Biological; Biological; Biological; Biological; Biological
Intervention description(s): 0.5 mL intramuscular dose of Flublok; 0.5 mL intramuscular dose of Flucelvax; 0.5 mL intramuscular dose of Fluarix; 0.5 mL intramuscular dose of Fluzone; 0.5 mL intramuscular dose of Fluzone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention