Immunogenicity Trial of Egg- Versus Non-Egg-Based Influenza Vaccines Among HCP

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 and again during August-September of 2019. 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
longitudinal 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.

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.

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.

Inclusion Criteria:

- Healthcare personnel (HCP) who have direct contact with patients, including dentists
and other dental health personnel

- Enrolled in Scott & White Healthcare or Kaiser Permanente health network for at least
one month

- Aged 18-64 years

- Available and willing to participate in study follow-up through the end of the
2019-2020 influenza season (i.e. at least approximately 18 months if enrolled during
season 1 or 6 months if enrolled during season 2)

Exclusion Criteria:

- Already received an influenza vaccine during the current influenza season

- Previous hypersensitivity reaction to the study vaccines as reported by the subject

- Received any vaccine in the 4 weeks prior to the first study visit or plans to receive
a vaccine (other than influenza vaccine provided through the study protocol) in the 4
weeks following the first study visit

- Currently participating in a study that involves an experimental agent (vaccine, drug,
biologic, device, blood product, or medication), or has received an experimental agent
within 1 month prior to enrollment in this study, or expects to receive an
experimental agent during participation in this study

- Any condition that the principle investigator (PI) believes may interfere with
successful completion of the study