This randomized, active comparator trial will compare the clinical efficacy of
recombinant influenza vaccine (RIV) to standard-dose egg-based inactivated influenza
vaccine (SD IIV) among adults aged 18-64 years. The primary study hypothesis is that the
clinical efficacy of RIV is superior to that of SD IIV to prevent and attenuate
influenza-like illness (ILI)-associated influenza virus infection. Relative efficacy will
be assessed by comparing rates of ILI-associated reverse transcription polymerase chain
reaction (RT-PCR)-confirmed influenza virus infection and measures of infection and
illness attenuation among participants who receive RIV versus SD IIV. A secondary
hypothesis is that humoral and cell-mediated immune responses to RIV are superior to
responses to SD IIV. Relative immunogenicity will be assessed by comparing markers of
humoral and cell-mediated immune responses post-vaccination among a subset of
participants who receive RIV versus SD IIV
The trial will be conducted at up to 6 sites in the United States during at least two
influenza seasons (2022-23 and 2023-24). Stratified enrollment procedures will be used to
enroll a representative mix of participants based on age (18-49 and 50-64 years). In
addition, an enrollment quota will be used to enroll a minimum proportion of trial
participants that self-identify as from a racial or ethnic group that has been
historically underrepresented in clinical trials to optimize the racial and ethnic
representativeness of the trial population compared to the US source population.
Eligible participants at each site will be randomized 1:1 to receive a single dose of RIV
(Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain) versus a single dose of
SD IIV (Fluzone® Quadrivalent by Sanofi Pasteur, 15 µg of HA per strain) during
approximately September through mid-November of 2022 or 2023. At a subset of sites,
approximately 120 participants per trial season will be recruited and enrolled into an
immunogenicity substudy with blood collection. All study vaccines are licensed for use in
adults aged >18 years in the United States; RIV is licensed for adults aged >=18 years
and SD IIV is licensed for persons aged >=6 months. Participants and study investigators
will be blinded to study arm assignment. Designated study staff administering vaccines
will be aware of study arm assignment and will not be involved with study surveillance to
avoid involvement with measurement of study outcomes.
All participants will be followed with surveillance for ILI-associated RT-PCR-confirmed
influenza virus infection. ILI will be defined as subjective (i.e., participant-reported)
fever, cough, runny nose, or sore throat. Starting at enrollment, participants will
respond to weekly text messages or emails asking about new onset of ILI symptoms to
familiarize them with the electronic surveillance procedures and keep them engaged in the
study prior to circulation of influenza viruses in the community. Once national and/or
state influenza surveillance systems indicate that influenza viruses have begun
circulating in the United States or no later than the first week of December,
participants will also self-collect mid-turbinate nasal swabs (henceforth referred to as
'nasal swabs') with onset of ILI symptoms and self-ship or drop off swabs at designated
sites for shipment to a central laboratory. Samples will be tested for influenza viruses
by real-time reverse transcription polymerase chain reaction (RT-PCR). Samples may also
be tested for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection and
other respiratory viruses. During the influenza virus circulation period or no later than
the first week of December, participants who report ILI symptoms during the surveillance
contacts will complete follow-up questionnaires to provide detailed information about
their illnesses. Electronic surveillance and nasal swab collection will continue until
local influenza virus circulation ends with the option to restart surveillance if
additional periods of influenza virus circulation occur through May of each trial season.
Participants in the immunogenicity substudy will have blood collected just prior to
vaccination and at approximately 7 days, 28 days, and 6 months post-vaccination to
evaluate humoral and cell-mediated immune responses to vaccination; these participants
will also have two nasal swabs collected prior to vaccination and at approximately 7 and
28 days post-vaccination for human microbiome characterization.
Sites will aim to enroll a combined total of up to 16,247 participants during the 2022-23
and 2023-24 seasons; up to about 7,000 of these will be in the first year. The
immunogenicity substudy site(s) will aim to enroll 120 participants each season (60 per
vaccine arm) who will contribute blood for serum, plasma, and peripheral blood
mononuclear cell (PBMC) collection and nasal swabs for human microbiome characterization.
A blinded sample size re-estimation will be conducted at the end of the first trial
season by an independent designated statistician with experience with adaptive trial
approaches. The analysis will follow a pre-specified analysis plan, and the recommended
revised sample size will be shared with the trial steering committee for decision-making.
Participants from the first trial season may be eligible for the second trial season; all
participants will complete eligibility screening and consent processes at the start of
each trial season. Participants from the first trial season who consent to participate in
the second trial season will be rerandomized.
