Influenza
Conditions
Keywords
Influenza
Brief summary
The goal of this study is to establish that Flublok Quadrivalent is non-inferior to fully licensed (traditional approval status) quadrivalent inactivated influenza vaccine (IIV4) in protecting against laboratory-confirmed clinical influenza disease in the ≥50 year age population.
Detailed description
The goal of this study is to establish that Flublok Quadrivalent is non-inferior to fully licensed (traditional approval status) quadrivalent inactivated influenza vaccine (IIV4) in protecting against laboratory-confirmed clinical influenza disease in the ≥50 year age population. Real-time Polymerase Chain Reaction (rtPCR) will be used to confirm influenza infection and to type the strains involved, as molecular methodologies have been demonstrated to be more sensitive than other more traditional methodologies, e.g. culture. For rtPCR-positive clinical samples, reserved aliquots will be processed for culture, so that antigenic similarity to the HA present in study vaccines can be tested. In various clinical studies the investigators demonstrated that the immune response against the influenza A viruses is improved as a result of the higher hemagglutinin content. Furthermore, influenza virus disease and hospitalization associated with influenza-related illness in older adults (\> 50 years) was considerably reduced (90%) following vaccination with TIV, even though the circulating influenza A strain was antigenically dissimilar to that in the vaccine. However, more recently Skowronski et al. reported that the low influenza vaccine effectiveness in 2012-2013 was not associated with antigenic drift but was instead related to mutations in the egg-adapted H3N2 vaccine strain. Flublok manufactured using recombinant technology does not contain the mutations responsible for the reported lower effectiveness and may thus offer improved protection when mutations such as those described are induced in the process of adapting the influenza virus to growth in eggs.
Interventions
BIOLOGICALFlublok Quadrivalent Influenza Vaccine
Intramuscular injection of vaccine
BIOLOGICALInactivated Influenza Vaccine
Intramuscular injection of vaccine
Sponsors
Protein Sciences Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Ambulatory adults aged 50 and older. 2. Medically stable, as determined by medical history and targeted physical examination. Medically stable is defined as no change in diagnoses or chronic medications (dose or class) for medical reasons in the 3 months prior to study. 3. Absence of underlying conditions that make participation in the study contrary to the subject's best interest. 4. Able to understand and comply with planned study procedures. 5. Provides written informed consent prior to initiation of any study procedure.
Exclusion criteria
1. Known contraindication to either study vaccine (see product package inserts) 2. Receipt of any other influenza vaccine within 180 days prior to enrollment in this study. 3. Underlying disease or ongoing therapy that might cause immunocompromise, e.g. cytotoxic agents or supraphysiologic doses of corticosteroids, such that response to vaccination might be sub-optimal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With rtPCR-confirmed Influenza-Like Illness | 14 days post vaccination through and up to 32 weeks post vaccination | rtPCR-confirmed, protocol-defined Influenza-Like Illness (ILI) caused by any influenza strain that begins at least 14 days post-vaccination |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Culture-confirmed CDC-defined Influenza-Like Illness | 14 days post vaccination through and up to 32 weeks post vaccination | Culture-confirmed CDC-defined Influenza-Like Illness (ILI) that begins at least 14 days post-vaccination caused by an influenza strain (identified from the same clinical sample) antigenically matched to those in the study vaccines. CDC-defined ILI is defined as body temperature ≥100°F accompanied by cough and/or sore throat. |
| Number of Participants With rtPCR-confirmed CDC-defined Influenza-Like Illness | 14 days post vaccination through and up to 32 weeks post vaccination | rtPCR-confirmed CDC-defined ILI that begins at least 14 days post-vaccination caused by any influenza strain. |
| Percentage of Participants With Seroconversion | Days 0 through 28 | Seroconversion rates (SCR) for all four antigens in a preselected subset of subjects. |
| Number of Participants With Local Injection Site Reactogenicity | Days 0 through 7 | Solicited events of injection site reactogenicity reported during Day 0-7. |
| Number of Participants With Culture-confirmed Influenza-Like Illness | 14 days post vaccination through and up to 32 weeks post vaccination | Culture-confirmed protocol-defined Influenza-Like Illness (ILI) that begins at least 14 days post-vaccination caused by an influenza strain (identified from the same clinical sample) antigenically matched to those strains represented in the study vaccines. Protocol-defined ILI is defined as at least one of the following respiratory symptoms accompanied by at least one of the following systemic symptoms: Respiratory symptoms: sore throat, cough, sputm production, wheezing, difficulty breathing Systemic symptoms: fever, chills (shivering), tiredness (fatigue), headache, myalgia (muscle ache) |
| Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) | Day 0 through and up to 32 weeks post vaccination | Serious adverse events (SAEs) and medically-attended adverse events (MAEs) occurring during the period of follow-up through the influenza season (at least 6 months post-vaccination). A MAE is an event that prompts an unplanned visit to a medical professional for diagnosis and/or treatment. |
| Measure of Post-vaccination HAI GMTs | Days 0 through 28 | GMT titers for all four antigens in a preselected subset of subjects. |
| Number of Participants With Systemic Reactogenicity | Days 0 through 7 | Solicited events of systemic reactogenicity reported during Day 0-7. |
| Number of Participants With Unsolicited Adverse Events | Days 0 through 28 | Unsolicited adverse events reported in the 28 days following vaccine administration. |
Countries
United States
Participant flow
Pre-assignment details
Excludes 40 subjects who received randomization numbers, but who either withdrew prior to vaccination (n=15) or for whom the vaccine received could not be verified (n=25; 12 assigned to Flublok quadrivalent and 13 assigned to IIV4).
Participants by arm
| Arm | Count |
|---|---|
| Flublok Quadrivalent Influenza Vaccine Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL
Flublok Quadrivalent Influenza Vaccine: Intramuscular injection of vaccine | 4,328 |
| Inactivated Influenza Vaccine Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL.
Inactivated Influenza Vaccine: Intramuscular injection of vaccine | 4,344 |
| Total | 8,672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 8 |
| Overall Study | Lost to Follow-up | 176 | 172 |
| Overall Study | Other Reasons | 7 | 10 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Withdrawal by Subject | 53 | 61 |
Baseline characteristics
| Characteristic | Flublok Quadrivalent Influenza Vaccine | Inactivated Influenza Vaccine | Total |
|---|---|---|---|
| Age, Customized 50-64 years | 2569 participants | 2617 participants | 5186 participants |
| Age, Customized 65-74 years | 1234 participants | 1254 participants | 2488 participants |
| Age, Customized 75 years and older | 525 participants | 473 participants | 998 participants |
| Sex: Female, Male Female | 2532 Participants | 2537 Participants | 5069 Participants |
| Sex: Female, Male Male | 1796 Participants | 1807 Participants | 3603 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,122 / 4,328 | 1,206 / 4,344 |
| serious Total, serious adverse events | 145 / 4,328 | 132 / 4,344 |
Outcome results
Primary
Number of Participants With rtPCR-confirmed Influenza-Like Illness
rtPCR-confirmed, protocol-defined Influenza-Like Illness (ILI) caused by any influenza strain that begins at least 14 days post-vaccination
Time frame: 14 days post vaccination through and up to 32 weeks post vaccination
Population: The efficacy population includes all randomized subjects who received study vaccine and provided any follow-up for ILI beginning at least 14 days following vaccine administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With rtPCR-confirmed Influenza-Like Illness | 96 participants |
| Inactivated Influenza Vaccine | Number of Participants With rtPCR-confirmed Influenza-Like Illness | 138 participants |
Comparison: The primary efficacy analysis was based on the numbers of protocol-defined influenza-like illnesses with rtPCR-positive nasopharyngeal swabs detecting influenza virus of any strain. The Relative Vaccine Efficacy was 30% (10, 47). Non-inferiority would be concluded if the lower bound of the 95% CI for rVE was \> -20%. Superiority of RIV4 in a pre-specified exploratory analysis required that the lower bound of the two-sided 95% CI of rVE be \> +9%.95% CI: [10, 47]
Secondary
Measure of Post-vaccination HAI GMTs
GMT titers for all four antigens in a preselected subset of subjects.
Time frame: Days 0 through 28
Population: The immunogenicity population includes all randomized subjects at the specific study sites pre-selected for serology who received study vaccine and provided serum samples on Days 0 and 28 for serologic testing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - A/California | 45 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - A/California | 194 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - A/Texas | 88 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - A/Texas | 530 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - B/Massachusetts | 17 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - B/Massachusetts | 56 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - B/Brisbane | 14 titer |
| Flublok Quadrivalent Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - B/Brisbane | 30 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - B/Brisbane | 44 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - A/California | 49 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - B/Massachusetts | 18 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - A/California | 224 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - B/Brisbane | 15 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 0 - A/Texas | 100 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - B/Massachusetts | 58 titer |
| Inactivated Influenza Vaccine | Measure of Post-vaccination HAI GMTs | Day 28 - A/Texas | 366 titer |
Secondary
Number of Participants With Culture-confirmed CDC-defined Influenza-Like Illness
Culture-confirmed CDC-defined Influenza-Like Illness (ILI) that begins at least 14 days post-vaccination caused by an influenza strain (identified from the same clinical sample) antigenically matched to those in the study vaccines. CDC-defined ILI is defined as body temperature ≥100°F accompanied by cough and/or sore throat.
Time frame: 14 days post vaccination through and up to 32 weeks post vaccination
Population: The efficacy population includes all randomized subjects who received study vaccine and provided any follow-up for ILI beginning at least 14 days following vaccine administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Culture-confirmed CDC-defined Influenza-Like Illness | 38 participants |
| Inactivated Influenza Vaccine | Number of Participants With Culture-confirmed CDC-defined Influenza-Like Illness | 64 participants |
Secondary
Number of Participants With Culture-confirmed Influenza-Like Illness
Culture-confirmed protocol-defined Influenza-Like Illness (ILI) that begins at least 14 days post-vaccination caused by an influenza strain (identified from the same clinical sample) antigenically matched to those strains represented in the study vaccines. Protocol-defined ILI is defined as at least one of the following respiratory symptoms accompanied by at least one of the following systemic symptoms: Respiratory symptoms: sore throat, cough, sputm production, wheezing, difficulty breathing Systemic symptoms: fever, chills (shivering), tiredness (fatigue), headache, myalgia (muscle ache)
Time frame: 14 days post vaccination through and up to 32 weeks post vaccination
Population: The efficacy population includes all randomized subjects who received study vaccine and provided any follow-up for ILI beginning at least 14 days following vaccine administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Culture-confirmed Influenza-Like Illness | 58 participants |
| Inactivated Influenza Vaccine | Number of Participants With Culture-confirmed Influenza-Like Illness | 101 participants |
Secondary
Number of Participants With Local Injection Site Reactogenicity
Solicited events of injection site reactogenicity reported during Day 0-7.
Time frame: Days 0 through 7
Population: Solicited local reactogenicity events include subjects who recorded any injection site reaction data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Local Injection Site Reactogenicity | 1621 participants |
| Inactivated Influenza Vaccine | Number of Participants With Local Injection Site Reactogenicity | 1745 participants |
Secondary
Number of Participants With rtPCR-confirmed CDC-defined Influenza-Like Illness
rtPCR-confirmed CDC-defined ILI that begins at least 14 days post-vaccination caused by any influenza strain.
Time frame: 14 days post vaccination through and up to 32 weeks post vaccination
Population: The efficacy population includes all randomized subjects who received study vaccine and provided any follow-up for ILI beginning at least 14 days following vaccine administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With rtPCR-confirmed CDC-defined Influenza-Like Illness | 54 participants |
| Inactivated Influenza Vaccine | Number of Participants With rtPCR-confirmed CDC-defined Influenza-Like Illness | 83 participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs)
Serious adverse events (SAEs) and medically-attended adverse events (MAEs) occurring during the period of follow-up through the influenza season (at least 6 months post-vaccination). A MAE is an event that prompts an unplanned visit to a medical professional for diagnosis and/or treatment.
Time frame: Day 0 through and up to 32 weeks post vaccination
Population: The safety population includes all randomized and vaccinated subjects who provided any safety data (solicited or unsolicited) following administration of study vaccine.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) | SAEs | 145 participants |
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) | MAEs | 774 participants |
| Inactivated Influenza Vaccine | Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) | SAEs | 132 participants |
| Inactivated Influenza Vaccine | Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) | MAEs | 785 participants |
Secondary
Number of Participants With Systemic Reactogenicity
Solicited events of systemic reactogenicity reported during Day 0-7.
Time frame: Days 0 through 7
Population: Solicited systemic reactogenicity events include subjects who recorded any systemic reaction data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Systemic Reactogenicity | 1077 participants |
| Inactivated Influenza Vaccine | Number of Participants With Systemic Reactogenicity | 1106 participants |
Secondary
Number of Participants With Unsolicited Adverse Events
Unsolicited adverse events reported in the 28 days following vaccine administration.
Time frame: Days 0 through 28
Population: The safety population includes all randomized and vaccinated subjects who provided any safety data (solicited or unsolicited) following administration of study vaccine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Number of Participants With Unsolicited Adverse Events | 1345 participants |
| Inactivated Influenza Vaccine | Number of Participants With Unsolicited Adverse Events | 1355 participants |
Secondary
Percentage of Participants With Seroconversion
Seroconversion rates (SCR) for all four antigens in a preselected subset of subjects.
Time frame: Days 0 through 28
Population: The immunogenicity population includes all randomized subjects at the specific study sites pre-selected for serology who received study vaccine and provided serum samples on Days 0 and 28 for serologic testing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Flublok Quadrivalent Influenza Vaccine | Percentage of Participants With Seroconversion | A/California | 44.9 percentage of participants |
| Flublok Quadrivalent Influenza Vaccine | Percentage of Participants With Seroconversion | A/Texas | 54.5 percentage of participants |
| Flublok Quadrivalent Influenza Vaccine | Percentage of Participants With Seroconversion | B/Massachusetts | 38.9 percentage of participants |
| Flublok Quadrivalent Influenza Vaccine | Percentage of Participants With Seroconversion | B/Brisbane | 21.0 percentage of participants |
| Inactivated Influenza Vaccine | Percentage of Participants With Seroconversion | B/Brisbane | 34.3 percentage of participants |
| Inactivated Influenza Vaccine | Percentage of Participants With Seroconversion | A/California | 49.0 percentage of participants |
| Inactivated Influenza Vaccine | Percentage of Participants With Seroconversion | B/Massachusetts | 38.3 percentage of participants |
| Inactivated Influenza Vaccine | Percentage of Participants With Seroconversion | A/Texas | 43.3 percentage of participants |