Influenza, Influenza-like Illness, Influenza Vaccines
Conditions
Keywords
Influenza vaccine
Brief summary
A total of 18,000 eligible subjects (or 6,000 subject distributed evenly between the 3 study arms) will be enrolled. Eligible subjects will be randomized in 1:1:1 (cell-culture-based vaccine, the recombinant vaccine, or the egg-based vaccine) over four influenza seasons (2018-2019, 2019-2020, 2020-2021, and 2021-2022).
Detailed description
This four-year, pragmatic, prospective study will compare the effectiveness of licensed egg-based inactivated influenza vaccines to the effectiveness of two other types of licensed vaccines, the cell-culture based inactivated influenza vaccine and the recombinant influenza vaccine, in the prevention of laboratory-confirmed influenza infection in active duty members, military retirees, and other DoD beneficiaries. Military treatment facilities (MTFs) in the United States will participate in this protocol. Enrollment will be restricted to adults (≥18 years and older) who are preparing to receive seasonal influenza vaccination at participating DoD sites. Subjects will be randomized to receive one of the three licensed influenza vaccines types for evaluation of effectiveness. There is no exclusion for pregnancy, as none of these licensed products are contraindicated in pregnant women.
Interventions
BIOLOGICALEgg based influenza vaccines
Participants will be randomly allocated to one of three vaccine types in accordance with standard clinical practices for those in the US military. All vaccines are FDA licensed for use in the United States.
BIOLOGICALRecombinant influenza vaccines
Participants will be randomly allocated to one of three vaccine types in accordance with standard clinical practices for those in the US military. All vaccines are FDA licensed for use in the United States.
BIOLOGICALCell-culture based influenza vaccines
Participants will be randomly allocated to one of three vaccine types in accordance with standard clinical practices for those in the US military. All vaccines are FDA licensed for use in the United States.
Sponsors
Henry M. Jackson Foundation for the Advancement of Military Medicine
National Institute of Allergy and Infectious Diseases (NIAID)
Food and Drug Administration (FDA)
US Department of Defense Armed Forces Health Surveillance Center
Naval Health Research Center
United States Air Force School of Aerospace Medicine
Uniformed Services University of the Health Sciences
Defense Health Agency
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
A total of 18,000 eligible subjects (or 6,000 subject distributed evenly between the 3 study arms) will be enrolled. eligible subjects will be randomized in 1:1:1 (cell-culture-based vaccine, the recombinant vaccine, or the egg-based vaccine) over four influenza seasons (2018-2019,2019-2020, 2020-2021, and 2021-2022).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Eligible for care in Department of Defense medical facilities (Defense Enrollment Eligibility Reporting System eligible) 2. ≥18 years of age. 3. At a participating Military Treatment Facility site for the purpose of receiving a seasonal (2018-2019, 2019-2020,2020-2021, 2021-2022) influenza vaccination. 4. Able to speak English and able to provide informed consent 5. Able to receive and respond to texts and/or emails, or a military recruit
Exclusion criteria
1. Adults intending to receive or who have received the current seasons FluMist Vaccine (LAIV) 2. Adults who have already received a flu vaccine within the current season 3. Individual who cannot receive a flu vaccine or standard dosing due to another medical condition 4. Allergic to gentamicin, polymyxin and/or neomycin 5. Individuals who fail to meet the inclusion criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Laboratory Confirmed Influenza | Onset > 13 days after vaccination up to 1 year | Laboratory-confirmed influenza as ascertained by a sensitive and specific assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | Baseline to 21-35 days post vaccine | Strain-specific seroconversion rate determined by reference hemagglutination inhibition assay. |
| Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Baseline to 21-35 days post vaccine | Neutralizing antibody responses (4-fold rise) to HA-psuedoviruses corresponding to vaccine-matched viruses, recently circulating influenza virus, and emerging influenza strain. |
| Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | Baseline to 21-35 days post vaccine | Anti-Neuraminidase (Anti-NA) titer responses determined by enzyme linked immuno-assay. |
| Number of Participants With Influenza-Like Illness | Onset > 13 days after vaccination up to 1 year | Rate of protocol defined influenza-like illness ascertained by participant response to active surveillance. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTimothy Burgess, MD
Uniformed Services University of the Health Sciences
STUDY_DIRECTORRhonda Colombo, MD
Infectious Diseases Clinical Research Program
Participant flow
Recruitment details
Participants were recruited from adult military health system (MHS) beneficiaries preparing to receive a seasonal influenza vaccination at a participating DoD site. Eligible participants who provided informed consent were block randomized 1:1:1 to receive one of three types of licensed influenza vaccines (cell-culture-based vaccine, recombinant vaccine, or egg-derived vaccine). The first participant was enrolled in November 2018, and the last participant was enrolled in January 2022.
Pre-assignment details
Among 15448 enrolled participants, 16 were excluded from analysis due to ineligibility (i.e., not eligible for care in MHS, already received an influenza vaccination, etc.)
Participants by arm
| Arm | Count |
|---|---|
| Egg-based Vaccine Subjects vaccinated with egg-based vaccine. | 5,145 |
| Recombinant Vaccine Subjects vaccinated with Recombinant vaccine. | 5,150 |
| Cell-derived Vaccine Subjects vaccinated with Cell-derived vaccine. | 5,137 |
| Total | 15,432 |
Baseline characteristics
| Characteristic | Egg-based Vaccine | Recombinant Vaccine | Cell-derived Vaccine | Total |
|---|---|---|---|---|
| Age, Customized < 65 years | 4948 Participants | 4957 Participants | 4940 Participants | 14845 Participants |
| Age, Customized >=65 years | 200 Participants | 197 Participants | 190 Participants | 587 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 997 Participants | 987 Participants | 951 Participants | 2935 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4026 Participants | 4049 Participants | 4050 Participants | 12125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 125 Participants | 118 Participants | 129 Participants | 372 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 51 Participants | 49 Participants | 44 Participants | 144 Participants |
| Race (NIH/OMB) Asian | 289 Participants | 315 Participants | 316 Participants | 920 Participants |
| Race (NIH/OMB) Black or African American | 601 Participants | 642 Participants | 606 Participants | 1849 Participants |
| Race (NIH/OMB) More than one race | 280 Participants | 270 Participants | 285 Participants | 835 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 48 Participants | 63 Participants | 50 Participants | 161 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 300 Participants | 306 Participants | 291 Participants | 897 Participants |
| Race (NIH/OMB) White | 3579 Participants | 3509 Participants | 3538 Participants | 10626 Participants |
| Region of Enrollment United States | 5148 Participants | 5154 Participants | 5130 Participants | 15432 Participants |
| Sex: Female, Male Female | 1639 Participants | 1673 Participants | 1644 Participants | 4956 Participants |
| Sex: Female, Male Male | 3509 Participants | 3481 Participants | 3486 Participants | 10476 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5,148 | 0 / 5,154 | 0 / 5,130 |
| other Total, other adverse events | 0 / 5,148 | 0 / 5,154 | 0 / 5,130 |
| serious Total, serious adverse events | 0 / 5,148 | 0 / 5,154 | 0 / 5,130 |
Outcome results
Primary
Number of Participants With Laboratory Confirmed Influenza
Laboratory-confirmed influenza as ascertained by a sensitive and specific assay.
Time frame: Onset > 13 days after vaccination up to 1 year
Population: Analysis based on actual vaccine received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Egg-based Vaccine | Number of Participants With Laboratory Confirmed Influenza | 68 participants |
| Cell-derived Vaccine | Number of Participants With Laboratory Confirmed Influenza | 86 participants |
| Recombinant Vaccine | Number of Participants With Laboratory Confirmed Influenza | 77 participants |
Comparison: Relative vaccine effectiveness with the outcome laboratory confirmed influenza identified via surveillance and/or abstracted from clinical records.p-value: 0.141295% CI: [-73.7, 7.6]Chi-squared
Comparison: Relative vaccine effectiveness with the outcome laboratory confirmed influenza identified via surveillance and/or abstracted from clinical records.p-value: 0.455295% CI: [-56.4, 18.2]Chi-squared
Secondary
Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine.
Anti-Neuraminidase (Anti-NA) titer responses determined by enzyme linked immuno-assay.
Time frame: Baseline to 21-35 days post vaccine
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Egg-based Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Pre-vaccination | 53.7 geometric mean titer |
| Egg-based Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Post-vaccination | 207.1 geometric mean titer |
| Egg-based Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Pre-vaccination | 121.2 geometric mean titer |
| Egg-based Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Post-vaccination | 291.5 geometric mean titer |
| Cell-derived Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Post-vaccination | 230.5 geometric mean titer |
| Cell-derived Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Pre-vaccination | 121.2 geometric mean titer |
| Cell-derived Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Pre-vaccination | 126.0 geometric mean titer |
| Cell-derived Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Post-vaccination | 118.3 geometric mean titer |
| Recombinant Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Post-vaccination | 78.4 geometric mean titer |
| Recombinant Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Post-vaccination | 77.7 geometric mean titer |
| Recombinant Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N2 Titer, Pre-vaccination | 83.0 geometric mean titer |
| Recombinant Vaccine | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | N1 Titer, Pre-vaccination | 80.7 geometric mean titer |
Secondary
Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains.
Strain-specific seroconversion rate determined by reference hemagglutination inhibition assay.
Time frame: Baseline to 21-35 days post vaccine
Population: Substudy participants were included if they had pre- and post-vaccination samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Egg-based Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H1N1: Number with 4-fold rise in HI | 103 participants |
| Egg-based Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H3N2: Number with 4-fold rise in HI | 108 participants |
| Egg-based Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Victoria: Number with 4-fold rise in HI | 49 participants |
| Egg-based Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Yamagata: Number with 4-fold rise in HI | 19 participants |
| Cell-derived Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Yamagata: Number with 4-fold rise in HI | 24 participants |
| Cell-derived Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H1N1: Number with 4-fold rise in HI | 114 participants |
| Cell-derived Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Victoria: Number with 4-fold rise in HI | 48 participants |
| Cell-derived Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H3N2: Number with 4-fold rise in HI | 158 participants |
| Recombinant Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Yamagata: Number with 4-fold rise in HI | 64 participants |
| Recombinant Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H3N2: Number with 4-fold rise in HI | 267 participants |
| Recombinant Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | B-Victoria: Number with 4-fold rise in HI | 92 participants |
| Recombinant Vaccine | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | H1N1: Number with 4-fold rise in HI | 184 participants |
Secondary
Number of Participants With Influenza-Like Illness
Rate of protocol defined influenza-like illness ascertained by participant response to active surveillance.
Time frame: Onset > 13 days after vaccination up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Egg-based Vaccine | Number of Participants With Influenza-Like Illness | 1055 Participants |
| Cell-derived Vaccine | Number of Participants With Influenza-Like Illness | 1120 Participants |
| Recombinant Vaccine | Number of Participants With Influenza-Like Illness | 1080 Participants |
Secondary
Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine.
Neutralizing antibody responses (4-fold rise) to HA-psuedoviruses corresponding to vaccine-matched viruses, recently circulating influenza virus, and emerging influenza strain.
Time frame: Baseline to 21-35 days post vaccine
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against egg-passaged HA-pseudovirus (SGP/19/16 NIB-104) | 8.7 percentage of participants |
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against cell-passaged HA-pseudovirus (NC/04/16) | 8.7 percentage of participants |
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against wild-type (SGP/19/16; recombinant HA-pseudovirus) | 4.3 percentage of participants |
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to prior season vaccine strain | 6.5 percentage of participants |
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to recently circulating virus | 4.3 percentage of participants |
| Egg-based Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to emerging infuenza strain | 2.2 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to emerging infuenza strain | 0 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against egg-passaged HA-pseudovirus (SGP/19/16 NIB-104) | 13.9 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to prior season vaccine strain | 13.9 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to recently circulating virus | 11.1 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against cell-passaged HA-pseudovirus (NC/04/16) | 8.3 percentage of participants |
| Cell-derived Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against wild-type (SGP/19/16; recombinant HA-pseudovirus) | 16.7 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against cell-passaged HA-pseudovirus (NC/04/16) | 43.1 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against wild-type (SGP/19/16; recombinant HA-pseudovirus) | 56.9 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to emerging infuenza strain | 21.6 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to prior season vaccine strain | 62.7 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against egg-passaged HA-pseudovirus (SGP/19/16 NIB-104) | 47.1 percentage of participants |
| Recombinant Vaccine | Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. | Seroconversion rate against HA-pseudovirus corresponding to recently circulating virus | 52.9 percentage of participants |
Other Pre-specified
Number of Participants With SARS-CoV-2 and Influenza Co-Infection
Laboratory-confirmed SARS CoV2, and SARS CoV2 plus influenza co-infection, as ascertained by nasal swab PCR.
Time frame: Onset > 13 days after influenza vaccination up until one year
Population: Participants enrolled in PAIVED beginning in 2019-20 season.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Egg-based Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | SC2 Status | 131 Participants |
| Egg-based Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | Influenza/SC2 Coinfection Status | 0 Participants |
| Cell-derived Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | SC2 Status | 157 Participants |
| Cell-derived Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | Influenza/SC2 Coinfection Status | 1 Participants |
| Recombinant Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | SC2 Status | 141 Participants |
| Recombinant Vaccine | Number of Participants With SARS-CoV-2 and Influenza Co-Infection | Influenza/SC2 Coinfection Status | 1 Participants |
Other Pre-specified
Symptom Severity of SARS CoV2
Symptom severity scores were reported by participants using FLU-PRO Plus (Influenza Patient Reported Outcomes), a standardized instrument developed to measure the intensity and frequency of viral respiratory tract symptoms. FluPRO Plus symptom scores range from 0 (not at all) to 4 (very much), with higher scores indicating greater severity.
Time frame: onset >13 days after Influenza vaccination up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Egg-based Vaccine | Symptom Severity of SARS CoV2 | 1.00 score on a scale |
| Cell-derived Vaccine | Symptom Severity of SARS CoV2 | 1.10 score on a scale |
| Recombinant Vaccine | Symptom Severity of SARS CoV2 | 1.10 score on a scale |