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| ID | Type | Description | Link |
|---|---|---|---|
| AAI1201200007000 | Other Grant/Funding Number | NIAID |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
| Food and Drug Administration (FDA) | FED |
| US Department of Defense Armed Forces Health Surveillance Center | FED |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Egg based influenza vaccines | Active Comparator | Quadrivalent egg-based vaccines, which contain an inactivated form of the virus. Vaccines will be given to the participant in accordance with standard clinical practices for those in the US military. All egg-based vaccines are FDA licensed for use in the United States. |
|
| Recombinant influenza vaccines | Active Comparator | FluBlok, recombinant HA influenza vaccine. Vaccines will be given to the participant in accordance with standard clinical practices for those in the US military. Flublok Quadrivalent is a quadrivalent recombinant influenza vaccine that has been licensed by the FDA for use in the United States. |
|
| Cell-culture based influenza vaccines | Active Comparator | Flucelvax, Madin-Darby canine kidney (MDCK)-cell-culture based inactivated influenza vaccine. Vaccines will be given to the participant in accordance with standard clinical practices for those in the US military. Flucelvax quadrivalent, the only cell-based flu vaccine FDA licensed for use in the United States. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Egg based influenza vaccines | Biological | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Laboratory Confirmed Influenza | Laboratory-confirmed influenza as ascertained by a sensitive and specific assay. | Onset > 13 days after vaccination up to 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | Strain-specific seroconversion rate determined by reference hemagglutination inhibition assay. | Baseline to 21-35 days post vaccine |
| Pseudovirion Neutralization (PVN) Responses to Influenza Vaccine. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Onset > 13 days after influenza vaccination up until one year |
| Symptom Severity of SARS CoV2 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Timothy Burgess, MD | Uniformed Services University of the Health Sciences | Principal Investigator |
| Rhonda Colombo, MD | Infectious Diseases Clinical Research Program | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Naval Medical Center San Diego | San Diego | California | 34800 | United States | ||
| United States Naval Academy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26085551 | Background | Sanchez JL, Cooper MJ, Myers CA, Cummings JF, Vest KG, Russell KL, Sanchez JL, Hiser MJ, Gaydos CA. Respiratory Infections in the U.S. Military: Recent Experience and Control. Clin Microbiol Rev. 2015 Jul;28(3):743-800. doi: 10.1128/CMR.00039-14. | |
| 29447141 | Background | Flannery B, Chung JR, Belongia EA, McLean HQ, Gaglani M, Murthy K, Zimmerman RK, Nowalk MP, Jackson ML, Jackson LA, Monto AS, Martin ET, Foust A, Sessions W, Berman L, Barnes JR, Spencer S, Fry AM. Interim Estimates of 2017-18 Seasonal Influenza Vaccine Effectiveness - United States, February 2018. MMWR Morb Mortal Wkly Rep. 2018 Feb 16;67(6):180-185. doi: 10.15585/mmwr.mm6706a2. |
| Label | URL |
|---|---|
| Influenza. Centers for Disease Control and Prevention | View source |
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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 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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Egg-based Vaccine | Subjects vaccinated with egg-based vaccine. |
| FG001 | Recombinant Vaccine | Subjects vaccinated with recombinant vaccine. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 13, 2022 | Sep 15, 2023 |
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| Naval Health Research Center |
| FED |
| United States Air Force School of Aerospace Medicine | FED |
| Uniformed Services University of the Health Sciences | FED |
| Defense Health Agency | FED |
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).
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| Recombinant influenza vaccines | Biological | 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. |
|
| Cell-culture based influenza vaccines | Biological | 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. |
|
Neutralizing antibody responses (4-fold rise) to HA-psuedoviruses corresponding to vaccine-matched viruses, recently circulating influenza virus, and emerging influenza strain. |
| Baseline to 21-35 days post vaccine |
| Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | Anti-Neuraminidase (Anti-NA) titer responses determined by enzyme linked immuno-assay. | Baseline to 21-35 days post vaccine |
| Number of Participants With Influenza-Like Illness | Rate of protocol defined influenza-like illness ascertained by participant response to active surveillance. | Onset > 13 days after vaccination up to 1 year |
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. |
| onset >13 days after Influenza vaccination up to 1 year |
| Annapolis |
| Maryland |
| 21402 |
| United States |
| USU | Bethesda | Maryland | 20307 | United States |
| Walter Reed National Military Medical Center | Bethesda | Maryland | 20814 | United States |
| Womack Army Medical Center | Fort Bragg | North Carolina | 28310 | United States |
| Brooke Army Medical Center | Fort Sam Houston | Texas | 78234 | United States |
| Lackland Airforce Base | San Antonio | Texas | 78243 | United States |
| Naval Medical Center Portsmouth | Portsmouth | Virginia | 23704 | United States |
| Madigan Army Medical Center | Tacoma | Washington | 98431 | United States |
| 29109276 | Background | Zost SJ, Parkhouse K, Gumina ME, Kim K, Diaz Perez S, Wilson PC, Treanor JJ, Sant AJ, Cobey S, Hensley SE. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12578-12583. doi: 10.1073/pnas.1712377114. Epub 2017 Nov 6. |
| 29059230 | Background | Wu NC, Zost SJ, Thompson AJ, Oyen D, Nycholat CM, McBride R, Paulson JC, Hensley SE, Wilson IA. A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathog. 2017 Oct 23;13(10):e1006682. doi: 10.1371/journal.ppat.1006682. eCollection 2017 Oct. |
| 24667168 | Background | Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, Fonseca K, Winter AL, Gubbay JB, Krajden M, Petric M, Charest H, Bastien N, Kwindt TL, Mahmud SM, Van Caeseele P, Li Y. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One. 2014 Mar 25;9(3):e92153. doi: 10.1371/journal.pone.0092153. eCollection 2014. |
| 29471464 | Background | Cobey S, Gouma S, Parkhouse K, Chambers BS, Ertl HC, Schmader KE, Halpin RA, Lin X, Stockwell TB, Das SR, Landon E, Tesic V, Youngster I, Pinsky BA, Wentworth DE, Hensley SE, Grad YH. Poor Immunogenicity, Not Vaccine Strain Egg Adaptation, May Explain the Low H3N2 Influenza Vaccine Effectiveness in 2012-2013. Clin Infect Dis. 2018 Jul 18;67(3):327-333. doi: 10.1093/cid/ciy097. |
| 18722473 | Background | Wang W, Butler EN, Veguilla V, Vassell R, Thomas JT, Moos M Jr, Ye Z, Hancock K, Weiss CD. Establishment of retroviral pseudotypes with influenza hemagglutinins from H1, H3, and H5 subtypes for sensitive and specific detection of neutralizing antibodies. J Virol Methods. 2008 Nov;153(2):111-9. doi: 10.1016/j.jviromet.2008.07.015. Epub 2008 Sep 4. |
| 20153374 | Background | Wang W, Xie H, Ye Z, Vassell R, Weiss CD. Characterization of lentiviral pseudotypes with influenza H5N1 hemagglutinin and their performance in neutralization assays. J Virol Methods. 2010 May;165(2):305-10. doi: 10.1016/j.jviromet.2010.02.009. Epub 2010 Feb 11. |
| 40973113 | Derived | Colombo RE, Richard SA, Schmidt K, Schofield C, Ganesan A, Campbell W, Hrncir D, Lalani T, Mende K, Markelz AE, Berjohn CM, Housel L, Becher D, Zell ER, Ewing D, Sundaram AK, Modi JR, Saperstein A, Tilley DH Jr, Williams A, McClenathan B, Collins L, Spooner C, Seshadri S, Fries A, Maves RC, Powers Iii JH, O'Connell RJ, Pollett SD, Simons MP, Coles CL, Burgess TH; PAIVED Study Group. Randomized Pragmatic Trial of the Comparative Effectiveness of Chicken Egg-Based Inactivated, Mammalian Cell Culture-Based Inactivated, and Recombinant Protein Quadrivalent Seasonal Influenza Vaccines in United States Military Health System Beneficiaries. Clin Infect Dis. 2025 Dec 24;81(5):e454-e463. doi: 10.1093/cid/ciaf503. |
| FG002 | Cell-derived Vaccine | Subjects vaccinated with cell-derived vaccine. |
| COMPLETED |
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| NOT COMPLETED |
|
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Egg-based Vaccine | Subjects vaccinated with egg-based vaccine. |
| BG001 | Recombinant Vaccine | Subjects vaccinated with Recombinant vaccine. |
| BG002 | Cell-derived Vaccine | Subjects vaccinated with Cell-derived vaccine. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants | No |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Laboratory Confirmed Influenza | Laboratory-confirmed influenza as ascertained by a sensitive and specific assay. | Analysis based on actual vaccine received. | Posted | Number | participants | Onset > 13 days after vaccination up to 1 year |
|
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| Secondary | Hemagglutination Inhibition (HI) Titer Responses to Influenza Vaccine Strains. | Strain-specific seroconversion rate determined by reference hemagglutination inhibition assay. | Substudy participants were included if they had pre- and post-vaccination samples. | Posted | Number | participants | Baseline to 21-35 days post vaccine |
|
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| 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. | Posted | Number | percentage of participants | Baseline to 21-35 days post vaccine |
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Anti-Neuraminidase (Anti-NA) Titer Responses to Influenza Vaccine. | Anti-Neuraminidase (Anti-NA) titer responses determined by enzyme linked immuno-assay. | Posted | Geometric Mean | 95% Confidence Interval | geometric mean titer | Baseline to 21-35 days post vaccine |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Influenza-Like Illness | Rate of protocol defined influenza-like illness ascertained by participant response to active surveillance. | Posted | Count of Participants | Participants | Onset > 13 days after vaccination up to 1 year |
|
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| 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. | Participants enrolled in PAIVED beginning in 2019-20 season. | Posted | Count of Participants | Participants | Onset > 13 days after influenza vaccination up until one year |
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| 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. | Posted | Median | Inter-Quartile Range | score on a scale | onset >13 days after Influenza vaccination up to 1 year |
|
|
28 days post-vaccination
This study pre-specified that hospitalization would not be considered a serious adverse event unless related to a study procedure. No SAEs occurred during the study
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Egg-based Vaccine | Subjects vaccinated with egg-based vaccine. | 0 | 5,148 | 0 | 5,148 | 0 | 5,148 |
| EG001 | Recombinant Vaccine | Subjects vaccinated with recombinant vaccine. | 0 | 5,154 | 0 | 5,154 | 0 | 5,154 |
| EG002 | Cell-derived Vaccine | Subjects vaccinated with cell-derived vaccine. | 0 | 5,130 | 0 | 5,130 | 0 | 5,130 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Timothy Burgess, MD, MPH | USUHS | (301) 295-9792 | timothy.burgess@usuhs.edu |
| Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 15, 2023 | Sep 15, 2023 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 2, 2021 | Nov 13, 2023 | ICF_004.pdf |
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| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
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| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
Relative vaccine effectiveness with the outcome laboratory confirmed influenza identified via surveillance and/or abstracted from clinical records. |
| Chi-squared |
| 0.41 |
| Risk Ratio (RR) |
| -14.36 |
| 2-Sided |
| 95 |
| -57.59 |
| 17.01 |
| Equivalence |
Null Hypothesis: RR=1, Alternative hypothesis: RR not equal to 1. |
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