A Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Influenza; Influenza-like Illness; Influenza Vaccines
• Intervention / Treatment: Biological: Egg based influenza vaccines; Biological: Recombinant influenza vaccines; Biological: Cell-culture based influenza vaccines

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.

• Study Type: Interventional
• Enrollment (Actual): 16023
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 34800
      • Naval Medical Center San Diego
  • Maryland
    • Annapolis, Maryland, United States, 21402
      • United States Naval Academy
    • Bethesda, Maryland, United States, 20814
      • Walter Reed National Military Medical Center
    • Bethesda, Maryland, United States, 20307
      • USU
  • North Carolina
    • Fort Bragg, North Carolina, United States, 28310
      • Womack Army Medical Center
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • San Antonio, Texas, United States, 78243
      • Lackland Airforce Base
  • Virginia
    • Portsmouth, Virginia, United States, 23704
      • Naval Medical Center Portsmouth
  • Washington
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Egg based influenza vaccines; 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.	Biological: Egg 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.
Active Comparator: Recombinant influenza vaccines; 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.	Biological: Recombinant 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.
Active Comparator: Cell-culture based influenza vaccines; 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.	Biological: Cell-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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory confirmed influenza attack rates	Laboratory-confirmed influenza as ascertained by a sensitive and specific assay is needed to assess effectiveness.	Onset > 13 days after vaccination up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemagglutination Inhibition (HI) titer responses to vaccine and circulating strains of influenza	A subset of volunteers may participate it in this outcome.	Baseline to 21-35 days post vaccine
Pseudovirion neutralization (PVN) responses to vaccine and circulating strains of influenza	A subset of volunteers may participate it in this outcome.	Baseline to 21-35 days post vaccine
Anti-Neuraminidase (Anti-NA) titer responses to vaccine and circulating strains of influenza	A subset of volunteers may participate it in this outcome.	Baseline to 21-35 days post vaccine
Cellular Responses: Frequency of antigen specific CD4 and CD8 cells, B cells	A subset of volunteers may participate it in this outcome.	Baseline to 21-35 days post vaccine
Rate of Influenza-like Illness		Onset > 13 days after vaccination up to 1 year
Frequency of influenza confirmed hospitalization		Onset > 13 days after vaccination up to 1 year
Number of duty (work) days lost due to Influenza-like Illness		Onset > 13 days after vaccination up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tertiary Arm- Assess the burden of covid-19 and explore the inter-relationship between influenza and covid-19	Endpoints: incidence of COVID-19 incidence of co-infection with influenza & Severity of COVID-19, symptoms associated with COVID-19 infection (compared with influenza, other respiratory viruses)	onset >13 days after vaccination

Collaborators and Investigators

• Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Food and Drug Administration (FDA); Uniformed Services University of the Health Sciences; Naval Health Research Center; Defense Health Agency Immunization Healthcare Branch; Armed Forces Health Surveillance Branch; United States Air Force School of Aerospace Medicine
• Investigators: Principal Investigator: Timothy Burgess, MD, Uniformed Services University of the Health Sciences; Study Director: Rhonda Colombo, MD, Infectious Diseases Clinical Research Program

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Influenza. Centers for Disease Control and Prevention

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2018
• Primary Completion (Actual): July 7, 2022
• Study Completion (Estimated): May 31, 2024

Study Registration Dates

• First Submitted: November 2, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 7, 2018

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Influenza vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: IDCRP-120; AAI1201200007000 (Other Grant/Funding Number: NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigative team members with knowledge and experience with statistical and scientific procedures will de-identify PHI and prepare the data set to be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No