Comparative Immunogenicity of Respiratory Virus Vaccines (CIRV2) Study (CIRV2)

April 30, 2026 updated by: Henry M. Jackson Foundation for the Advancement of Military Medicine

IDCRP-154: Comparative Immunogenicity of Respiratory Virus Vaccines (CIRV2) Study

CIRV2 is a Phase IV randomized, open-label, trial of FDA-approved COVID-19 and/or influenza vaccines (no more than minimal risk) with longitudinal follow-up. In 2025 CIRV2 will compare immunogenicity and reactogenicity of the recombinant Novavax COVID-19 vaccine and the mRNA Pfizer-BioNTech COVID-19 vaccine.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The goal of the Comparative Immunogenicity of Respiratory Virus Vaccines (CIRV2) study is to conduct, on a yearly basis, direct comparisons of immunogenicity and reactogenicity of the most recent versions of FDA-approved vaccines for COVID-19 and/or influenza. Studies will be conducted on individuals that are FDA eligible to receive these vaccines and do not have a medical condition that severely impairs their immune system. For 2025, the study will directly compare the immunogenicity and reactogenicity of the 2025 Novavax recombinant COVID-19 vaccine with the 2025 Pfizer/BioNTech mRNA COVID-19 vaccine.

Study Type

Interventional

Enrollment (Estimated)

54

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20814
        • Walter Reed National Military Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria

  1. 18-79 years old

  2. Have a history of any of the following risk factors for severe COVID:

    • Asthma
    • Physical inactivity (defined as <150 mins of moderate activity per week or <75 mins of vigorous activity per week)
    • HIV with CD4 count ≥ 500 cells/ul
    • Current or prior smoker
    • Depression or other mood disorder
    • Schizophrenia spectrum disorder
    • Cerebrovascular disease
    • Heart failure
    • Coronary artery disease
    • Cardiomyopathy
    • Pulmonary embolism
    • Pulmonary hypertension
    • Cystic fibrosis
    • Bronchiectasis
    • Chronic obstructive pulmonary disease
    • Interstitial Lung Disease
    • Stage I or II chronic kidney disease
    • Stage 1 defined as normal GFR (> 90) but with other signs of kidney damage such as proteinuria or hematuria
    • Stage 2 defined as having a glomerular filtration rate (GFR) of 60 - 89 ml/min/1.73m2
    • Gestational diabetes
    • Type 1 diabetes with most recent HgbA1C < 7.5%
    • Type 2 diabetes with most recent HgbA1C < 7.5%
    • Obesity with BMI ≥ 30 and < 40
    • Liver disease without cirrhosis and with liver enzyme levels
    • (AST and ALT) no greater than three times the upper limit of normal
  3. Military Health System beneficiary and DEERS eligible
  4. Willing to be randomized to receive either the Novavax COVID-19 vaccine or the mRNA Pfizer-BioNTech COVID-19 vaccine
  5. Will be able to return for a clinic visit in approximately 30 days and be able to follow-up online for the next 9 months.

Exclusion Criteria

  1. History of severe allergy or severe adverse reaction such as myocardial inflammation to any component of the mRNA COVID-19 vaccines or the Novavax recombinant COVID-19 vaccine
  2. Received a COVID-19 vaccine in the last 3 months.

  3. Tested positive for COVID-19 in the past 3 months.

    - Presence of fever, cough, chills, shortness of breath, runny nose, or sore throat today on day of screening/enrollment visit.

  4. Active use of immune modulating medications.

    - Defined as active use of chronic immune modulating medications such as systemic corticosteroids at a dose equivalence of 20 mg prednisone or greater daily for over one month, chemotherapy, cytokine inhibitors, or agents that reduce T cell or B cell numbers or function.

  5. Diagnosed with immunocompromised stated.

    - Defined as: presence of a disease that is actively causing severe immune suppression or history of prior splenectomy (removal of spleen).

  6. Diabetes with the most recent HgbA1C ≥ 7.5.

  7. Stage III or greater chronic kidney disease

    - Defined as estimated glomerular filtration rate < 60 ml/min/1.73m2)

  8. Obesity with a BMI ≥ 40
  9. HIV with a CD4 cell count < 500 cells/ul
  10. History of solid organ or bone marrow transplant.

  11. Active malignancy

    - Defined as any cancer that is currently being treated or has shown evidence of progression within the past year.

  12. Chronic liver disease with compensated or decompensated cirrhosis, or liver enzyme levels (AST or ALT) greater than three times the upper limit of normal.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: For fall of 2025, Arm 1 of the study will be the Pfizer-BioNTech mRNA COVID-19 vac
Arm 1 of the study will be Pfizer-BioNTech mRNA COVID-19 vaccine
Drug: Pfizer-BioNTech mRNA COVID-19 vaccine
COVID-19 Vaccine, mRNA
Active Comparator: For fall of 2025, Arm 2 of the study will be the Novavax recombinant protein vaccine
Arm 2 of the study will be the Novavax recombinant protein vaccine
Drug: Novavax recombinant protein vaccine
Recombinant protein vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Variant-specific immune responses
Time Frame: IgG binding antibody levels and neutralizing antibody titers will be assessed on serum samples obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.
The primary endpoint is variant-specific immune response (magnitude and breadth) to licensed recombinant and mRNA COVID-19 products administered to healthy adult MHS beneficiaries. This will include quantifying the magnitude of binding and neutralizing antibodies to the vaccine variants and to the dominant variant present one month post-vaccination. Specifically, we will test neutralizing titers (defined as the inverse serum dilution causing a 50% reduction in relative light units in a pseudovirus neutralization assay) and IgG binding antibody levels (measured in arbitrary units) against the following SARS-CoV-2 variants: NB.1.8.1 and XFG (predominant circulating strains in fall 2025), JN.1 and LP.8.1 (vaccine strains), and Wuhan-1 (ancestral strain).
IgG binding antibody levels and neutralizing antibody titers will be assessed on serum samples obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Vaccine reactogenicity and other incident adverse events (compared between two licensed COVID-19 platforms - recombinant and mRNA)
Time Frame: Reactogenicity and other incident adverse events will be assessed through 9 months after vaccination.
For vaccine reactogenicity and other incident adverse events, we will use Fisher exact test or a Chi-square test between study arms. Any comparisons among substrata (e.g., age strata, infection histories) will use multiplicity adjustment.
Reactogenicity and other incident adverse events will be assessed through 9 months after vaccination.
Frequency of participant-reported test positive (antigen and/or PCR) SARS-CoV-2 infections (compared between two licensed COVID-19 platforms - recombinant and mRNA) during the eight months following COVID vaccination and assessment of their symptom patte
Time Frame: Through 9 months after vaccination.

Frequency of participant-reported test positive infections during the eight months following COVID-19 vaccination will be compared using Fisher exact test or a Chi-square test between study arms. Any comparisons among substrata (e.g., age strata, infection histories) will use multiplicity adjustment.

Frequency of self-reported COVID-19 symptom severity (% with moderate or greater severity), and duration of illness (in days), will be compared using Fisher exact test or a Chi-square test between study arms. Any comparisons among substrata (e.g., age strata, infection histories) will use multiplicity adjustment.
Through 9 months after vaccination.
Salivary and nasopharyngeal IgG and IgA antibody levels to vaccine SARS-CoV-2 strain and dominant SARS-CoV-2 circulating strain at 30 days post vaccination
Time Frame: These antibody tests will be conducted on biosamples obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.
Salivary and nasopharyngeal IgG and IgA antibody levels to vaccine SARS-CoV-2 strain and dominant SARS-CoV-2 circulating strain at 30 days post vaccination will be compared between the study arms using GMT and GSD. T-tests will compare responses across two SARS-CoV-2 variants (i.e., the vaccine variant and the dominant circulating variant at the time of vaccination), stratified by vaccine type and adjusted for multiple comparisons (e.g., a Tukey's adjustment). A non-parametric comparison can be used if there is non-normally distributed data despite the use of GMT, these approaches also account for multiplicity (e.g., Kruskall-Wallis with a Dunn's adjustment for multiplicity adjustment).
These antibody tests will be conducted on biosamples obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.
Antigenic cartography and antibody landscapes
Time Frame: Antigenic cartography studies may be conducted using neutralizing antibody titers obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.
Antigenic cartography and antibody landscapes may be performed by FDA collaborators to visualize antigenic drift from the vaccine with sequential variants, leveraging prior analysis approaches used by the study team. These analyses use relative differences in neutralizing antibody responses to generate two-dimensional maps (antigenic cartography) or three-dimensional landscapes that enable one to assess how antigenically similar different virus strains are to each other. Antibody landscapes are useful tools which can capture differential multiple serial antigenic exposures in comparisons of antibody titer and breadth between individuals assigned to receive the recombinant or mRNA vaccines (see examples from Wang et al., Cell Host Microbe, 2022).
Antigenic cartography studies may be conducted using neutralizing antibody titers obtained just prior to vaccination and 30 days (+/- 10 days) after vaccination.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Henry M. Jackson Foundation for the Advancement of Military Medicine

Collaborators

Centers for Disease Control and Prevention
Food and Drug Administration (FDA)

Investigators

  • Principal Investigator: Edward Mitre, MD, Uniformed Services University of the Health Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 12, 2025

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

November 18, 2025

First Submitted That Met QC Criteria

December 11, 2025

First Posted (Actual)

December 17, 2025

Study Record Updates

Last Update Posted (Actual)

May 4, 2026

Last Update Submitted That Met QC Criteria

April 30, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IDCRP-154

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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