A Deep Longitudinal Analysis of Next Generation Influenza Vaccines in Older Adults (FluVax3)

July 30, 2026 updated by: Duygu Ucar, Ph.D., The Jackson Laboratory
This is a prospective, single-arm study designed to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults. The investigators will recruit and longitudinally follow a cohort of 75 older adults (65 years and older) who will receive three different influenza vaccines over three annual influenza seasons. Blood samples will be collected from the participants at sixteen study visits over three years. Nasal swab and stool samples will also be collected from participants at seven time-points across the study period. After completion of study visits other than the End of Study visit around vaccination in Year 3, participants will be offered the opportunity to be vaccinated with a different FDA approved influenza vaccine and participate in study visits for Year 4. The study is not designed to assess safety or tolerability of the influenza vaccines administered as part of this study.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

This prospective, single-arm study is designed to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through the establishment of the FluVax3 cohort of healthy older adults. In this study, the investigators will perform comprehensive profiling of blood antibodies and immune cells over time, and associate specific age-related immune alterations with vaccine responder or non-responder status. This will allow the investigators to pinpoint biological pathways that can be targeted to enhance vaccine efficacy and that can also help the investigators progress towards developing a universal influenza vaccine. The results are expected to provide the foundation for new approaches to improve overall vaccine efficacy and protection in older adults, an outcome of significant public health relevance considering the vulnerability of this population.

In this study, up to seventy-five (75) healthy adults aged 65 years and older who have not received influenza vaccination for the approaching influenza season will be enrolled in the study and vaccinated with influenza vaccines approved by the U.S Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) for individuals ≥65 years. All participants receive influenza vaccine during the 2022-23, 2023-24, and 2024-25 influenza seasons. Participants will receive Fluzone® Quadrivalent High-Dose vaccine during the 2022-23 flu season, FLUAD® Quadrivalent during the 2023-24 flu season and Flublok Quadrivalent in the 2024-2025 flu season. The study sample will be drawn from the population of healthy older participants in the catchment area of UConn Health in Farmington, CT.

Study participation will involve six study visits around the flu vaccine each year and one final study visit for a total of nineteen study visits over three years. Blood samples will be collected at sixteen study visits for transcriptional, epigenetic and biological analyses pre- and post-vaccination. Nasal swab and stool samples will also be collected from participants at seven time-points across the study period. These microbiome samples will be stored and used in future research. After completion of study visits other than the End of Study visit around vaccination in Year 3, participants will be offered the opportunity to be vaccinated with the FDA approved Fluzone High Dose (trivalent) vaccine during the 2025-26 flu season and participate in study visits for Year 4. Blood samples will be collected from participants at an additional 5 timepoints and nasal swabs at an additional 2 timepoints across Year 4. The study is not designed to assess safety or tolerability of the influenza vaccines administered as part of this proposed study.

This project will yield an unparalleled dataset from healthy older adults that will be used to identify fundamental mechanisms, cell populations, and pathways associated with durable protective antibody immune responses, and lack thereof, upon influenza vaccination. In sum, this study will reveal the mechanistic alterations that explain the heterogeneity in response to vaccines observed in older individuals. Understanding this heterogeneity opens the possibility of stratifying older adults for personalized vaccines. In addition, understanding the mechanistic overlap between the correlates of responsiveness to four different influenza vaccines will advance the ultimate development of a universal influenza vaccine, which is a key focus of NIAID's influenza research program. Finally, this study will generate a considerable amount of transcriptional and functional data related to the outputs of key innate immune and T/B-cell subsets involved in responses to influenza vaccines in older adults. These data will collectively become an important resource for future studies focused on the older adult immune system in health and disease.

Study Type

Interventional

Enrollment (Estimated)

75

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
    • Connecticut
      • Farmington, Connecticut, United States, 06030
        • UConn Health, Center On Aging

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

65 years and older (Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Able to speak and read English
  • Male or Female, 65 years and older by date of enrollment
  • Weight of 110 lbs or greater
  • Has received influenza vaccine in the past seasons without severe adverse reactions
  • Willing to receive an FDA-approved age-appropriate and CDC-recommended influenza vaccine for each of the 2022-23, 2023-24, and 2024-25 influenza seasons
  • Willing to withhold all other vaccinations 2 weeks prior and 2 weeks after flu vaccination for the 2022-23, 2023-24, and 2024-25 influenza seasons
  • Willing and available to participate in 19 study visits over three years around influenza vaccination
  • Willing to provide blood samples at sixteen visits over three years
  • Willing to agree to genomic testing of samples and sharing of de-identified genomic data generated from samples at the conclusion of the research

Exclusion Criteria:

  • Received any vaccine (shingles, pneumococcal, COVID, etc.) within 2 weeks of anticipated flu vaccination for the 2022-23, 2023-24, and 2024-25 influenza seasons.
  • Has already received an influenza vaccine for the approaching influenza season (2022-23)
  • Has known allergy to eggs or any component of the flu vaccine. [Although the Advisory Committee on Immunization Practices (ACIP) has concluded that a history of anaphylactic/anaphylactoid or severe allergic reaction to eggs should no longer be considered a contraindication to vaccination with any age-appropriate vaccine, for the purposes of this research study we elected to exclude individuals with these allergies]
  • History of Guillain-Barre syndrome (GBS)
  • Body temperature greater than 100.3°F (38°C) on date of vaccination or within 2 days prior to vaccination by participant report (study entry may be delayed to meet this requirement)
  • Rockwood Frailty Index score of >0.21

  • Known history of any of the following co-morbid conditions:

    • Chronic or recent (within past 2 months) infection requiring oral or intravenous antibiotics, antifungals, or antivirals
    • Cancer other than basal cell carcinoma requiring active surgical or medical treatment (chemotherapy or radiation therapy)
    • Congestive Heart Failure
    • Ischemic Heart Disease
    • Congenital abnormalities (PI to evaluate)
    • Paget's disease
    • Renal failure requiring ongoing dialysis
    • Chronic obstructive pulmonary disease, emphysema, or asthma
    • Severe autoimmune disease requiring biological therapy
    • Diabetes mellitus requiring insulin
    • Use of medicines during past 6 months known to alter immune response such as high-dose corticosteroids (≥ 10 mg/day of prednisone or equivalent)
    • HIV, AIDS or other immunodeficiency disorders
    • Recent (≤ 3 months) severe trauma or major surgery (PI to evaluate)
    • Current substance and/or alcohol abuse
  • Patients currently residing in the Department of Correction
  • Inability to comply with the protocol requirements
  • Any other condition that, in the opinion of the PI, might interfere with study objectives

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: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Healthy Older Adults
Will receive FDA-approved influenza vaccine (Fluzone HD (Quadrivalent) Year 1, FLUAD Year 2, Flublok Quadrivalent Year 3, Fluzone HD (Trivalent) Year 4)
Biological: Flu Vaccine (Year 1)
Participants will receive Fluzone® Quadrivalent High-Dose in the 2022-2023 flu season.
Other Names:
  • Fluzone® Quadrivalent High-Dose
Biological: Flu Vaccine (Year 2)
Participants will receive FLUAD® Quadrivalent in the 2023-2024 flu season.
Other Names:
  • FLUAD
Biological: Flu Vaccine (Year 3)
Participants will receive Flublok Quadrivalent in the 2024-2025 flu season.
Other Names:
  • Flublok Quadrivalent
Biological: Flu Vaccine (Year 4)
Participants will receive Fluzone® High-Dose Trivalent in the 2025-2026 flu season.
Other Names:
  • Fluzone® High-Dose Trivalent

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Antibody Responses to Influenza Vaccine Year One
Time Frame: Baseline, Day 35, Day 180
In year one, healthy older participants will receive Fluzone Quadrivalent HD vaccine. Longitudinal blood samples will be collected and influenza-specific antibody responses will be assessed. Change in antibody response will be measured using Hemagglutination Inhibition (HAI) from baseline to day 35 and day 180.
Baseline, Day 35, Day 180
Change in Antibody Responses to Influenza Vaccine Year Two
Time Frame: Baseline, Day 35, Day 180
In year two, healthy older participants will receive FLUAD vaccine. Longitudinal blood samples will be collected and influenza-specific antibody responses will be assessed. Change in antibody response will be measured using Hemagglutination Inhibition (HAI) from baseline to day 35 and day 180.
Baseline, Day 35, Day 180
Change in Antibody Responses to Influenza Vaccine Year Three
Time Frame: Baseline, Day 35, Day 180
In year three, healthy older participants will receive Flublok Quadrivalent vaccine. Longitudinal blood samples will be collected and influenza-specific antibody responses will be assessed. Change in antibody response will be measured using Hemagglutination Inhibition (HAI) from baseline to day 35 and day 180.
Baseline, Day 35, Day 180
Change in Antibody Responses to Influenza Vaccine Year Four
Time Frame: Baseline, Day 35, Day 180
In year four, healthy older participants will receive Fluzone® High-Dose Trivalent vaccine. Longitudinal blood samples will be collected and influenza-specific antibody responses will be assessed. Change in antibody response will be measured using Hemagglutination Inhibition (HAI) from baseline to day 35 and day 180.
Baseline, Day 35, Day 180

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate changes in functional status of immune cells in response to Influenza Vaccine in Year One
Time Frame: Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in older participants following administration of Fluzone Quadrivalent HD vaccine. A longitudinal analysis of different cell populations (B Cells, Functional T/B Cells, and monoclonal antibodies) in whole blood samples will be analyzed at baseline and 35 days post vaccination using single cell assays and ELISA.
Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in response to Influenza Vaccine in Year Two
Time Frame: Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in older participants following administration of FLUAD vaccine. A longitudinal analysis of different cell populations (B Cells, Functional T/B Cells, and monoclonal antibodies) in whole blood samples will be analyzed at baseline and 35 days post vaccination using single cell assays and ELISA.
Baseline, Day 7, Day 35
Number of genes upregulated in response to Influenza Vaccine in Year One
Time Frame: Baseline, Day1, Day 7
RNA-seq and scRNA-seq will be used to assess the number of genes upregulated in response to Fluzone Quadrivalent HD vaccination.
Baseline, Day1, Day 7
Number of genes upregulated in response to Influenza Vaccine in Year Two
Time Frame: Baseline, Day 1, Day 7
RNA-seq and scRNA-seq will be used to assess the number of genes upregulated in response to FLUAD vaccination.
Baseline, Day 1, Day 7
Number of chromatin accessibility regions activated in response to Influenza Vaccine in Year One
Time Frame: Baseline, Day1, Day 7
snATAC-seq will be used to assess the number of open chromatin regions activated in response to Fluzone Quadrivalent HD vaccination.
Baseline, Day1, Day 7
Number of chromatin accessibility regions activated in response to Influenza Vaccine in Year Two
Time Frame: Baseline, Day1, Day 7
snATAC-seq will be used to assess the number of open chromatin regions activated in response to FLUAD vaccination.
Baseline, Day1, Day 7
Changes in number of cDCs, Tfh, Th10, and B lymphocytes in response to Influenza Vaccine in Year One
Time Frame: Baseline, Day1, Day 7, Day 35, Day 180
Flow cytometry will be used to assess cell compositional changes in PBMCs and immune cell subsets (cDCs, Tfh, Th10, and B lymphocytes) in response to Fluzone Quadrivalent HD vaccination.
Baseline, Day1, Day 7, Day 35, Day 180
Changes in number of cDCs, Tfh, Th10, and B lymphocytes in response to Influenza Vaccine in Year Two
Time Frame: Baseline, Day1, Day 7, Day 35, Day 180
Flow cytometry will be used to assess cell compositional changes in PBMCs and immune cell subsets (cDCs, Tfh, Th10, and B lymphocytes) in response to FLUAD vaccination.
Baseline, Day1, Day 7, Day 35, Day 180
Number of chromatin accessibility regions activated in response to Influenza Vaccine in Year Three
Time Frame: Baseline, Day1, Day 7
snATAC-seq will be used to assess the number of open chromatin regions activated in response to Flublok Quadrivalent influenza vaccination.
Baseline, Day1, Day 7
Changes in number of cDCs, Tfh, Th10, and B lymphocytes in response to Influenza Vaccine in Year Three
Time Frame: Baseline, Day1, Day 7, Day 35, Day 180
Flow cytometry will be used to assess cell compositional changes in PBMCs and immune cell subsets (cDCs, Tfh, Th10, and B lymphocytes) in response to Flublok Quadrivalent influenza vaccination.
Baseline, Day1, Day 7, Day 35, Day 180
Evaluate changes in functional status of immune cells in response to Influenza Vaccine in Year Three
Time Frame: Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in older participants following administration of Flublok Quadrivalent vaccine. A longitudinal analysis of different cell populations (B Cells, Functional T/B Cells, and monoclonal antibodies) in whole blood samples will be analyzed at baseline and 35 days post vaccination using single cell assays and ELISA.
Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in response to Influenza Vaccine in Year Four
Time Frame: Baseline, Day 7, Day 35
Evaluate changes in functional status of immune cells in older participants following administration of Fluzone High Dose Trivalent vaccine. A longitudinal analysis of different cell populations (B Cells, Functional T/B Cells, and monoclonal antibodies) in whole blood samples will be analyzed at baseline and 35 days post vaccination using single cell assays and ELISA.
Baseline, Day 7, Day 35
Number of genes upregulated in response to Influenza Vaccine in Year Three
Time Frame: Baseline, Day1, Day 7
RNA-seq and scRNA-seq will be used to assess the number of genes upregulated in response to Flublok Quadrivalent vaccination.
Baseline, Day1, Day 7
Number of genes upregulated in response to Influenza Vaccine in Year Four
Time Frame: Baseline, Day1, Day 7
RNA-seq and scRNA-seq will be used to assess the number of genes upregulated in response to Fluzone High Dose Trivalent vaccination.
Baseline, Day1, Day 7
Number of chromatin accessibility regions activated in response to Influenza Vaccine in Year Four
Time Frame: Baseline, Day1, Day 7
snATAC-seq will be used to assess the number of open chromatin regions activated in response to Fluzone High Dose Trivalent vaccination.
Baseline, Day1, Day 7
Changes in number of cDCs, Tfh, Th10, and B lymphocytes in response to Influenza Vaccine in Year Four
Time Frame: Baseline, Day1, Day 7, Day 35, Day 180
Flow cytometry will be used to assess cell compositional changes in PBMCs and immune cell subsets (cDCs, Tfh, Th10, and B lymphocytes) in response to Fluzone High Dose Trivalent influenza vaccination.
Baseline, Day1, Day 7, Day 35, Day 180

Collaborators and Investigators

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

Sponsor

The Jackson Laboratory

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
University of Chicago
Icahn School of Medicine at Mount Sinai
Weill Medical College of Cornell University
UConn Health

Investigators

  • Principal Investigator: George Kuchel, MD, FRCP, UConn Center on Aging

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)

August 31, 2022

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

August 2, 2022

First Submitted That Met QC Criteria

August 24, 2022

First Posted (Actual)

August 26, 2022

Study Record Updates

Last Update Posted (Actual)

August 3, 2026

Last Update Submitted That Met QC Criteria

July 30, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22-179J-1
  • U01AI165452 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Participants will provide permission within the ICF for sharing their randomly recoded (new code that is different than the study code) genomic data in controlled access scientific databases.

Participants will provide permission within the ICF for sharing of randomly recoded (new code that is different than the study code) residual samples and linked data with other researchers to be used in future research studies.

IPD Sharing Time Frame

Conclusion of the study

IPD Sharing Access Criteria

Pending dbGaP/ImmPORT registration

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

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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