Systems Investigation of Vaccine Responses in Aging and Frailty

This study will compare the immune response signatures (including immunologic, transcriptomic and metabolomic) of the two influenza vaccines approved for use in adults age 65 and over (Fluad and Fluzone High-Dose).

Study Overview

• Status: Recruiting
• Conditions: Influenza
• Intervention / Treatment: Biological: Fluad; Biological: Fluzone

Detailed Description

There are two vaccines currently approved for use in adults age 65 and greater: a high-dose (HD) influenza vaccine (Fluzone High-Dose) that contains 4 times the hemagglutinin dose found in the standard vaccine, and a standard-dose (SD) vaccine containing the proprietary MF59 adjuvant (Fluad). Both vaccines give significantly highly antibody responses to influenza in older adults. This study will directly compare the HD and SD vaccines in nursing home residents, the population of older adults most vulnerable to influenza outbreaks and morbidity and mortality. It will comprehensively study the innate and adaptive response to vaccination, as well as elucidate transcriptomic and proteomic signatures of vaccine response.

This is a randomized, open label study comparing the two vaccines currently approved for use in adults age ≥ 65 years: the high-dose influenza vaccine and the MF59 adjuvanted standard-dose vaccine, both quadrivalent. The young group will be comprised of individuals 21-30 years of age, and the older cohorts will consist of nursing home residents ≥65 years. Participants will also be evaluated for evidence of influenza-like illness (ILI). ILI is defined to include clinical presentation in older adults: by the presence of either two respiratory symptoms (cough, sore throat, shortness of breath, and nasal stuffiness) or one respiratory and one systemic symptom (headache, malaise, temperature >99° F, report of feverishness and muscle aches, or altered mental status). Diagnoses of influenza will be confirmed using a real-time polymerase chain reaction (PCR) test on a nasopharyngeal (NP) swab specimen done by the hospital Virology Laboratory and facilitated by the participating medical directors.

Although this is neither an efficacy or effectiveness study, participants will be randomized 1:1 to either the high-dose influenza vaccine or the MF59 vaccine within age strata. This will ensure a non-biased allocation of the two vaccines and attempts to balance participant characteristics within age strata.

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Irene Matos, RN; Phone Number: (203) 737-4739; Email: irene.matos@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale School of Medicine
      • Contact: Irene Matos, RN; Phone Number: 203-737-4739; Email: irene.matos@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 21-40 or 65 and older
• Ability to understand and give informed consent (surrogate consent may apply to nursing home subjects who are decisionally impaired, with verbal assent to be obtained from subject)
• Plan to be in the New Haven, CT area for the next 4-6 weeks

Exclusion Criteria:

• Current use of medication, such as antibiotics in past two weeks. To clarify, patients taking antibiotics for the reason of a current acute infection will not be eligible. Those potential participants receiving antibiotics for prophylaxis purposes will be eligible to participate. The intention is not to create a separate group to drawn conclusions, but not to exclude these participants who are not acutely ill.
• Evidence of acute infection, identified by self- report of fever or symptoms in past two weeks
• Treatment for cancer in past three months.
• Previous adverse reaction to influenza vaccine requiring medical attention, such as allergic response (rash, anaphylaxis) or Guillain-Barré syndrome.
• Pregnant/possibly pregnant.
• History of organ, bone marrow or stem cell transplant, liver cirrhosis, kidney disease requiring dialysis, HIV/AIDS, hepatitis C or active hepatitis B
• Blood donation of 1 pint or more in past 2 months
• Treatment with clinical trial medication
• Presence of any other condition (e.g., geographical or social), actual or projected, that the investigator feels would restrict or limit the patient's participation for the duration of the study. This provision includes participants who have 50% or more missed appointments in the last three months.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 21-30 standard dose Fluad; Participants age 21-30 years will receive the standard dose Fluad	Biological: Fluad; Fluad Quadrivalent, MF59 adjuvanted 0.5 ml intramuscular injection, standard as recommended by manufacturer
Active Comparator: 21-30 high dose Fluzone; Participants age 21-30 years will receive the high dose Fluzone	Biological: Fluzone; Fluzone High-Dose 0.7 ml intramuscular injection, standard as recommended by manufacturer
Experimental: ≥65 years standard dose Fluad; Participants age ≥65 years will receive standard dose Fluad	Biological: Fluad; Fluad Quadrivalent, MF59 adjuvanted 0.5 ml intramuscular injection, standard as recommended by manufacturer
Experimental: ≥65 years high dose Fluzone; Participants age ≥65 years will receive high dose Fluzone	Biological: Fluzone; Fluzone High-Dose 0.7 ml intramuscular injection, standard as recommended by manufacturer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in production of IL-6 in monocytes to assess innate immune inflammatory response	Measurement of IL-6 production in monocytes via flow cytometry	Baseline and at Day 2, 7, and 28 post-vaccine

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in transcriptomic analyses of gene expression	RNA-seq analysis of RNA derived from peripheral blood mononuclear cells (PBMCs) and platelet-rich plasma (PRP)	At Baseline, Day 2, Day 7, Day 28 and Day 70
Change in proteomic analyses	Analysis of protein expression using Mass Spectrometry in plasma	At Baseline, Day 2, Day 7, Day 28 and Day 70
Number of participants with changes in B and T cell function from PBMCs as assessed using flow cytometry	This will include analysis of number and proportion of antibody-secreting cells post-vaccine, and analyses of T cells following ex vivo stimulation of PBMCs with influenza hemagglutinins.	At Baseline, Day 2, Day 7, Day 28 and Day 70
Change in Hemagglutination inhibition titer (HAI) in response to vaccination	HAI titers levels in blood measured prior to and at day 28 post-vaccine	Baseline and Day 28
Number of participants with changes in innate immune function from PBMCs and PRP as assessed using flow cytometry	Analyses will include intracellular production of cytokines including IL-10 and TNF-alpha in monocyte populations from PBMCs and expression of platelet activation markers such as CD63 and P-selectin on platelets. The effects of ex vivo Toll-like Receptor stimulation on these parameters will also be assessed.	At Baseline, Day 2, Day 7, Day 28 and Day 70

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Albert Shaw, MD, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2023
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: March 7, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 23, 2022

Study Record Updates

• Last Update Posted (Actual): June 12, 2025
• Last Update Submitted That Met QC Criteria: June 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: older adults; vaccine; influenza vaccine; immune response; vaccine response; toll-like receptors
• Additional Relevant MeSH Terms: Pathologic Processes; Frailty
• Other Study ID Numbers: 2000035834; 0409027018 (Other Identifier: previous Yale IRB); U19AI089992 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data with Protected Health Information (PHI) removed on participant demographics and health conditions, and primary and secondary outcome data will be uploaded to the NIH ImmPort as required by the NIH Human Immunology Project Consortium.

Publicly available data will be released after publication. Registration on ImmPort required by the NIH. Timeframe for data upload will be approximately 6-12 months after each influenza vaccine season during the study.

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