FLUAD vs. FLUZONE HD Influenza Vaccine in Residents of Long Term Care

May 26, 2023 updated by: David H. Canaday

Non-inferiority Study of Adjuvanted vs. High Dose Flu Vaccine in Residents of Long Term Care

Adjuvanted flu vaccine, Fluad, is not immunologically inferior to HD influenza vaccine in older persons living in long-term care.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

As the primary endpoint, this trial is be using pre- to post-vaccine changes in HAI titers to compare seroconversion rates and post-vaccination HAI titers to calculate the ratio of the geometric mean titers in the two treatment groups. HAI is an in vitro bioassay that determines a subject's serum levels of anti-influenza antibodies. The FDA uses this as a standard immunogenicity assay for licensure. The trial will follow guidelines set out in the FDA guidance document discussing non-inferiority immunogenicity studies. As additional methods to assess immunogenicity, an assessment of anti-NA by performing NA inhibition assays (NAI) and SVN assays will be added. A recent trial supported the use of NAI and SVN assays as a correlate for protection in a trial of geriatric subjects. A healthy human challenge model showed that NAI is more predictive of protection and reduced disease than HAI

In the large HD vaccine clinical efficacy trial (n=31,989) one third of subjects also had immunogenicity data that allowed looking for correlations of immune assays with protection. Their conclusions were that HAI and other immune assays are potential correlates of influenza vaccine protection in older adults, and that the protective thresholds for the HAI assay in the elderly appear consistent with those previously described for younger adults, provided the assay virus matches the circulating virus.

Significance Data compiled by CDC in 2011-2012 showed that there were 1,383,700 residents in NHs. Also about 4,742,500 patients received services from home health agencies, and 1,244,500 patients received services from hospices, collectively accounting for much of the frailest in the US. Overall, these provider sectors served over 8 million people annually (2013). This study will focus on residents in NHs but the findings of this study are highly relevant to persons frail enough to require such services in all of settings where the vast majority are at least 65 years old and thus appropriate for Fluad or HD, influenza vaccines licensed for this age group.

The SD influenza vaccine has diminished efficacy in the older population with the more debilitated LTC residents being among the worst responders yet with the highest mortality. Deaths due to pneumonia and influenza and chronic lung disease were 20 times higher among NH residents compared to community residents. The current availability of two vaccines specifically for the elderly that both appear to work better than SD vaccine begs the question: is the newer and less-costly Fluad vaccine non-inferior or even superior to HD vaccine? The proposed study aims to initially address non-inferiority using immunologic endpoints as this is feasible in the clinical trial R01 grant structure and a critical first step to obtain head-to-head data from the same trial, cohort and vaccine years. This proposed study itself may provide direct guidance on vaccine usage or inform a future trial assessing actual superiority should that be appropriate based on the results of this study.

HD vaccine is increasingly used by older Americans despite its greater cost over the SD vaccine and no preferential recommendation by the Advisory Committee on Immunization Practices (ACIP), the CDC committee responsible for making the vaccine recommendations for the U.S. A finding of non-inferiority in the primary endpoint would provide a strong rationale to consider using Fluad over HD that could result in some cost avoidance across large long-term care system in the U.S. The trial is not powered for a superiority analysis but in a non-inferiority trial if the findings are substantial enough they may show superiority.

In the normal seasonal setting, influenza strains drift antigenically and therefore vary from year to year. The CDC's prediction many months before the vaccination season sets the composition for the next season's vaccine, but does not always correctly anticipate the exact strain match that eventually actually circulates. There are Medicare claims data and modeling in the NH population that there is a significant increase in death and hospitalization in bad match over good match years particularly when A/H3N2 predominates. In those mismatched years in particular, heterologous immunity or immunity to other non-exact match strains becomes much more important if the vaccine is going to provide any benefit that season. Fluad is an adjuvanted vaccine that has been shown to have a more broad-based or heterologous immunity than SD vaccine that is not adjuvanted. HD is also not adjuvanted. Broad based immunity is especially desirable for A/H3N2 immunity as that has had 4 different circulating strains in the last 5 years while circulating A/H1N1 has been the same for 5 years; i.e., vaccine mismatch is more likely with the A/H3N2 circulating strain. A/H3N2 is associated with the majority of influenza hospitalizations and death among the elderly.

Study Type

Interventional

Enrollment (Actual)

478

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
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • University Hospitals Cleveland Medical Center
      • Cleveland, Ohio, United States, 44106
        • Louis Stokes Cleveland VA 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

65 years and older (Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • > 65 years old
  • Able to obtain consent from subject or legally authorized representative (subject to provide assent if cognitively/physically able to do so)
  • Able to participate throughout the study period

Exclusion Criteria:

  • Recent illness (within 30 days) severe enough to require hospitalization or physician-directed outpatient pharmacotherapy
  • Administration of immunomodulatory agents (e.g. oral corticosteroids except prednisone < 10 mg daily, cyclosporine, and biologics (DMARDS) for Rheumatologic/Dermatologic conditions) in the last 3 months
  • Cancer requiring treatment in the past three years, except for non- melanoma skin cancers or cancers that have clearly been cured or carry an excellent prognosis including prostate cancer.
  • Myocardial infarction, major heart surgery (i.e. valve replacement or bypass surgery), stroke, deep vein thrombosis or pulmonary embolus in the past 4 months
  • Allergies or history of significant adverse reactions to any component of influenza vaccine including egg protein and latex or after a previous dose of any influenza vaccine.
  • History of Guillian-Barré Syndrome within 6 weeks of a prior influenza vaccine.

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Fluad Vaccine
A single adjuvanted dose (AD) intramuscular injection
Drug: Fluad Vaccine
single adjuvanted dose (AD) intramuscular injection
Active Comparator: Fluzone Vaccine
A single high dose (HD) intramuscular injection
Drug: Fluzone HD Vaccine
single high dose (HD) intramuscular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-inferiority in overall hemagglutinin inhibition (HAI) titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined.
Time Frame: 1 month post vaccine administration
HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.
1 month post vaccine administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-inferiority in overall neuraminidase inhibition (NAI) titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined.
Time Frame: 1 month post vaccine administration
Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer.
1 month post vaccine administration
Non-inferiority in overall serum virus neutralization (SVN) assays titer and seroconversion rate between FLUAD and FLUZONE HD at 1 month post-vaccination will be determined.
Time Frame: 1 month post vaccine administration
Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infecgtion. Seroconversion is 4-fold rise in serum titer of inhibitory activity.
1 month post vaccine administration
Heterologous immunity at 1 month post-vaccination will be compared between FLUAD and FLUZONE HD.
Time Frame: 1 month post vaccine administration
Hemagglutinin inhibition (HAI), neuraminidase inhibition (NAI) assays and serum virus neutralization (SVN) assays will be performed with heterologous A/H3N2 strains to determine if Fluad has an increased breadth of both B and T cell responses as would be predicted from an adjuvanted vaccine.
1 month post vaccine administration

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
To Pilot clinical objective: Efficacy of FLUAD will be compared to FLUZONE HD.
Time Frame: 6-8 months post vaccine administration
A record review and a blood 2 weeks after the influenza season is over will be done. From a record review the dates and diagnoses of hospitalizations and/or "influenza like illness" (ILI) will be recorded. Serologic evidence of influenza infection ( >=4-fold titer rise beyond the post-vaccine titers) will be determined from the remote blood draw. An exploratory analysis will be performed comparing the efficacy of the two vaccines.
6-8 months post vaccine administration

Collaborators and Investigators

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

Sponsor

David H. Canaday

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Brown University
National Institutes of Health (NIH)
US Department of Veterans Affairs
Case Western Reserve University

Investigators

  • Principal Investigator: David Canaday, MD, University Hospitals Cleveland Medical Center/Case Western Reserve University/Louis Stokes Cleveland VA Medical Center
  • Principal Investigator: Steven Gravenstein, MD, MPH, Brown University and Providence VA Medical Center

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)

September 23, 2018

Primary Completion (Actual)

January 31, 2023

Study Completion (Actual)

January 31, 2023

Study Registration Dates

First Submitted

September 26, 2018

First Submitted That Met QC Criteria

October 1, 2018

First Posted (Actual)

October 3, 2018

Study Record Updates

Last Update Posted (Actual)

May 30, 2023

Last Update Submitted That Met QC Criteria

May 26, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10-27-29
  • 1R01AI129709-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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