Flu Vaccine Effectiveness in Aging

(FluVax3 Trial)

Overseen By George Kuchel, MD, FRCP

Age: 65+

Sex: Any

Trial Phase: Phase 4

Sponsor: The Jackson Laboratory

Must not be taking: High-dose corticosteroids

Disqualifiers: Cancer, Heart disease, COPD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 19

75 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are taking medicines that alter immune response, like high-dose corticosteroids, you may not be eligible to participate.

What data supports the effectiveness of the flu vaccine in preventing hospital admissions?

Preliminary results from the 2014/15 season show that the flu vaccine reduced the chance of hospital admission due to influenza by 44% and was 40% effective in people aged 65 and older. ^{1 2 3 4 5}

Is the flu vaccine safe for older adults?

The flu vaccines, including the trivalent adjuvanted (aIIV3) and high-dose (HD-IIV3) versions, have been shown to be safe for adults aged 65 and older. Studies indicate that these vaccines maintain a favorable safety profile while providing enhanced immune responses in older adults. ^{6 7 8 9 10}

How is the flu vaccine treatment unique compared to other treatments for flu prevention?

The flu vaccine treatment is unique because it involves multiple types of vaccines over three years, including high-dose and adjuvanted versions, which are specifically designed to enhance immune response in older adults, making it more effective for aging populations compared to standard flu vaccines. ^{11 12 13 14 15}

What is the purpose of this trial?

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. The study is not designed to assess safety or tolerability of the influenza vaccines administered as part of this study.

Research Team

George Kuchel, MD, FRCP

Principal Investigator

UConn Center on Aging

Eligibility Criteria

This trial is for English-speaking men and women aged 65 or older, weighing at least 110 lbs, who are willing to participate in a three-year study involving 19 visits. Participants must be open to receiving annual flu vaccines and providing blood samples. They should not have severe reactions to past flu vaccines but cannot join if they've had Guillain-Barre syndrome after vaccination, recent other vaccinations, egg allergies, certain chronic diseases, or conditions affecting the immune system.

Inclusion Criteria

Able to speak and read English

I agree not to get any vaccines 2 weeks before and after my flu shots for the next three flu seasons.

I am 65 years old or older as of September 1, 2022.

Exclusion Criteria

You are allergic to eggs or any ingredient in the flu vaccine.

I have not received any vaccines within 2 weeks before my flu shot for the 2022-25 seasons.

I have received the flu vaccine for the 2022-23 season.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Vaccination Year 1

Participants receive the Fluzone Quadrivalent High-Dose vaccine and undergo blood sampling for antibody and immune cell analysis

6 months

6 visits (in-person)

Vaccination Year 2

Participants receive the FLUAD Quadrivalent vaccine and undergo blood sampling for antibody and immune cell analysis

6 months

6 visits (in-person)

Vaccination Year 3

Participants receive the Flublok Quadrivalent vaccine and undergo blood sampling for antibody and immune cell analysis

6 months

6 visits (in-person)

Follow-up

Participants are monitored for immune response and effectiveness after each vaccination year

6 months

1 visit (in-person)

Treatment Details

Interventions

• Flu Vaccine (Year 1)
• Flu Vaccine (Year 2)
• Flu Vaccine (Year 3)

Trial Overview The study aims to understand why older adults may have a reduced response to influenza vaccines by administering different flu shots over three years. It involves regular collection of blood samples as well as nasal swabs and stool samples at specific times during the study period.

Participant Groups

Group I: Healthy Older Adults Experimental Treatment 3 Interventions

Will receive FDA-approved influenza vaccine (Fluzone HD Year 1, FLUAD Year 2, Flublok Quadrivalent Year 3)

Flu Vaccine (Year 1) is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Fluzone High-Dose for:

• Prevention of influenza A and B in individuals 65 years and older

Approved in European Union as Fluad for:

• Prevention of influenza A and B in adults 65 years and older

Approved in Canada as Fluvirin for:

• Prevention of influenza A and B in individuals 6 months and older, including those 65 years and older

Approved in Japan as Fluarix Tetra for:

• Prevention of influenza A and B in individuals 6 months and older, including those 65 years and older

Who Is Running the Clinical Trial?

The Jackson Laboratory

Lead Sponsor

Trials

6

Recruited

2,200+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator

Trials

3,361

Recruited

5,516,000+

UConn Health

Collaborator

Trials

218

Recruited

59,100+

Icahn School of Medicine at Mount Sinai

Collaborator

Trials

933

Recruited

579,000+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Findings from Research

In a study of 233 patients with lumbar foraminal stenosis (LFS), selective nerve root block (SNRB) significantly reduced pain by 51% after just 2 weeks, indicating its efficacy as a treatment option.

Patients with lower grades of LFS (1T, 2, 3) experienced greater and more sustained symptomatic improvement compared to those with grade IV LFS, highlighting the importance of stenosis severity in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Pain-reducing Effect After Selective Nerve Root Block According to the Type of Lumbar Foraminal Stenosis. Ko, S., Kwon, J., Lee, Y., et al.[2020]

Stage III lung cancer, which includes both IIIa and IIIb, accounts for about one third of all non-small-cell lung cancer cases, with 40,000 to 50,000 new diagnoses each year.

Current treatment strategies for stage III lung cancer involve surgery combined with chemotherapy and/or radiation for stage IIIa, while stage IIIb primarily relies on chemoradiation, with ongoing clinical trials exploring targeted therapies and improved radiation techniques to reduce tumor failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy for stage III non-small-cell lung cancer. Anderson, CS., Curran, WJ.[2010]

A study of 1,553 patients with stage III melanoma found that their 5-year melanoma-specific survival (MSS) rates were lower than those reported in the American Joint Committee on Cancer (AJCCv8) guidelines, indicating a need for improved treatment strategies.

Specifically, the MSS rates for stage IIIA and IIIB patients were significantly less favorable in the Central Malignant Melanoma Registry cohort compared to AJCCv8, highlighting the ongoing challenges in managing these melanoma stages despite recent therapy advancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts. Garbe, C., Keim, U., Suciu, S., et al.[2021]

During the 2014/15 flu season, the effectiveness of the influenza vaccine against the A(H3N2) strain was relatively low, with an overall effectiveness of only 33%.

For individuals aged 65 and older, the vaccine showed a slightly better effectiveness of 40%, and it was found to reduce the likelihood of hospital admissions due to influenza by 44%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of influenza vaccination programme in preventing hospital admissions, Valencia, 2014/15 early results. Puig-Barbera, J., Mira-Iglesias, A., Tortajada-Girbes, M., et al.[2019]

In a Phase III study involving 234 patients with Stage III non-small-cell lung cancer, neither split-course b.i.d. radiotherapy nor standard q.d. radiotherapy showed superior survival outcomes, with median overall survival rates of 14 months for q.d. and 15 months for b.i.d.

The incidence of severe acute toxicities was similar between the two treatment arms, indicating that both treatment regimens had comparable safety profiles, with no significant differences in time to progression or local failure rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer. Schild, SE., Stella, PJ., Geyer, SM., et al.[2019]

A comprehensive analysis of 36 trials involving 7532 adults aged 65 and older showed that the MF59-adjuvanted trivalent influenza vaccine (aIIV3) has a similar safety profile to the nonadjuvanted vaccine (IIV3), with comparable rates of adverse events (24.8% for aIIV3 vs 26.7% for IIV3).

The study found no significant differences in serious adverse events or other safety concerns between the two vaccines, indicating that aIIV3 is a safe option for older adults receiving influenza vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cumulative clinical experience with MF59-adjuvanted trivalent seasonal influenza vaccine in young children and adults 65 years of age and older. Lindert, K., Leav, B., Heijnen, E., et al.[2019]

Fluzone® High Dose, approved by the FDA for individuals 65 and older, contains four times more hemagglutinin than standard vaccines, leading to a stronger immune response against influenza.

A recent randomized controlled trial showed that this high-dose vaccine maintains a favorable safety profile while enhancing immunologic response, supporting its use in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. Sullivan, SJ., Jacobson, R., Poland, GA.[2010]

In a study involving 757 adults aged 65 and older, the safety profile of the trivalent adjuvanted inactivated influenza vaccine (aIIV3) was found to be noninferior to that of the trivalent high-dose inactivated influenza vaccine (HD-IIV3), with similar rates of moderate-to-severe injection-site pain and other reactions.

Both vaccines did not show significant differences in health-related quality of life (HRQOL) changes post-vaccination, indicating that either vaccine is a safe option for preventing influenza in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial. Schmader, KE., Liu, CK., Harrington, T., et al.[2021]

In a study involving over 3.8 million older adults with health conditions during the 2017-2019 influenza seasons, the MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) was found to be significantly more effective than the standard quadrivalent inactivated influenza vaccine (IIV4) in preventing influenza-related medical encounters, with a relative vaccine effectiveness increase of 7.1% in 2017-2018 and 20.4% in 2018-2019.

The high-dose trivalent inactivated influenza vaccine (HD-IIV3) showed comparable effectiveness to aIIV3, indicating that both enhanced vaccines provide better protection for older adults who are at higher risk for influenza complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of the Adjuvanted Influenza Vaccine in Older Adults at High Risk of Influenza Complications. Boikos, C., Imran, M., Nguyen, VH., et al.[2021]

The MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) showed consistent effectiveness over standard egg-based quadrivalent vaccines (IIV4e) in preventing influenza-related medical encounters among adults aged 65 and older during the 2017-2020 influenza seasons.

When compared to the high-dose influenza vaccine (HD-IIV3), aIIV3 provided better overall benefits while showing comparable effectiveness in at-risk populations, indicating its potential as a superior option for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative Vaccine Effectiveness of Adjuvanted Trivalent Influenza Vaccine over Three Consecutive Influenza Seasons in the United States. Boikos, C., McGovern, I., Ortiz, JR., et al.[2022]

In a study of 59 patients with hypothyroidism, combination therapy using T(3) and T(4) showed significant improvements in quality of life and depression scores compared to T(4) monotherapy, with 49% of participants preferring the combination therapy.

The study maintained stable serum TSH levels across both treatment groups, indicating that the combination therapy was effective without disrupting thyroid hormone balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Nygaard, B., Jensen, EW., Kvetny, J., et al.[2022]

Recent studies indicate that while levothyroxine (L-T4) is the standard treatment for hypothyroidism, some patients may benefit from adding triiodothyronine (T3) due to genetic factors affecting thyroid hormone activation.

Specifically, a polymorphism in the D2 gene (Thr92Ala) may lead to reduced conversion of T4 to T3, which could explain persistent fatigue in patients on L-T4 alone, suggesting that T3 could be considered for a trial in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination L-T3 and L-T4 therapy for hypothyroidism. Wartofsky, L.[2013]

A joint conference by major thyroid associations concluded that there is still uncertainty about the benefits of combining levothyroxine (LT4) and liothyronine (LT3) for thyroid treatment, despite 14 clinical trials showing inconsistent results.

Consensus statements were developed to guide future clinical trials, emphasizing the need for studies to include patients dissatisfied with current therapy, utilize patient-reported outcomes, and ensure robust trial designs to better assess the efficacy of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. Jonklaas, J., Bianco, AC., Cappola, AR., et al.[2022]

The incidence of differentiated thyroid cancer is rising globally, especially among older patients who tend to have more aggressive forms of the disease and higher mortality rates.

A risk-benefit analytic approach is recommended for treating thyroid cancer in older individuals, focusing on individual patient factors and balancing treatment effectiveness with potential side effects to optimize care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal differentiated thyroid cancer management in the elderly. McLeod, DS., Carruthers, K., Kevat, DA.[2018]

In a systematic review of 7 randomized controlled trials involving 348 hypothyroid patients, about 46.2% preferred the combination of L-T3 and L-T4 over L-T4 alone, indicating a significant level of interest in combination therapy, though this preference was not statistically significant compared to chance.

The preference for combination therapy was partially linked to improvements in thyroid-stimulating hormone (TSH) levels, mood, and symptoms, suggesting that these factors may influence patient satisfaction with treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review and Meta-Analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism. Akirov, A., Fazelzad, R., Ezzat, S., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Comparison of Pain-reducing Effect After Selective Nerve Root Block According to the Type of Lumbar Foraminal Stenosis. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Combined modality therapy for stage III non-small-cell lung cancer. [2010]

3. United States pubmed.ncbi.nlm.nih.gov

Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts. [2021]

4. Sweden pubmed.ncbi.nlm.nih.gov

Effectiveness of influenza vaccination programme in preventing hospital admissions, Valencia, 2014/15 early results. [2019]

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Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer. [2019]

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Cumulative clinical experience with MF59-adjuvanted trivalent seasonal influenza vaccine in young children and adults 65 years of age and older. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. [2010]

8. United States pubmed.ncbi.nlm.nih.gov

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of the Adjuvanted Influenza Vaccine in Older Adults at High Risk of Influenza Complications. [2021]

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Relative Vaccine Effectiveness of Adjuvanted Trivalent Influenza Vaccine over Three Consecutive Influenza Seasons in the United States. [2022]

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Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Combination L-T3 and L-T4 therapy for hypothyroidism. [2013]

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Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. [2022]

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A Systematic Review and Meta-Analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism. [2020]