High vs Standard Dose Flu Vaccine for Lung Transplant Recipients

Recruiting in Nashville (>99 mi)

Overseen By Natasha Halasa, MD, MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt University Medical Center

Must not be taking: B-cell depleting, T-cell depleting

Disqualifiers: Multi-organ transplant, HIV, 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: 3

Duration: 8 weeks

270 Participants Needed

Trial Summary

What is the purpose of this trial?

Lung allograft recipients have a higher burden of influenza disease and greater associated morbidity and mortality compared with healthy controls. Induction and early maintenance immunosuppression is thought to impair immunogenicity to standard dose inactivated influenza vaccine. This early post-transplant period is when immunity is most desirable, since influenza disease during this time frame is associated with adverse consequences. Thus, strategies to reduce severe influenza disease in this highly susceptible population are critical. No trials in lung transplant recipients have evaluated two doses of HD-IIV within the same influenza season as a strategy to improve immunogenicity and durability of influenza prevention. Furthermore, no influenza vaccine trials have focused on enrollment of subjects at early post-transplant timepoints. Very few studies have been performed in solely lung allograft recipients. Immunosuppression intensity is highest in lung patients, thereby limiting comparisons to recipients of heart, liver, and kidney transplants. Therefore, studies to assess both HD-IIV and two-dose strategies in the same influenza season in post-lung transplant recipients are greatly needed. The central hypothesis of our proposal is that lung allograft recipients who are 1-35 months post-transplant and receiving two doses of HD-quadrivalent inactivated influenza vaccine (QIV) will have higher HAI geometric mean titers (GMT) to influenza antigens compared to those receiving two doses of SD-QIV. To test this hypothesis and address the above critical knowledge gaps, we propose to conduct a phase II, multi-center, randomized, double-blind, controlled immunogenicity and safety trial comparing the administration of two doses of HD-QIV to two doses of SD-QIV in lung allograft recipients 1-35 months post-transplant. The results of this clinical trial will address significant knowledge gaps regarding influenza vaccine strategies (e.g., one vs. two doses and HD-QIV vs. SD-QIV) and immune responses in lung transplant recipients and will guide vaccine recommendations during the post-transplant period.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have received certain treatments like rituximab or other B-cell depleting therapies within 3 months before the first study vaccine, you may not be eligible to participate.

What data supports the effectiveness of the high-dose flu vaccine for lung transplant recipients?

Research shows that the high-dose flu vaccine provides better protection against the flu compared to the standard-dose vaccine, especially in older adults. This suggests it might also be more effective for lung transplant recipients, who often have weakened immune systems. ^{1 2 3 4 5}

Is the high-dose flu vaccine generally safe for humans?

The high-dose flu vaccine, known as Fluzone High-Dose, has been studied for safety in older adults. Most reported side effects are mild, like injection site reactions, fever, headache, and nausea, with serious events being rare. No new safety concerns have been identified. ^{1 2 3 4 6}

How does the flu vaccine for lung transplant recipients differ from other flu vaccines?

The flu vaccine for lung transplant recipients in this trial uses a high dose of the quadrivalent inactivated influenza vaccine, which is designed to provide stronger protection compared to the standard dose, potentially offering better immunity for those with weakened immune systems. ^{7 8 9 10 11}

Research Team

Natasha Halasa, MD, MPH

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for lung transplant recipients aged 16 or older, who are between 1-35 months post-transplant. Participants must be reachable and available throughout the study. Exclusions include re-do transplants, multi-organ transplants, HIV positive individuals, severe latex allergy sufferers, recent recipients of certain immune therapies, pregnant women, those with egg allergies or a history of Guillain-Barre syndrome.

Inclusion Criteria

People who have had a lung transplant

I had a lung transplant between 1 and 36 months ago.

I am 16 years old or older.

Exclusion Criteria

I had the flu after September 1st but before getting the study vaccine.

I have had Guillain-Barre syndrome in the past.

I haven't received T-cell depleting therapy in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of either HD-QIV or SD-QIV 28-42 days apart

8 weeks

2 visits (in-person)

Influenza Surveillance

Active surveillance for influenza-like symptoms during the influenza season

Influenza season

Weekly telephone/electronic communication

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• High Dose Quadrivalent Inactivated Influenza Vaccine
• Standard Dose Quadrivalent Inactivated Influenza Vaccine

Trial Overview The trial tests whether two doses of a High Dose (HD) influenza vaccine provide better protection than two doses of a Standard Dose (SD) vaccine in lung transplant patients. It's designed to see if higher antibody levels against flu result from the HD vaccine in these immunocompromised individuals.

Participant Groups

Group I: Two Doses Standard Dose Quadrivalent Inactivated Influenza Vaccine Experimental Treatment 1 Intervention

receive two doses of SD-QIV (0.5 mL; 15µg of each influenza antigen) 28-42 days apart

Group II: Two Doses High Dose Quadrivalent Inactivated Influenza Vaccine Experimental Treatment 1 Intervention

two doses of HD-QIV (0.7 mL; 60µg of each influenza antigen) 28-42 days apart

High Dose Quadrivalent Inactivated Influenza Vaccine is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Fluzone High-Dose for:

• Influenza prevention in individuals 65 years and older

Approved in Canada as Fluzone High-Dose for:

• Influenza prevention in individuals 65 years and older

Approved in European Union as Fluzone High-Dose for:

• Influenza prevention in individuals 65 years and older

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Feinberg School of Medicine, Northwestern University

Collaborator

Trials

34

Recruited

12,300+

Northwestern University Feinberg School of Medicine

Collaborator

Trials

42

Recruited

15,500+

University of Washington

Collaborator

Trials

1,858

Recruited

2,023,000+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Findings from Research

The study involving 661 children aged 6 months to under 18 years demonstrated that the high-dose quadrivalent influenza vaccine (IIV4-HD) is safe, with no serious adverse events reported and similar rates of mild reactions compared to the standard-dose vaccine.

IIV4-HD at a dose of 60 µg significantly improved immune responses, particularly in younger children (6 months to <3 years), showing higher antibody titers against various influenza strains compared to the standard-dose vaccine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of high doses of quadrivalent influenza vaccine in children 6 months through Chang, LJ., Anderson, EJ., Jeanfreau, R., et al.[2021]

The high-dose inactivated influenza vaccine quadrivalent (HD-IIV4) has been shown to be safe and effective in preventing influenza in adults aged 65 and older, with improved immunogenicity against additional B strains compared to standard vaccines.

Despite some increased adverse reactions like injection-site pain and myalgia, HD-IIV4 is recommended as the vaccine of choice for older adults due to its superior efficacy compared to other influenza vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Inactivated Influenza Vaccine Quadrivalent for Older Adults. Chahine, EB.[2021]

The high-dose quadrivalent influenza vaccine (QIV-HD) was approved for individuals 65 years and older, and a review of 2,122 adverse event reports showed that 95.1% were non-serious, aligning with findings from prelicensure trials.

No new safety concerns were identified, with the most common serious events being Guillain-Barré syndrome and local reactions, suggesting that QIV-HD is a safe option for preventing influenza in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postmarketing safety surveillance of high-dose quadrivalent influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. Woo, EJ., Moro, PL.[2022]

The high-dose influenza vaccine (QIV-HD) demonstrated significantly higher immune responses compared to the standard-dose vaccine (QIV-SD) in older adults, with greater geometric mean titers for all four influenza strains tested.

Both QIV-HD and QIV-SD had similar safety profiles, indicating that the high-dose vaccine is not only more effective but also safe for use in individuals aged 65 and older.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunogenicity and safety of high-dose quadrivalent influenza vaccine in older adults in Taiwan: A phase III, randomized, multi-center study. Chen, JY., Hsieh, SM., Hwang, SJ., et al.[2023]

In a study involving 2100 adults aged 60 and older, the high-dose quadrivalent influenza vaccine (IIV4-HD) administered intramuscularly showed superior immune responses compared to the standard-dose vaccine (IIV4-SD) given subcutaneously, indicating better protection against influenza.

Both vaccines had similar safety profiles, with IIV4-HD being well tolerated and no significant safety concerns identified, suggesting it is a safe option for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superior immunogenicity of high-dose quadrivalent inactivated influenza vaccine versus Standard-Dose vaccine in Japanese Adults ≥ 60 years of age: Results from a phase III, randomized clinical trial. Sanchez, L., Nakama, T., Nagai, H., et al.[2023]

In a study involving 2670 healthy adults aged 65 and older, the quadrivalent high-dose influenza vaccine (IIV4-HD) demonstrated non-inferior immunogenicity compared to the licensed trivalent high-dose vaccine (IIV3-HD) for all four influenza strains.

IIV4-HD showed superior immune responses for both B strains compared to IIV3-HD that did not contain the same B-lineage strain, while maintaining a similar safety profile, indicating it is a more effective option without added safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized clinical trial. Chang, LJ., Meng, Y., Janosczyk, H., et al.[2020]

Inhaled corticosteroids, such as beclometasone dipropionate, budesonide, and fluticasone propionate, are effective for asthma treatment, showing a dose-response relationship where most benefits are achieved with low to moderate doses, especially in mild-to-moderate cases.

While high doses of fluticasone can provide slight improvements in asthma control, they also significantly increase the risk of oral side effects, highlighting the importance of balancing efficacy and safety in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. Adams, NP., Jones, PW.[2022]

The Airmax multidose dry powder inhaler delivering salbutamol is equally effective as the standard pressurized metered dose inhaler (Ventolin) in improving lung function (FEV1) in asthmatic patients, with a 1:1 dose equivalence established in a study of 61 adults.

Both Airmax and Ventolin showed similar safety profiles, and the Airmax inhaler offers advantages such as eliminating the need for coordinated actuation and inhalation, along with a built-in dose counter.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bronchodilating effects of salbutamol from a novel inhaler Airmax. Middle, MV., Terblanché, J., Perrin, VL., et al.[2019]

In a study involving 21 adult asthmatic patients, a single dose of salbutamol delivered via a novel multiple dose powder inhaler (MDPI) showed equivalent effectiveness in improving lung function compared to a conventional metered dose inhaler (MDI), with similar spirometric outcomes.

Both inhaler types were well tolerated, with no significant effects on blood pressure or heart rate, and most patients found the MDPI easier or equally easy to use, suggesting it could be a favorable alternative to traditional MDIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Easyhaler, a novel multiple dose powder inhaler: clinically equivalent to salbutamol metered dose inhaler and easier to use. Nieminen, MM., Vidgren, M., Laurikainen, K., et al.[2018]

The study aimed to determine if a lower dose combination inhaler of salmeterol and fluticasone (50/250 microg) could provide similar benefits in treating moderate to severe COPD as the higher dose (50/500 microg) inhaler, particularly in improving lung function and reducing exacerbations.

Previous studies have shown that the higher dose inhaler improves forced expiratory volume (FEV1), quality of life, and decreases exacerbations, but most were conducted for less than a year, highlighting the need for longer-term data on the lower dose's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does low-dose seretide reverse chronic obstructive pulmonary disease and are the benefits sustained over time? An open-label Swedish crossover cohort study between 1999 and 2005. Rustscheff, S., Rydén, L.[2017]

The albuterol multi-dose dry-powder inhaler (mDPI) simplifies the delivery of medication by eliminating the need for patients to coordinate inhalation with actuation, making it easier for asthma patients to use.

In two studies involving a total of 118 patients, albuterol mDPI demonstrated comparable efficacy and safety to the ProAir HFA metered-dose inhaler, with both treatments significantly improving lung function (FEV1) compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies. Kerwin, EM., Taveras, H., Iverson, H., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of high doses of quadrivalent influenza vaccine in children 6 months through [2021]

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

High-Dose Inactivated Influenza Vaccine Quadrivalent for Older Adults. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Postmarketing safety surveillance of high-dose quadrivalent influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Immunogenicity and safety of high-dose quadrivalent influenza vaccine in older adults in Taiwan: A phase III, randomized, multi-center study. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Superior immunogenicity of high-dose quadrivalent inactivated influenza vaccine versus Standard-Dose vaccine in Japanese Adults ≥ 60 years of age: Results from a phase III, randomized clinical trial. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized clinical trial. [2020]

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

The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Bronchodilating effects of salbutamol from a novel inhaler Airmax. [2019]

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

Easyhaler, a novel multiple dose powder inhaler: clinically equivalent to salbutamol metered dose inhaler and easier to use. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Does low-dose seretide reverse chronic obstructive pulmonary disease and are the benefits sustained over time? An open-label Swedish crossover cohort study between 1999 and 2005. [2017]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies. [2022]