High vs. Standard Dose Flu Vaccine for Transplant Patients

(PSOT Trial)

Recruiting at 9 trial locations

Overseen By Laura Stewart, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: HIV, Lung transplant, Intestine transplant, 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: 2

Duration: 8 weeks

312 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is the high-dose flu vaccine safe for humans?

The high-dose flu vaccine, known as Fluzone High-Dose, has been studied in both children and adults, particularly those 65 and older. Most reported side effects are mild, like injection site reactions, fever, headache, and nausea, with serious events being rare. Overall, no new safety concerns have been identified, suggesting it is generally safe for use. ^{1 2 3 4 5}

How does the high dose flu vaccine differ from standard treatments for transplant patients?

The high dose flu vaccine is unique because it contains a higher amount of antigen (the part of the vaccine that helps your body build protection) compared to the standard dose, which may provide better protection for transplant patients who have weakened immune systems. ^{6 7 8 9 10}

What is the purpose of this trial?

Influenza virus is a significant pathogen in pediatric solid organ transplant (SOT) recipients. However, these individuals respond poorly to standard-dose (SD) inactivated influenza vaccine (IIV). Recent studies have investigated two strategies to overcome poor immune responses in SOT recipients: (1) administration of high-dose (HD)-IIV compared to SD-IIV and (2) two doses of SD-IIV compared to one dose of SD-IIV in the same influenza season. One study compared HD-IIV vs. SD-IIV in adult SOT recipients and noted that HD-IIV was safe and more immunogenic; however, the median post-transplant period was 38 months. A phase I pediatric study comparing a single dose of HD-IIV vs. SD-IIV was safe with higher immunogenicity, but the study was limited by small sample size and median post-transplant vaccine administration was 26 months. In another phase II trial of adult SOT recipients, two doses of SD-IIV one month apart compared to one-dose of SD-IIV revealed modestly increased immunogenicity when given at a median of 18 months post-transplant. Therefore, these studies lack both evaluation in the early post-transplant period and substantive pediatric populations. Additionally, the administration of two-doses of HD-IIV in the same influenza season has not been evaluated in pediatric SOT recipients. Thus, the optimal immunization strategy for pediatric SOT recipients less than 24 months post-transplant is unknown. In addition, immunologic predictors and correlates of influenza vaccine immunogenicity in pediatric SOT recipients have not been well-defined. The central hypothesis of our proposal is that pediatric SOT recipients 1-23 months post-transplant who receive two doses of HD-quadrivalent inactivated influenza vaccine (QIV) will have similar safety but higher Hemagglutination Inhibition (HAI) geometric mean titers (GMTs) to influenza antigens compared to pediatric SOT recipients receiving two doses of SD-QIV.

Research Team

Natasha Halasa, MD, MPH

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for pediatric solid organ transplant recipients aged 3-17, within 1 to 24 months post-transplant. It includes those who've had kidney, heart, or liver transplants and are available for the study duration. Excluded are patients with recent immune treatments, severe allergies, HIV positive status, pregnancy/lactation in females of childbearing age without a negative pregnancy test prior to each vaccine dose.

Inclusion Criteria

I am between 3 and 17 years old.

I received a kidney, heart, or liver transplant between 1 month and 2 years ago.

I have received a transplant for my kidney, heart, or liver.

Exclusion Criteria

I have had a lung or intestine transplant.

History of severe latex hypersensitivity

I have had Guillain-Barre syndrome in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of either high-dose or standard-dose quadrivalent inactivated influenza vaccine 28-42 days apart

8 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including active surveillance for influenza-like symptoms

180 days

Weekly telephone/electronic communication

Treatment Details

Interventions

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

Trial Overview The trial tests whether two doses of High Dose Quadrivalent Inactivated Influenza Vaccine (HD-IIV) provide better immune response compared to Standard Dose (SD) in children who have received an organ transplant less than two years ago. The safety and increase in protective antibodies will be measured.

Participant Groups

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

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?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Children's Hospital Medical Center, Cincinnati

Collaborator

Trials

844

Recruited

6,566,000+

Lucile Packard Children's Hospital

Collaborator

Trials

16

Recruited

2,800+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

Ann & Robert H Lurie Children's Hospital of Chicago

Collaborator

Trials

275

Recruited

5,182,000+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Children's Mercy Hospital Kansas City

Collaborator

Trials

261

Recruited

941,000+

Children's Healthcare of Atlanta

Collaborator

Trials

172

Recruited

108,000+

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 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 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]

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]

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 326 patients with severe influenza across multiple hospitals in Southeast Asia, doubling the dose of oseltamivir (150 mg twice a day) did not show any significant virological or clinical benefits compared to the standard dose (75 mg twice a day).

Both treatment groups had similar rates of viral clearance and mortality, indicating that higher doses of oseltamivir may not be necessary or more effective for treating severe influenza.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. [2021]

In a study of 38 patients with Common Variable Immunodeficiency (CVID) who showed a decline in lung function, increasing the dosage of immunoglobulin replacement therapy (IGRT) significantly improved lung function measures (FEF25-75% and FEV1/FVC) in those with moderate obstruction, indicating a potential benefit of dose adjustment.

Patients with severe obstruction did not show improvement with increased IgG dosage, suggesting that higher doses may be more effective for those with moderate lung function decline rather than severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of FEF25-75% to Guide IgG Dosing to Protect Pulmonary Function in CVID. Hwangpo, T., Wang, Z., Ghably, J., et al.[2021]

In a study involving five patients with severe chronic systemic diseases, high dose intravenous immunoglobulin (IV Ig) treatment (2g/kg/session) showed little to no improvement in their conditions, with only one patient experiencing a transient response.

The inconsistent results and high cost of IV Ig highlight the need for double-blind studies to better understand when this treatment may be more effective than standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Failure of intravenous immunoglobulins in certain systemic diseases. 5 cases]. Bahadoran, P., De Bandt, M., Echard, M., et al.[2016]

In a study of 40 CMV seronegative renal transplant recipients receiving polyvalent intravenous immunoglobulins (IVIg) as prophylaxis, 95% had successful one-year allograft survival, indicating that IVIg is effective in preventing CMV infection and supporting graft health.

The use of IVIg resulted in excellent tolerance with no acute renal failure episodes, suggesting it is a safe option for high-risk patients, and it may also help reduce the incidence of acute rejection, warranting further investigation in randomized studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients. Leroy, F., Sechet, A., Abou Ayache, R., et al.[2006]

In a study of 17 renal transplant patients, administering a short-term high-dose IVIG regimen (4 g/kg total) resulted in 47.1% achieving negative T cell crossmatch status, indicating potential desensitization to donor-specific antibodies.

The cumulative T cell crossmatch-negative conversion rate increased with higher IVIG doses, suggesting that a total dose of 3 g/kg or more may be more effective than the conventional 2 g/kg single-dose protocol for desensitizing patients before transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Desensitization of T cell Flow Cytometry Crossmatch Positive Renal Transplant Recipients Using Plasmapheresis and Super High-Dose Intravenous Immunoglobulin. Kakuta, Y., Satoh, S., Watarai, Y., 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. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

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

4. 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]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Use of FEF25-75% to Guide IgG Dosing to Protect Pulmonary Function in CVID. [2021]

8. France pubmed.ncbi.nlm.nih.gov

[Failure of intravenous immunoglobulins in certain systemic diseases. 5 cases]. [2016]

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

Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients. [2006]

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

Successful Desensitization of T cell Flow Cytometry Crossmatch Positive Renal Transplant Recipients Using Plasmapheresis and Super High-Dose Intravenous Immunoglobulin. [2022]