High Dose Flu Vaccine in Treating Children Who Have Undergone Donor Stem Cell Transplant

Study Overview
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Brief Summary
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This phase II randomized trial studies how well high dose flu vaccine works in treating children who have undergone done stem cell transplant. Higher dose flu vaccine may build a better immune response and may provide better protection against the flu than the standard vaccine.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether high-dose trivalent inactivated influenza vaccine (HD-TIV) compared with standard dose quadrivalent inactivated influenza vaccine (QIV) will increase the probability of achieving a >= 4-fold rise in hemagglutination-inhibition (HAI) titers, >= 1:40 HAI titer, or higher geometric mean titer (GMT) to influenza A antigens in pediatric hematopoietic stem cell transplant (HSCT) recipients. SECONDARY OBJECTIVES: I. To determine whether HD-TIV compared with standard dose QIV will increase the probability of achieving a >= 4-fold rise in HAI titers, >= 1:40 HAI titer, or higher GMT titers to influenza B antigens in pediatric HSCT recipients. II. To determine the frequency and severity of solicited local injection site adverse events (e.g. pain/ tenderness, redness, and swelling at injection site) with HD-TIV compared to standard QIV in pediatric HSCT recipients. III. To determine the frequency and severity of solicited systemic adverse events (e.g. fevers, headache, fatigue/malaise, nausea, body ache/myalgia, general activity level, and vomiting) with HD-TIV compared to standard dose QIV in pediatric HSCT recipients. IV. To define the relationship between HAI titers, in vivo T and B cell phenotype, and in vitro influenza-specific T and B cell response in pediatric HSCT recipients receiving either HD-TIV or standard dose QIV. V. To correlate HAI responses to microneutralization responses. VI. To compare the persistent HAI and microneutralization (MN) titers for all four antigen seven months after the last vaccine dose to assess for persistence of antibody titers. VII. To compare influenza detection by PCR during influenza season in pediatric HSCT recipients receiving either HD-TIV or standard dose QIV. VIII. To assess HAI and MN response in children vaccinated during year 1 and revaccinated during year 2 using the same antigen dose. OUTLINE: Patients are randomized to 1 of 2 treatment groups. GROUP I (Experimental): Patients receive HD-TIV intramuscularly (IM) on day 0 and day 28. GROUP II (Standard): Patients receive standard dose QIV IM on day 0 and day 28. After completion of study treatment, patients are followed up at 28-42 days, and at 7 months.

Official Title
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Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients

Conditions
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Hematopoietic Cell Transplantation Recipient, Malignant Neoplasm, Influenza

Intervention / Treatment
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* Biological: Trivalent Influenza Vaccine
* Biological: Quadrivalent Influenza Vaccine
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Allogeneic HSCT recipients who are 3-35 months post-transplant; 3-17 years of age, inclusive; Available for duration of study; Patients with stable GVHD for at least 4 weeks will be eligible (stable is defined as having no major increases in systemic immunosuppressive therapy for GVHD; adjustments of established medications to obtain a stable target level are acceptable and do not impact eligibility). Parent/legal guardian willing and capable of signing written informed consent; Parent/legal guardian expected to be available for entire study; Parent/legal guardian can be reached by telephone and/or electronic communication. Subjects must have a platelet count of ≥30,000 to receive the immunizations. Patients requiring platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 hours prior to their immunization, or platelet count ≥75,000 without transfusion documented within 30 days for subjects <12 months post-transplant and within 90 days for subjects 12-35 months post-transplant. Exclusion criteria History of hypersensitivity to previous influenza vaccination or severe hypersensitivity to eggs/egg protein; History of Guillain-Barre syndrome; Evidence of hematologic malignancy or disease relapse post-transplant (stable mixed chimerism is permitted); History of receiving current year seasonal influenza vaccine post-transplant; Pregnant female; History of proven influenza disease after September 1, 2018 prior to enrollment Non-allogeneic (e.g. autologous) or syngeneic hematopoietic SCT recipients; History of known active infection with HIV, Hepatitis B or Hepatitis C; History of known severe latex hypersensitivity; Subjects who have received stem cell boost or delayed donor lymphocyte infusion within 90 days prior to enrollment, including day of enrollment; Receipt of IVIG/SCIG <27 days prior to calendar day of vaccination; Subjects who have participated in year 1 and/or 2 of the study, and received study vaccine Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-limiting, and a subject may be included in the study once the condition has resolved, provided that the subject is otherwise eligible: 1). Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of enrollment 2). Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks prior to potential study vaccination. Note: if patients were eligible for vaccine 1, they will be eligible to receive vaccine 2 regardless of any changes on their GVHD status, unless it is deemed not medically safe to receive influenza vaccine. For subjects who were enrolled and vaccinated in 2016-17, 2017-18, or 2018-19, the goal is to enroll individuals who participated in the previous influenza season year and administer the same vaccination as the previous year. These subjects are referred to as repeaters. For example, subjects enrolled in 2016-17 could re-enroll in 2017-18, subjects enrolled in 2017-18 could re-enroll in 2018-19, and subjects in 2018-19 are deemed eligible to re-enroll in 2019-20 as repeaters. Subjects may only enroll as a repeater one time and must enroll the year after their original enrollment. Subjects must receive at least one vaccine to be eligible as a repeater in the subsequent year. Enrollment Criteria for Subjects who Participated in the previous influenza season Repeaters will retain their original study ID and their randomization number Previous screen failures will not be enrolled. If visit 4 from the previous influenza season and visit 1 from the current influenza season year occur on the same day, lab results from visit 4 (prior to consent) can be part of visit 1. Inclusion criteria Available for duration of study; Patients with stable GVHD for at least 4 weeks will be eligible (stable is defined as no major change in systemic immunosuppressive therapy for worsening GVHD; adjustment of actual dose to obtain a stable target level is acceptable). Subjects must have a platelet count of ≥30,000 to receive the immunizations. Patients requiring platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 hours prior to their immunization, or platelet count ≥75,000 without transfusion documented within 30 days for subjects <12 months post-transplant and within 90 days for subjects 12-35 months post-transplant. Parent/legal guardian willing and capable of signing written informed consent; Parent/legal guardian expected to be available for entire study; Parent/legal guardian can be reached by telephone and/or electronic communication. Exclusion criteria History of hypersensitivity to previous influenza vaccination or severe hypersensitivity to eggs/egg protein; History of Guillain-Barre syndrome; Evidence of hematologic malignancy or disease relapse post-transplant (stable mixed chimerism is permitted); History of receiving current year seasonal influenza vaccine post-transplant; Pregnant female; History of proven influenza disease after September 1, 2019 but prior to enrollment History of known active infection with HIV, Hepatitis B or Hepatitis C; Subjects who have received stem cell boost or delayed donor lymphocyte infusion within 90 days of enrollment, including day of enrollment Receipt of IVIG/SCIG <27 days prior to calendar day of vaccination Non-allogeneic (e.g. autologous) or syngeneic hematopoietic SCT recipients; Subjects who have participated in year 1 and/or 2 of the study and received study vaccine. Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-limiting, and a subject may be included in the study once the condition has resolved, provided that the subject is otherwise eligible: 1). Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of enrollment 2). Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks prior to potential study vaccination. Note: if patients were eligible for vaccine 1, they will be eligible to receive vaccine 2 regardless of any changes on their GVHD status, unless it is deemed not medically safe to receive influenza vaccine. Note: Previous Screen failures who were not vaccinated can be enrolled and will be assigned the same study ID number. Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-limiting, and a subject may be included in the study once the condition has resolved, provided that the subject is otherwise eligible: 1). Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of enrollment 2). Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks of study vaccination.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - High Dose TIV<br>Patients receive HD-TIV intramuscularly (IM) on day 0 and day 28. | Biological: Trivalent Influenza Vaccine<br>* High dose Trivalent Influenza Vaccine given intramuscular<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Active Comparator: Group 2 - Standard Dose QIV<br>Patients receive standard dose QIV IM on day 0 and day 28. | Biological: Quadrivalent Influenza Vaccine<br>* Standard dose Quadrivalent Influenza Vaccine given intramuscular<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity as Measured by the Number of Subjects Who Achieve a 4-fold (or Greater) Rise in Post-vaccination HAI Titers | Point estimates and 95% confidence intervals for proportion of subjects achieving seroconversion (4-fold or greater rise in HAI titers from visit 1). | Visit 1 (baseline) was day 0; visit 2 was 28-42 days after visit 1; visit 3 was 28-42 days after visit 2; and visit 4 was 138-222 days after visit 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Solicited Local and Systemic Adverse Events | The proportion of subjects in each group experiencing at least one solicited AE with 95% posterior credible intervals, separated by vaccine number and adverse event type. AEs were assessed by clinicians using Tables 4 and 5 within section C16 of the protocol. Solicited injection site AEs included: pain, tenderness, erythema/redness, and swelling/induration. The diameter of any erythema/redness and swelling/induration was measured to evaluate redness size and swelling size. Solicited systemic AEs included: fevers, fatigue/malaise, headache, nausea, body ache/myalgia, generally activity, and vomiting. | Up to 7 days following each vaccination: up to day 7 for vaccine 1 and up to day 35-49 for vaccine 2 | 
| T and B Cell Phenotype Assessed by Mass Cytometry | T and B cell response was assessed at visit 1,visit 2, visit 3, and visit 4. Results are incomplete due to pending grant funding for laboratory testing. This outcome will be updated once the funding has been obtained and results are available. | Visit 1 (baseline) was day 0; visit 2 was 28-42 days after visit 1; visit 3 was 28-42 days after visit 2; and visit 4 was 138-222 days after visit 2. | 
| T and B Cell Response Assessed by Mass Cytometry and In-vitro Functionality Assays | T and B cell response was assessed at visit 1, an optional visit 5-10 days after visit 1, visit 2, an optional visit 5-10 days after visit 2, visit 3, and visit 4. Results are pending due to pending grant funding for laboratory testing. This outcome will be updated once the funding has been obtained and results are available. | Visit 1 (baseline) was day 0; optional visit 1 was 5-10 days after visit 1; visit 2 was 28-42 days after visit 1; optional visit 2 was 5-10 days after visit 2; visit 3 was 28-42 days after visit 2; and visit 4 was 138-222 days after visit 2. | 
| Percentage of Individuals in Each Group Who Test Positive for Influenza | The percentage of breakthrough flu in vaccinated participants, separated by treatment group. | During the influenza season, up to 6 months |