Vaccinating Children After Chemotherapy

Study Overview
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Brief Summary
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This multi-center open label clinical trial aims to identify predictors of low antibody titers to vaccine antigens in children with ALL who completed chemotherapy in the prior 6 months, and to determine the immunogenicity and safety of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis-Haemophilus influenzae type b (DTaP-IPV-Hib) and 13-valent pneumococcal conjugate vaccine (PCV13) booster immunization administered 6 months post-chemotherapy, followed by 23-valent pneumococcal polysaccharide vaccination (PPV23) 2 months later. The results will support the development of clinical practice guidelines for this population.

Detailed Description
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Rationale and Aims: Children with acute lymphoblastic leukemia (ALL) have evidence of persistent immunosuppression following chemotherapy and may experience waning of immunity to vaccines received prior to treatment. There is no standard of care in Canada regarding immunologic evaluation or booster immunization of children with ALL after chemotherapy. This study aims to identify predictors of low baseline immunity to vaccine antigens in children with ALL and to evaluate the immunogenicity and safety of a standard immunization regimen: DTaP-IPV-Hib and PCV13 booster immunization administered 6 months post-chemotherapy, followed by PPV23. Study Design: This will be a multi-center open-label clinical trial in which children who were diagnosed with ALL at ≥1 year of age, and have not received immunizations other than influenza since completing chemotherapy will undergo immunologic evaluation and serologic testing for pneumococcus, tetanus, pertussis and varicella. They will then be immunized with PCV13, DTaP-IPV-Hib, regardless of immunization history [unless PPV23 was received within the prior 12 months]. Other routine vaccines required as per provincial and centre-specific immunization policies will also be administered. PPV23 will be administered 8 weeks after PCV13. Repeat serologic testing will be conducted at 2 months and 12-15 months after DTaP-IPV-Hib and PCV13 immunization to assess short and long-term immune responses. Adverse events following immunization (AEFI) will be captured through standardized telephone interviews on days 8-10 and 30-33 post-immunization that will capture local and systemic AEFI.

Official Title
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Vaccinating Children After Chemotherapy for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: Prevnar®13
* Biological: Pneumovax® 23
* Biological: Pediacel®


Participation Criteria
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Eligibility Criteria
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Cases with ALL: Inclusion Criteria: Diagnosed with standard, high-risk or very-high risk ALL Age at diagnosis: ≥1 year of age (age at enrollment: ≥3 years) Completed chemotherapy 3 to 12 months prior to enrollment No evidence of ALL relapse or secondary malignancy No known primary immunodeficiency No receipt of pneumococcal or tetanus-containing vaccines since completing chemotherapy No history of allergy to any component of PCV13 Caregiver and/or participant is English or French-speaking and able to provide written informed consent Exclusion Criteria: Infantile ALL Evidence of disease relapse or secondary malignancy History of underlying primary immunodeficiency Transplant recipient Received intravenous immunoglobulin (IVIG) within past 9 months or other blood products within the prior 3 months.Children who received PPV23 within 12 months of enrollment will not be eligible to receive PCV13 or PPV23. These children can still participate in the baseline evaluation, receive DTaP-Hib-IPV vaccine, and have tetanus and pertussis serology measured at 2 and 12-15 months post-immunization. Controls: Inclusion criteria Children 3-18 years of age, age-matched to cases Caregiver and/or participant is English or French-speaking and able to provide written informed consent Exclusion criteria History of primary or secondary immunodeficiency including aplastic anemia, malignancy, nephrotic syndrome, malabsorption or severe malnutrition Immunosuppressive therapy within 3 months of enrollment (excluding inhaled corticosteroids) Received intravenous immunoglobulin (IVIG) within past 9 months or other blood products within the prior 3 months.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental<br>Children who were diagnosed with ALL at ≥1 year of age, and are within 6-8 months of completing chemotherapy will receive 1 dose each of: Prevnar®13 and Pediacel® vaccines, followed by 1 dose of Pneumovax® 23 given 2 months after PCV13. | Biological: Prevnar®13<br>* A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.<br>* Other names: PCV13;Biological: Pneumovax® 23<br>* A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13<br>* Other names: PPV23;Biological: Pediacel®<br>* A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.<br>* Other names: DTaP-IPV-Hib;|
| No Intervention: Healthy Control<br>Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | The percentage of participants with protective titres (with protective level defined as ≥0.35 ug/ml, as per World Health Organization criteria) to PCV13 serotypes will be assessed at 2 months and 12-15 months post PCV13+PPV23 and compared to baseline levels. | Pre-vaccination Baseline, 2 months and 12-15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | The number of participants with protective titres (≥0.35 ug/ml) to PCV7 serotypes at baseline will be compared to age-matched controls. | Day 0 | 
| Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Baseline geometric mean titers (GMT) and percentage of subjects with protective titres to pneumococcal serotypes in children with ALL versus age-matched controls. | Day 0 | 
| Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Baseline, Short-term (baseline - 2 months after vaccination) and long-term (baseline - 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMT ratios. | Prevaccination baseline, 2 months, 12-15 months | 
| Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Day 0 | 
| Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Day 0 | 
| Baseline Varicella Titers in Children With ALL Versus Controls. | Geometric mean titers (95% confidence interval) in AI (antibody index) | Day 0 | 
| Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Baseline, short-term (baseline to 2 months after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMTs with 95% confidence intervals | baseline, 2 months, 12-15 months |