Vaccinating Children After Chemotherapy

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: Prevnar®13; Biological: Pneumovax® 23; Biological: Pediacel®

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Experimental; 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; A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.; Other Names: PCV13; 13- valent conjugate pneumococcal vaccine; Biological: Pneumovax® 23; A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13; Other Names: 23-valent polysaccharide pneumococcal vaccine; PPV23; Biological: Pediacel®; A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.; Other Names: DTaP-IPV-Hib
No Intervention: Healthy Control; Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability	Adverse Events Following Immunization requiring healthcare visit or leading to >=1 day of disability will be captured through structured telephone interviews on days 8-10 and 30-33 after each immunization	days 8-10 and 30-33

Collaborators and Investigators

• Sponsor: Canadian Immunization Research Network
• Investigators: Principal Investigator: Karina Top, MD, MS, Dalhousie University

Publications and helpful links

General Publications

• Top KA, Vaudry W, Morris SK, Pham-Huy A, Pernica JM, Tapiero B, Gantt S, Price VE, Rassekh SR, Sung L, McConnell A, Rubin E, Chawla R, Halperin SA. Waning Vaccine Immunity and Vaccination Responses in Children Treated for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study. Clin Infect Dis. 2020 Dec 3;71(9):e439-e448. doi: 10.1093/cid/ciaa163.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2015
• Primary Completion (Actual): March 5, 2018
• Study Completion (Actual): March 5, 2018

Study Registration Dates

• First Submitted: May 13, 2015
• First Submitted That Met QC Criteria: May 14, 2015
• First Posted (Estimate): May 19, 2015

Study Record Updates

• Last Update Posted (Actual): June 24, 2022
• Last Update Submitted That Met QC Criteria: June 22, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Immunologic Factors; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: SI02