Vaccinating Children After Chemotherapy

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.

• Prevnar®13 (Biological), also known as 13- valent conjugate pneumococcal vaccine, PCV13: A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.
• Pneumovax® 23 (Biological), also known as 23-valent polysaccharide pneumococcal vaccine, PPV23: A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13
• Pediacel® (Biological), also known as DTaP-IPV-Hib: A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy.

Primary outcomes

• Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 [Pre-vaccination Baseline, 2 months and 12-15 months]: 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.

Secondary outcomes

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

Other outcomes

• Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability [days 8-10 and 30-33]: 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

Sex: All, ages: 3 Years to 18 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 (Primary), Count of participants, Participants: Experimental 40
• Number of Participants With Protective Titres to PCV7 Serotypes at Baseline (Secondary), Count of participants, Participants: Experimental 4; Healthy Control 30
• Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls (Secondary), Geometric mean, mg/L: Experimental 0.19 (0.16 to 0.22); Healthy Control 0.52 (0.41 to 0.66)
• Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination (Secondary), Geometric mean, EU/ml: Experimental 4.10 (3.67 to 4.58)
• Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls (Secondary), Geometric mean, IU/ml: Experimental 0.16 (0.12 to 0.20); Healthy Control 1.73 (1.26 to 2.37)
• Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls (Secondary), Geometric mean, EU/ml: Experimental 4.10 (3.67 to 4.58); Healthy Control 10.35 (8.15 to 13.16)
• Baseline Varicella Titers in Children With ALL Versus Controls. (Secondary), Geometric mean, Antibody index: Experimental 0.33 (0.24 to 0.45); Healthy Control 1.00 (0.77 to 1.29)
• Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization (Secondary), Geometric mean, IU/ml: Experimental 0.16 (0.12 to 0.20)
• Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability (Other pre specified), Count of participants, Participants: Experimental 3

Adverse events

Time frame: AEFI was captured through structured telephone interviews on days 8-10 and 30-33 after each immunization

Other adverse events by term

Limitations and caveats: 1. Antibody levels to vaccine antigens were not measured before chemotherapy, cannot confirm that chemotherapy was the cause of low postchemotherapy titers. 2. Immunization status at ALL diagnosis was not assessed and therefore could not confirm whether postchemotherapy participants were underimmunized for age before diagnosis relative to their peers. 3. We were unable to assess antibodies to other pertussis antigens (eg, filamentous hemagglutinin, pertactin), only anti-PT antibodies alone.

• Results publication: 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. PMID 32067048

• Study Protocol and Statistical Analysis Plan (PDF, 2017-06-14)

• Karina Top, MD, MS, Principal investigator, Dalhousie University