Safety and Immunogenicity of Measles Vaccine, Varicella Vaccine and Hepatitis-A Vaccine

Phase 4

• Conditions: Measles; Hepatitis A; Varicella
• Interventions: Biological: Measles vaccine; Biological: Hepatitis-A vaccine; Biological: Varicella vaccine

• Registration Number: NCT03330171
• Lead Sponsor: University of Witwatersrand, South Africa

Brief Summary

This trial will evaluate the safety and immunogenicity of: i) measles vaccine (CAM-70) after primary dose at 6 months (MV1) and booster vaccination at 12 months (MV2); ii) a single dose of varicella vaccination at 18 months; and iii) a single dose of hepatitis-A vaccination at 18 months in HIV-exposed and HIV-unexposed South African children.

Detailed Description

Measles vaccine (MV) can reduce childhood mortality and is currently recommended to all South African children aged 6 months. Only one study has examined the safety and immunogenicity of the recommended CAM-70 measles vaccine strain in children under 9 months of age. In addition, there are limited data on the safety and immunogenicity of varicella vaccine (VV) and Hepatitis-A vaccination (Hep-AV) in HIV-exposed and HIV-unexposed children in Sub-Saharan Africa.

This is a prospective, observational cohort study nested within a larger randomized, open-label trial on pneumococcal-conjugate vaccine (PCV) titled PCV1+1. 70 HIV-exposed and 200 HIV-unexposed children will be enrolled at Chris Hani Baragwanath Academic Hospital (CHBAH) and neighbouring primary health clinics.

Immune responses to the vaccines will be measured as rate of seroconversion, rate of seroprotection, and geometric mean titres (GMT) one month post primary immunization (MV1, VV, Hep-AV) and one month post booster dose (MV2). In addition, pre-vaccination and medium long-term antibody levels at 4.5 months, 12 months and 18 months will be evaluated. Number of adverse events in all immunized infants will be recorded throughout the study duration and compared between groups. Long-term antibody levels at 3, 4 and 5 years of age will be measured during annual follow-up visits.

This study will add to the current evidence on immunizing infants with MV (CAM-70) at 6 and 12 months of age. Data will be stratified by HIV-exposure and HIV-infection, thereby offering insight in the influence of HIV on post-vaccination immune responses. The findings on VV/Hep-AV safety, immunogenicity and seroprevalence will be useful to informing future immunization policies in Sub-Saharan Africa.

Study Timeline

• Study Start: 2017-04-10
• Study First Submitted: 2017-10-12
• Study First Submitted QC: 2017-10-30
• Study First Posted: 2017-11-06
• Primary Completion: 2019-02-26
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-15
• Last Update Posted: 2020-03-17
• Study Completion: 2022-12-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 278

Inclusion Criteria

1. Aged ≤18 weeks;
2. Parent/guardian able to provide informed consent;
3. Available for the duration of the study;
4. Enrolled as a participant in the PVC1+1 trial AND born to HIV-uninfected woman; OR Born to HIV-infected mother AND infant CD4% ≥25% if HIV-infected;
5. Birth weight >2499g AND weight of >3.5 kg at time of proposed enrolment;
6. Being a healthy child (except for HIV status in HIV-exposed cohort) based on medical history and physical examination by the study staff.

Exclusion Criteria

1. Significant major congenital abnormalities;
2. Received measles vaccination, varicella vaccination or hepatitis-A vaccination since birth;
3. Previous hospitalization for respiratory illness following discharge from hospital at birth;
4. Known allergy to vaccine components;
5. Febrile illness (axillary temperature ≥37.8°C) at time of screening;
6. Known or suspected immunodeficiency condition other than HIV;
7. Planning to relocate outside of the study area during the study period;
8. Receipt of blood transfusion or any other blood products (including immunoglobulins) since birth, receipt of such products during the course of the study will require withdrawal of the child from the study;
9. History of confirmed measles, varicella or hepatitis-A disease since birth.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
HIV-unexposed children	Hepatitis-A vaccine	HIV-unexposed children enrolled in a randomized open label study on the pneumococcal conjugate vaccine (PCV1+1) will be invited to participate in this study. Children enrolled in the PCV1+1 study will receive all vaccines included in the South African public immunization program. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.
HIV-exposed children	Varicella vaccine	A cohort of HIV-exposed children will be recruited. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.
HIV-unexposed children	Measles vaccine	HIV-unexposed children enrolled in a randomized open label study on the pneumococcal conjugate vaccine (PCV1+1) will be invited to participate in this study. Children enrolled in the PCV1+1 study will receive all vaccines included in the South African public immunization program. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.
HIV-exposed children	Hepatitis-A vaccine	A cohort of HIV-exposed children will be recruited. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.
HIV-unexposed children	Varicella vaccine	HIV-unexposed children enrolled in a randomized open label study on the pneumococcal conjugate vaccine (PCV1+1) will be invited to participate in this study. Children enrolled in the PCV1+1 study will receive all vaccines included in the South African public immunization program. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.
HIV-exposed children	Measles vaccine	A cohort of HIV-exposed children will be recruited. Measles vaccine (0.5 mL, subcutaneous injection) will be adminstered at 6 months of age and 12 months of age. Varicella vaccine (0.5 mL, subcutaneous injection) or Hepatitis-A vaccine (0.5 mL, intra-muscular injection) will be administered to the participants at 18 months of age as an additional benefit for participating in the study.

Primary Outcome Measures

Name	Time	Method
Number of participants with seroprotective antibody titres (IgG ≥330 mIU/ml quantified by ELISA) one month post booster measles vaccination	13 months of age (one month post booster measles vaccine)	Measured as seroprotection rate one month post booster measles vaccine in HIV-exposed (HEU, HIV-infected) and HIV-unexposed South African children.

Secondary Outcome Measures

Name	Time	Method
Number of participants with vaccine-related adverse events after booster measles vaccination	12 months of age	Participants will be observed for at least 30 minutes after vaccination so that clinic personnel can observe and document any potential adverse reactions to the vaccine. Report of vaccine-related local (redness, swelling, pain/tenderness, itching) and systemic (fever, vomiting, poor appetite, irritability and decreased activity) adverse events will be solicited using diary card in the 7 days after vaccination.
Number of participants with vaccine-related adverse events after varicella vaccination	18 months of age	Participants will be observed for at least 30 minutes after vaccination so that clinic personnel can observe and document any potential adverse reactions to the vaccine. Report of vaccine-related local (redness, swelling, pain/tenderness, itching) and systemic (fever, vomiting, poor appetite, irritability and decreased activity) adverse events will be solicited using diary card in the 7 days after vaccination.
Number of participants with seroprotective antibody titres (IgG ≥300 mIU/ml quantified by ELISA) one month post varicella vaccination	19 months of age (one month post vaccination)	Measured as seroprotection rate one month post varicella immunization in HIV-exposed (HEU, HIV-infected) and HIV-unexposed South African children.
Number of participants with seroprotective antibody titres (IgG ≥20 mIU/ml quantified by ELISA) one month post hepatitis-A vaccination	19 months of age (one month post vaccination)	Measured as seroprotection rate one month post hepatitis-A immunization in HIV-exposed (HEU, HIV-infected) and HIV-unexposed South African children.
Number of participants with vaccine-related adverse events after primary measles vaccination	6 months of age	Participants will be observed for at least 30 minutes after vaccination so that clinic personnel can observe and document any potential adverse reactions to the vaccine. Report of vaccine-related local (redness, swelling, pain/tenderness, itching) and systemic (fever, vomiting, poor appetite, irritability and decreased activity) adverse events will be solicited using diary card in the 7 days after vaccination.
Number of participants with vaccine-related adverse events after hepatitis-A vaccination	18 months of age	Participants will be observed for at least 30 minutes after vaccination so that clinic personnel can observe and document any potential adverse reactions to the vaccine. Report of vaccine-related local (redness, swelling, pain/tenderness, itching) and systemic (fever, vomiting, poor appetite, irritability and decreased activity) adverse events will be solicited using diary card in the 7 days after vaccination.
Persistence of immunogenicity	3, 4 and 5 years of age	Antibody concentrations and number of participants with seroprotective antibody levels to measles, varicella and hepatitis-A vaccination

Trial Locations

Locations (1)

Chris Hani Baragwanath Academic Hospital; Nrf/Dst Vpd Rmpru; 🇿🇦 Soweto, Gauteng, South Africa