Evaluating Immunogenicity of a Birth Dose of HBV Vaccine in the DRC

Study Overview
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Brief Summary
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This project will assess the immunogenicity of a birth dose of hepatitis B vaccine in hepatitis B-exposed and hepatitis B-unexposed infants in Kinshasa, Democratic Republic of the Congo. A better understanding of the protection offered by the addition of birth dose vaccine to the EPI schedule is necessary in order to promote universal adoption of a birth dose vaccine in the DRC and throughout SSA.

Detailed Description
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Hepatitis B virus (HBV) remains a neglected tropical disease despite the availability of effective prevention measures. HBV vaccine has been incorporated into pediatric immunization schedules worldwide for nearly two decades, and yet 257 million people are still living with chronic HBV infection. Current control measures are failing to prevent further transmission of HBV, especially in sub-Saharan Africa (SSA), where hepatitis B surface antigen (HBsAg) prevalence surpasses 8% in highly endemic areas. An estimated 1% of infants (>365,000 per year) are infected with HBV by mother-to-child transmission (MTCT) in SSA, and when infected in the first year of life, these infants have a 90% risk of developing chronic infection. Pediatric HBV is a substantial problem in the Democratic Republic of the Congo (DRC). Preliminary data from the 2013-2014 Demographic and Health Survey in the DRC revealed that 2.2% of children under the age of five are infected with HBV. Why is the seroprevalence of HBV so high in children? The three-dose HBV vaccine has been part of the Expanded Program on Immunization (EPI) in the DRC since 2007, with vaccination rates now approaching 80%. However, the EPI vaccination schedule does not begin until six weeks of life. In contrast, in developed countries, infants receive the first dose of HBV vaccine at birth. This birth dose is rarely administered in SSA. Routine birth dose vaccination could be a simple and cost-effective means to reduce the pool of infected and highly infectious children in the DRC. While the protective efficacy of a three-dose series of HBV vaccine plus immunoglobulin (HBIG) initiated at birth is ≥95%, immunogenicity of HBV vaccine administered according to the EPI schedule (pentavalent vaccine administered at 6,10 and 14 weeks) is only 80-85%. This gap in antibody response leads to a significant population of children who are potentially vulnerable to infection in infancy or later in life. The immunogenicity of a four-dose HBV vaccine series including a monovalent birth dose prior to the EPI schedule has not been fully assessed to date. Furthermore, HBIG is not available in SSA due to prohibitive cost and storage issues, necessitating an evaluation of the effectiveness of the vaccine series alone without HBIG. In collaboration with the DRC Ministry of Health, Abbott Laboratories and Ohio State University, the investigators are conducting the Arresting Vertical Transmission of HBV (AVERT-HBV) study, which leverages the existing HIV PMTCT framework in the DRC to screen and treat pregnant women and their infants to prevent MTCT of HBV. The investigators will use the AVERT study population to recruit participants (HBV-exposed infants and their mothers) for this study. Women who screen negative for HBV as part of AVERT will be included in this study as the HBV-unexposed cohort. While HIV PMTCT programs have been successful in reducing the number of HIV-infected infants in the DRC, many infants fall into the HIV-exposed uninfected (HEU) category. These HEU infants are known to have lowered immune responses to vaccines than HIV-unexposed infants, including protective immunity to HBV after the EPI-associated three-dose series. Little is known about the effects of in utero HBV exposure on the immune response to HBV vaccine. The investigators hypothesize that because the immune response of infants exposed to HBV may be blunted, these infants may benefit from an additional dose of HBV vaccine at birth. Using the AVERT-HBV cohort as a basis, this project will assess the immunogenicity of the birth dose vaccine in HBV-exposed and HBV-unexposed infants. A better understanding of the protection offered by the addition of birth dose vaccine to the EPI schedule is necessary in order to promote universal adoption of a birth dose vaccine in the DRC and throughout SSA. This prospective cohort study will involve 100 HBV-exposed infants who will receive 4 doses of HBV vaccine starting at birth (Group A), 100 HBV-unexposed infants who receive 3 doses of HBV vaccine according to the EPI schedule (Group B) and 100 HBV-unexposed infants who receive 4 doses of HBV vaccine starting at birth (Group C). The infants will be followed for 12 months, at which time protective immunity against HBV, defined as HBsAb ≥10 milli-international units (mIU)/mL, will be measured.

Official Title
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Evaluating Immunogenicity of a Birth Dose of HBV Vaccine in the DRC

Conditions
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Hepatitis B

Intervention / Treatment
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* Biological: Birth dose hepatitis B vaccine


Participation Criteria
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Eligibility Criteria
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MOTHERS Inclusion Criteria HBsAg+ mothers and HBsAg- mothers will be recruited from the cohort screened during the AVERT study at 2 maternity centers (Binza and Kingasani) in Kinshasa. Exclusion Criteria Any women who do not intend to stay in Kinshasa for prenatal care through delivery or who deliver at a facility other than Binza or Kingasani Women <18 years of age INFANTS Inclusion Criteria Infants born to HBsAg-positive and HBsAg-negative women who receive care at Binza and Kingasani maternity centers will be recruited for participation in this study. Exclusion Criteria HIV-exposed infants (those born to HIV-positive mothers) will be excluded given an expected difference in immune response in these infants and inability to recruit enough HIV-exposed infants to be able to detect these differences in immune response HBV-unexposed infants weighing <2,000 grams at birth will not be eligible to receive the birth HBV vaccine. (HBV-exposed infants receive the birth dose vaccine regardless of birth weight because the potential benefit of preventing mother-to-child transmission outweighs the potential risk of vaccination in a low birthweight infant. The research team recognizes that Group B may include a disproportionate number of low birthweight infants compared to Group C, but will account for this in post-hoc analyses and if need be, will exclude low birthweight infants from the analysis to account for potential bias). Infants born at a facility other than one of the two maternity centers

Ages Eligible for Study
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Maximum Age: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Hepatitis B exposed, with birth dose<br>The 100 HBV-exposed (born to HBsAg-positive mothers) infants who are already enrolled in the parent AVERT study will also be enrolled in the current study, as the HBV-exposed cohort (Group A). These exposed infants will not receive additional interventions on top of the AVERT study since they will already be receiving a birth dose vaccine through the AVERT study. | Biological: Birth dose hepatitis B vaccine<br>* Groups A and C will receive a birth dose of hepatitis B vaccine within 24 hours of life.<br>|
| No Intervention: Group B: Hepatitis B unexposed, no birth dose<br>For the HBV-unexposed cohort in this study, the investigators will enroll 200 infants born to HBsAg-negative mothers. Half (100) of these infants will receive the routine three-dose series of HBV vaccine according to the standard EPI schedule in the DRC with no additional birth dose vaccine (Group B). | |
| Experimental: Group C: Hepatitis B unexposed, with birth dose<br>Group C will consist of the other half (100) of infants in the HBV-unexposed cohort who will receive four doses of HBV vaccine including a birth dose vaccine prior to the routine EPI schedule. | Biological: Birth dose hepatitis B vaccine<br>* Groups A and C will receive a birth dose of hepatitis B vaccine within 24 hours of life.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Infants with Protective Immunity | Protective immunity is defined as quantitative HBsAb ≥ 10 milli-International unit(mIU)/mL | At 12 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Infants with Adverse Reactions to the Birth Dose Hepatitis B Vaccine | Adverse reactions will include fever, fatigue and injection site soreness, as described in the Package Insert (https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm224503.pdf). Infants will be monitored for adverse reactions for safety purposes during the time they spend with their mothers at the maternity center after birth (expected average stay of 2-3 days). | Within 2-3 days after birth |