Effectiveness Trial to Evaluate Protection of Pregnant Women by Hepatitis E Vaccine in Bangladesh.

Study Overview
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Brief Summary
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The aim of the study is to determine the effectiveness of hepatitis E virus vaccine given in women of child bearing age in preventing HEV disease during pregnancy among women in rural Bangladesh.

Detailed Description
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Hepatitis E virus (HEV) infection is endemic in Bangladesh, causing severe or fatal complications in pregnant women. This GLOBVAC funded project aims to assess the safety, feasibility, acceptability, immunogenicity, effectiveness, and cost-effectiveness of the HEV vaccine (Hecolin, Innovax, China) when given women of childbearing age in a rural area in Bangladesh (Matlab). The vaccine has been shown to be both effective and safe in the general adult population in China, but there is insufficient data about its efficacy among pregnant women, the group with most to gain from vaccination. The research plan has been carefully designed and will be conducted by a multidisciplinary team of researchers at International Centre for Diarrhoeal Disease Research (iccdr,b) in Bangladesh and the Norwegian Institute of Public Health and Innlandet Hospital Trust in Norway. Over a period of 2 years, 20,745 non-pregnant women will be recruited and will receive either the hepatitis E vaccine or a hepatitis B vaccine (control group). All women who develop hepatitis E symptoms will be tested for the disease. Those who become pregnant during the study will also be checked and tested during regular home visits. Clinical outcomes and vaccine adverse events will be closely monitored. In order to evaluate the initial safety profile and immunogenicity of the vaccine, a pilot study was completed during summer 2017. A total of 100 non-pregnant females and males, aged 16-39, were enrolled and randomly received either the hepatitis E vaccine or a hepatitis B vaccine. Participants were vaccinated on day 0 and day 30, and blood, dried blood spots (DBS) and saliva samples were collected on day 0 and day 60 for use in laboratory assay validation and serological and cellular immunogenicity analyses. Following each vaccination, home visits were carried out for 7 days to record adverse reactions. No serious adverse reactions were observed, and only a few mild local adverse reactions were recorded which all resolved without sequela. Preliminary immunogenicity results, showed that 44 participants had seroconverted (HEV), after just two doses of the vaccine. Furthermore, during this pilot study the implementation of protocols and procedures for all stages of the trial were tested in preparation for the start of the main trial. Additionally, hepatitis surveillance in Matlab has been initiated in order to establish an HEV surveillance system. All women aged 16-39 are included in the surveillance, and requested to contact icddr,b staff if they experience jaundice of any duration, or other symptoms of hepatitis. Patients admitted to Matlab hospital have a blood sample taken for hepatitis diagnostics, and acute HEV cases are investigated virologically, clinically and immunologically. Household visits occur bi-weekly to document any possible hepatitis cases.

Official Title
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An Effectiveness Trial (Phase IV) to Evaluate Protection of Pregnant Women by Hepatitis E Virus (HEV) Vaccine in Bangladesh and Risk Factors for Severe HEV Infection.

Conditions
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Hepatitis E Infection

Intervention / Treatment
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* Drug: Hecolin
* Drug: Hepa-B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 16-39 years Living in Matlab area Exclusion Criteria: Pregnancy Allergic to vaccine components Serious chronic diseases Acute illness

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot study completed in 2017 with 100 participants, 50 women and 50 men aged 16-39, randomized to be vaccinated with either 2 doses of Hecolin or Hepa-B. These 100 participants are not included in the main trial. Main clinical trial designed to enroll 20.745 women aged 16-39 years living in Matlab area. All participants randomized to be vaccinated with either Hecolin or Hepa-B three doses.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HEV vaccine<br>Hecolin, 0.6 ml intramuscular injection day 0, 1 month and 6 months. | Drug: Hecolin<br>* 0.6ml Hecolin vaccine im. on day 0, 1 month and 6 months.<br>* Other names: HEV 239;|
| Placebo Comparator: HBV vaccine<br>Hepa-B, 1 ml intramuscular injection day 0, 1 month and 6 months. | Drug: Hepa-B<br>* 1ml Hepa-B vaccine im. on day 0, 1 month and 6 months.<br>* Other names: Hepatitis B virus (HBV) vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of HEV vaccine in preventing HEV diseases among women in Bangladesh | To determine the effectiveness of hepatitis E virus (HEV) vaccine in preventing HEV disease during pregnancy among women in rural Bangladesh | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of HEV vaccine in Bangladeshi women of childbearing age | Number of participants with adverse events related to vaccination as assessed by CTCAE v4.0 | 2 years | 
| To determine the immunogenicity of HEV vaccine in Bangladeshi women of childbearing age | Number of participants who seroconvert after three doses | 2 years | 
| Effectiveness of HEV vaccine in preventing HEV disease in non-pregnant Bangladeshi women of childbearing age | To determine the effectiveness of hepatitis E virus (HEV) vaccine in preventing HEV disease in participants | 2 years | 
| Estimate serological correlates of protection | Assess the anti-HEV IgG levels before and one month after the last dose of vaccine for primary vaccine response and record if any HEV disease occurs. | 2 years | 
| Assess the feasibility, acceptability and cost-effectiveness of HEV vaccination of women of childbearing age in rural Bangladesh | Analyse cost per disability, adjusted life year and quality adjusted life year | 2 years | 
| Investigate acute HEV cases virologically, clinically and immunologically in relation to outcome. | Examine acute HEV cases in relation to severity of illness and immunological responses | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis E virus, Viral Hepatitis Vaccines