An effectiveness trial to evaluate protection of pregnant women by a HEV vaccine in Bangladesh and risk factors for severe HEV infection.

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 was carefully designed and is 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. The initial safety profile and immunogenicity of the vaccine were tested in a pilot study before enrollment of participants in the main trial, where participants were vaccinated on day 0 and day 30. 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 most participants had seroconverted (HEV), after just two doses of the vaccine. During this pilot study, protocols and procedures for all phases of the study were tested, and the laboratory analyses were validated, in preparation for the initiation of the main trial. The safety and performance of the pilot study was approved. Recruitment of participants for the main study started 1/10-17, and was completed 28/02-19. As many as 19460 women aged 16-39 years were included and randomized to receive either the hepatitis E vaccine or a hepatitis B vaccine (control group). The vaccine is administered on a 0, 1 and 6 month schedule. The vaccination was completed on the 1st of October 2019, when all participants received all three planned doses of their respective vaccine. All participants who develop hepatitis symptoms are evaluated by a doctor, and if hepatitis is still suspected, a blood sample is taken for hepatitis diagnostics. Acute HEV cases are further examined virologically, clinically, and immunologically. Those who become pregnant during the study are followed up closely with regular home visits to follow up the pregnancy and to look for hepatitis symptoms. Currently, over 3900 pregnancies are reported, with more than 2600 births. Clinical outcomes and vaccine adverse events are monitored continuously, and through regular detailed visits from trial monitors. No vaccine related severe adverse events have been reported to date. All participants have been followed up for a 2 year period after the last dose, this surveillance finished in October 2021. Laboratory analyses of all the samples taken at 7 months after last vaccine dose have been finished and data on immunogenicity will soon be made available in a scientific article. Safety data are now rigorously analyzed and due to be published soon.

The project is anticipated to produce results on the efficacy, humoral and cellular immunogenicity of the hepatitis E virus vaccine (Hecolin), as well as to provide much needed safety data that WHO requested before giving recommendation for use in endemic areas. This vaccine has only been tested in a genotype 4 area in China, but the project will generate new efficacy data against genotype 1 as this genotype is endemic in Bangladesh. Additionally, data on the occurrence of adverse events in women of child-bearing age and efficacy in special risk groups like pregnant women will be provided by this study. The goal is to generate evidence base to enable recommendation of the HEV vaccine for women in LICs to reduce the burden of maternal and neonatal mortality caused by HEV.

This game-changing project aims to evaluate the protection against hepatitis E virus (HEV) disease in pregnant women by immunization with the HEV vaccine (Hecolin). HEV affects pregnant women and their fetuses in low income countries (LIC) with case-facility rates up to 25%. A cluster-randomized effectiveness trial (phase IV) will be conducted to assess the feasibility, acceptability, protective impact and cost-effectiveness of immunization of fertile women in Bangladesh. The vaccine is shown to be efficacious in an earlier phase III trial in China, but is currently only licensed in China. There is no data showing that this vaccine can prevent disease in pregnant women, the group that could benefit most from vaccination in this setting. The vaccine effect in preventing maternal and neonatal mortality will be thoroughly investigated in this trial with 20.000 participants in rural Bangladesh, ensuring the highest quality result. Technology transfer from China will make this vaccine widely available in Bangladesh. The study will assess immunity against HEV, estimate serological correlates of protection, and evaluate new sampling types for diagnosing. Risk factors for severe or fatal HEV infection will be investigated by comparing clinical, virological and immunological markers. To conduct the double-blind trial, the study population will be randomized to receive either HEV vaccine or the HBV vaccine with the same dosing regimen. The HEV epidemiology in the study area is similar to other parts of Asia and Africa, where the HEV mortality is equally substantial. The goal is to generate evidence base for all nations to enable rational introduction of the HEV vaccine for women in LICs to reduce the burden of maternal and neonatal mortality caused by HEV.