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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Oana Sandulescu, UMPCD - Carol Davila University of Medicine and Pharmacy,
- Second opponent: Professor Rebecca Jane Cox, UiB - University of Bergen,
- Third member and chair of the evaluation committee: Research group leader Ranveig Braathen, University of Oslo
Chair of the Defence
Associate Professor Ragnhild Eskeland, University of Oslo
Principal Supervisor
Professor Susanne Gjeruldsen Dudman, University of Oslo
Summary
Background. Hepatitis E is a common cause of acute viral hepatitis in many low- and middle-income countries, with pregnant women facing a disproportionate risk of severe disease and adverse pregnancy outcomes. While the HEV239 vaccine has demonstrated high efficacy in non-pregnant populations, evidence on its safety when administered during or shortly before pregnancy has been very limited.
Aim. This thesis evaluated HEV239 vaccination in rural Bangladesh through three linked studies. Specifically, it examined (1) the vaccine’s immunogenicity in the local population, (2) the association between vaccination shortly before or during pregnancy and the risk of spontaneous abortion, and (3) whether this association was concentrated within a narrower vaccination-timing window and attributable to maternal risk factors.
Methods. The work was based on a cluster-randomised, double-blind phase IV trial comparing HEV239 with hepatitis B vaccine in 19,460 non-pregnant women aged 16–39 years across 67 villages. Active weekly pregnancy surveillance and physician-verified pregnancy outcomes enabled analysis of 6,287 first pregnancies, with vaccination timing assessed relative to the last menstrual period (LMP).
Key findings. Study 1 supported the immunogenicity of HEV239. Study 2 identified a timing-sensitive association between HEV239 vaccination shortly before and during pregnancy and an increased risk of spontaneous abortion, while stillbirth and elective termination were not clearly elevated. Study 3 refined this signal, showing that the excess risk was concentrated within approximately the first eight weeks before LMP, particularly at 31–60 days pre-LMP, and was not explained by baseline maternal risk profiles or gestational age at spontaneous abortion.
Implications. Our clinical trial provides evidence for strong immunogenicity of HEV239 while identifying a clinically relevant safety signal for spontaneous abortion associated with vaccination around conception and during pregnancy. These findings highlight that pregnancy safety should be specifically evaluated rather than assumed for vaccines used in women of reproductive age. They also call for careful, evidence-based and non-alarmist communication, alongside further mechanistic studies, independent replication, and dedicated research on peri-conception and pregnancy safety to guide future vaccination policy in HEV-endemic settings.
Additional information
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