Safety of hepatitis E vaccine in pregnancy: an emulated target trial following a mass reactive vaccination campaign in Bentiu internally displaced persons camp, South Sudan

Abstract

Background: Epidemic forms of hepatitis E cause high mortality among pregnant people, with case fatality risks over 30% and adverse fetal outcomes. In 2022, the first mass reactive vaccination campaign against hepatitis E was conducted in South Sudan with the HEV239 vaccine. We aimed to assess whether vaccination against hepatitis E in pregnancy increases the risk of fetal loss in a cohort of vaccinated and unvaccinated pregnant people.

Methods: In this emulated target trial, an exhaustive pregnancy census was conducted in Bentiu internally displaced persons camp after the second of three vaccination rounds. Women and girls aged 14-45 years with no current jaundice or acute illness were eligible for participation. Individuals who consented were revisited 28 days after their delivery date to document the pregnancy outcome. We used an emulated target trial framework to address biases inherent in observational studies. We matched vaccinated to unvaccinated participants on age, gestational age, and vaccination propensity score and estimated cumulative incidence functions for fetal loss in vaccinated compared to unvaccinated women in a competing risks framework using the Aalen-Johansen estimator.

Findings: Between May 16 and June 30, 2022, 3421 participants were enrolled and followed up for inclusion in analysis. Among 2741 women who had a pregnancy outcome after the start of the vaccination campaign, 67 (2·4%) were vaccinated before conception, 2036 (74·3%) were vaccinated during pregnancy, and 638 (23·2%) were not vaccinated. Among the 2407 women retained in the matched analyses, the cumulative risk of fetal loss among individuals vaccinated during pregnancy was 7·2% (95% CI 5·6-8·7) compared with 6·1% (3·7-9·2) among unvaccinated individuals, implying a risk ratio of 1·2 (95% CI 0·7-1·9).

Interpretation: No evidence of increased risk of fetal loss was found among individuals vaccinated during pregnancy.

Funding: Médecins Sans Frontières.

Figure 1

Trial profile IDP=internally displaced persons.

Figure 2

Timeline of pregnancies within the full cohort Each horizontal line represents an enrolled participant's pregnancy start and end (dot), based on vaccination status (colour). Green lines represent vaccinated person-time and purple represents unvaccinated person-time. Dots represent pregnancy outcomes, with blue representing livebirths, orange representing miscarriages, and red representing stillbirths. Dashed lines represent the period of enrolment and transparent grey bars represent vaccination round periods. The recall period for pregnancy started on Jan 1, 2022.

Figure 3

Timeline (A) and cumulative Incidence curves for fetal loss (B) for matched women in pregnancy cohort emulated target trial 1 Each horizontal line represents an enrolled participant's pregnancy start and end (dot), based on vaccination status (colour). (A) Green lines represent person-time vaccinated and purple lines represent person-time unvaccinated. Grey vertical bars represent the vaccination campaign periods. (B) Green lines represent the cumulative incidence of fetal loss among people vaccinated during pregnancy and purple lines represent cumulative incidence among those unvaccinated. Bootstrap 95% CIs are shown in shaded area.