Hepatitis E (HEV) genotypes 1 and 2 are the common cause of jaundice and acute viral hepatitis that can cause large-scale outbreaks. HEV infection is associated with adverse fetal outcomes and case fatality risks up to 31% among pregnant women. An efficacious three-dose recombinant vaccine (Hecolin) has been licensed in China since 2011 but until 2022, had not been used for outbreak response despite a 2015 WHO recommendation. The first ever mass vaccination campaign against hepatitis E in response to an outbreak was implemented in 2022 in Bentiu internally displaced persons camp in South Sudan targeting 27,000 residents 16–40 years old, including pregnant women.
METHODS
We conducted a vaccination coverage survey using simple random sampling from a sampling frame of all camp shelters following the third round of vaccination. For survey participants vaccinated in the third round in October, we asked about the onset of symptoms experienced within 72 hours of vaccination. During each of the three vaccination rounds, passive surveillance of adverse events following immunisation (AEFI) was put in place at vaccination sites and health facilities in Bentiu IDP camp.
RESULTS
We surveyed 1,599 individuals and found that self-reported coverage with one or more dose was 86% (95% CI 84–88%), 73% (95% CI 70–75%) with two or more doses and 58% (95% CI 55–61%) with three doses. Vaccination coverage did not differ significantly by sex or age group. We found no significant difference in coverage of at least one dose between pregnant and non-pregnant women, although coverage of at least two and three doses was 8 and 14 percentage points lower in pregnant women. The most common reasons for non-vaccination were temporary absence or unavailability, reported by 60% of unvaccinated people. Passive AEFI surveillance captured few mild AEFI, and through the survey we found that 91 (7.6%) of the 1,195 individuals reporting to have been vaccinated in October 2022 reported new symptoms starting within 72 hours after vaccination, most commonly fever, headache or fatigue.
CONCLUSIONS
We found a high coverage of at least one dose of the Hecolin vaccine following three rounds of vaccination, and no severe AEFI. The vaccine was well accepted and well tolerated in the Bentiu IDP camp community and should be considered for use in future outbreak response.
A three-dose recombinant vaccine against hepatitis E, Hecolin, has been licensed for use in China since 2011. While not recommended for routine use due to lack of evidence on burden in the general population, in 2015 WHO recommended the vaccine be considered in outbreaks. As of early 2022 however, the vaccine had not been used in outbreak settings. A reduced-dose vaccination schedule, if effective, could make the vaccine an important outbreak response tool. In response to an increase in hepatitis E cases in a camp for internally displaced people in Bentiu, South Sudan in late 2021, MSF and South Sudan’s MoH implemented the first ever mass reactive vaccination campaign against hepatitis E virus (HEV). Three vaccination rounds took place in March, April, and October 2022, targeting 26,848 individuals aged 16-40 years, including pregnant women. We set up enhanced surveillance and conducted a case-control study to estimate two-dose vaccine effectiveness (VE).
METHODS
All suspected cases presenting to the MSF hospital who were eligible for vaccination and provided consent were enrolled in the study, comprising a questionnaire, laboratory examinations and a follow-up visit after 2-4 weeks. Vaccine-eligible suspect cases were matched to community controls. We estimated twodose VE against probable (anti-HEV IgM positive with elevated alanine transaminase, or a four-fold rise in IgG in paired samples) and confirmed (HEV RNA positive) hepatitis E using conditional logistic regression models.
ETHICS
This study was approved by the MSF and South Sudan Ethics Review Boards.
RESULTS
Considering the period two weeks after the second vaccination round between 11 May and 30 December 2022, 287 vaccine-eligible suspect hepatitis E cases were enrolled, including one probable and 16 confirmed cases. Among probable and confirmed cases, two (11.8%) were vaccinated with two or more doses compared to 40 (40%) of their 100 matched controls. We estimated a VE of 86.5% (95% confidence interval, CI, 36.3–97.1) for one/two doses and 83.9% (95% CI, -33.1–98.1%) for two doses. In addition to this direct protection, we observed a 5.5-fold decrease in the incidence rate of probable/confirmed cases hepatitis E cases before and after the second dose campaign (including those not eligible for vaccination). Laboratory confirmation of hepatitis E infection is ongoing, and we expect to revise VE estimates and incidence based on these results.
CONCLUSION
Following the first mass reactive vaccination campaign against hepatitis E, incidence has declined. Preliminary VE estimates suggest that the short-term protection provided by this reduced dose regimen may be high and potentially sufficient for outbreak response.
CONFLICTS OF INTEREST
None declared
INTRODUCTION
Hepatitis E causes high mortality among pregnant women, with case fatality risks over 30% and adverse fetal outcomes. There is an evidence gap on the safety of the only licensed vaccine, Hecolin®, in pregnancy. In 2015, WHO recommended vaccine use in response to outbreaks, including pregnant women. In 2022, the first mass reactive vaccination campaign against Hepatitis E was conducted in Bentiu displaced persons camp in South Sudan. We aimed to determine whether vaccination against hepatitis E in pregnancy increased the risk of fetal loss in a cohort of vaccinated and unvaccinated pregnant women.
METHODS
An exhaustive pregnancy census was conducted from 16 May 2022 until 30 June 2022 after the second vaccination round, and women were revisited 28 days after delivery date to document the pregnancy outcome. We used an emulated target trial framework to address biases inherent in observational studies. We matched (1:1, with replacement) vaccinated to unvaccinated women on age, gestational age, and vaccination propensity score, and we estimated cumulative incidence functions for fetal loss in vaccinated compared with unvaccinated women using the Nelson-Aalen estimator.
RESULTS
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 (23.3%) were not vaccinated. Among the 2407 women retained in the matched analyses, the cumulative risk of fetal loss in women vaccinated during pregnancy was 6.38% (95% CI 4.93–7.26) compared with 6.26% (3.9–9.19) among unvaccinated women (risk ratio [RR] 1.02 [95% CI 0.64–1.53]). In an analysis restricted to women vaccinated during pregnancy with less than 90 days gestation, the cumulative risk of miscarriage was 11.01% (95% CI 8.45–13.13) among vaccinated women and 11.62% (6.45–17.09) among unvaccinated women (RR 0.95 [95% CI 0.59–1.66]). In sensitivity analyses, we explored the impact of different matching criteria on the estimated RR and found no qualitative differences with the main analyses, with no evidence of increased risk of fetal loss among vaccinated women.
CONCLUSION
We used an emulated target trial methodology with matching to simulate a vaccine trial in pregnant women after a reactive vaccination campaign. This robust analytical method simulating a vaccine trial attempts to control for bias inherent in observational data. We found no evidence for increased risk of fetal loss among women vaccinated during pregnancy.