In 2021 in response to an outbreak of hepatitis E in Bentiu internally displaced persons camp the South Sudanese Ministry of Health with support from Médecins Sans Frontières implemented the first-ever mass reactive vaccination campaign with HEV239 (Hecolin; Innovax, Xiamen, China). We conducted qualitative research to assess knowledge, attitudes, and practices related to hepatitis E and the hepatitis E vaccine. We conducted 8 focus group discussions (FGDs) with community leaders, the general population of vaccine-eligible adults, vaccine-eligible pregnant women (vaccinated and non-vaccinated), and healthcare workers. FGDs were separate by gender and were audio recorded, transcribed, and translated to English. Two coders used inductive thematic analysis to organize emergent themes. Data were collected in November 2022. Most participants had experiences with hepatitis E (e.g., infected themselves or knowing someone that had been infected) and viewed hepatitis E as a dangerous disease. Participants believed children, pregnant women, and older persons were the highest risk groups and frequently made requests for additional hepatitis E vaccination campaigns and expanded eligibility criteria for vaccination. Knowledge of the negative impacts of hepatitis E and trusted relationships with the organizations offering the vaccine were key facilitators of vaccine acceptance. The primary barriers to vaccination were practical issues related to being away from the camp during the campaign or not knowing about the campaign, but participants shared that some in the community were unvaccinated due to fears about injections, social pressure, misinformation, and concerns about why some groups were eligible for vaccination and not others (e.g., young children). Personal experiences with hepatitis E illness, perceived severity of illness, and confidence in organizations recommending the vaccine were drivers of high demand for hepatitis E vaccines in the first-ever use of the vaccine in an outbreak setting. Addressing practical issues related to population mobility can improve coverage in future campaigns.

BACKGROUND

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis, particularly in Asia and Africa, where HEV genotypes 1 and 2 are prevalent. Although a recombinant vaccine, Hecolin, is available, it has not been used to control outbreaks. The licensed three-dose regimen might pose challenges for it to be an impactful outbreak control tool. Our study aimed to estimate the effectiveness of two doses of Hecolin in the context of the first-ever reactive use of the vaccine.

METHODS

We conducted a case-control study during an HEV outbreak in the Bentiu internally displaced persons camp, South Sudan. Patients with acute jaundice syndrome (suspected cases) seeking care at the Médecins Sans Frontières hospital were screened for study eligibility. Eligible participants were those that had been eligible for vaccination (ie, living in the camp and aged 16-40 years). Confirmed cases were defined as individuals who tested positive for hepatitis E by RT-PCR or anti-HEV IgM ELISA. Each case was matched to six controls by age, sex, pregnancy status, and residence. Self-reported vaccination status was verified through vaccination cards. The primary analysis was two-dose vaccine effectiveness, which we estimated with a matched case-control design using conditional logistic regression models. In secondary analyses we estimated vaccine effectiveness using a test-negative design and the screening method. We used test-negative cases and their matched controls as a bias indicator analysis to help quantify potential health seeking behaviour biases.

FINDINGS

Between May 10 and Dec 30, 2022, we identified 859 patients with suspected hepatitis E. Of these, 201 met the eligibility criteria and 21 cases had laboratory confirmed hepatitis E. Among the confirmed cases, 10 (48%) were unvaccinated compared with 33 (27%) of 121 matched controls. In the primary analysis we estimated an unadjusted two-dose vaccine effectiveness of 67·8% (95% CI -28·6 to 91·9), and a two-dose vaccine effectiveness of 84·0% (-208·5 to 99·2) after adjustment for potential confounders. The bias indicator analysis suggested that test-negative cases might have been more likely to have been vaccinated than their matched community controls due to different health-care seeking behaviours, potentially meaning underestimation of effectiveness estimates. The test-negative design, which uses facility-matched controls, led to an adjusted two-dose effectiveness of 89·4% (56·4 to 98·0).

INTERPRETATION

Despite the small sample size, our estimates provide evidence of effectiveness of a two-dose regimen against HEV genotype 1 during a protracted outbreak, supporting its use in similar contexts.

BACKGROUND

Hepatitis E was first identified in the 1990s, but major epidemics date back to the 1950s. There is no specific treatment, and it can be fatal especially for pregnant women, causing spontaneous abortion and stillbirths. In 2011, the first vaccine was made available, and in 2015, the WHO recommended its use during epidemics, including for pregnant women. However, several major epidemics occurred without vaccine use. The first mass reactive vaccination took place in 2022 at the Bentiu camp in South Sudan, alongside operational research.

METHODS

We assessed vaccination feasibility and acceptance through coverage surveys and conducted focus group discussions on acceptance. We monitored adverse events following immunization (AEFI) for pharmacovigilance. To assess safety in pregnancy, we monitored the pregnancy outcomes of all women identified as pregnant during the vaccination campaign through a census. Despite the significant efficacy shown in a phase 3 clinical trial after three doses, we aimed to evaluate the vaccine's efficacy in South Sudan during an epidemic after administering two doses through a case-control study.

RESULTS

Coverage of at least one dose of the Hecolin vaccine after three rounds was estimated at 86% (95% CI: 84-88), with no cases of severe AEFI. Focus groups revealed strong concern about hepatitis E and high confidence and demand for the vaccine. An emulated target trial showed a relative risk of foetal loss between vaccinated and unvaccinated pregnant women at 1.1 (95% CI: 0.7-1.8). Vaccine effectiveness after two doses was estimated at 88.3% (95% CI: 53.8-97.6) using a test-negative design.

CONCLUSION

We found high vaccine coverage, good acceptance, and demand from the population. There was no evidence of increased risk of foetal loss among vaccinated pregnant women. Despite the small number of cases, the reduced dose regimen appeared effective in reducing disease risk in this highly exposed population.

KEY MESSAGE

Studies from the first mass reactive vaccination against hepatitis E demonstrated high coverage and acceptance, no safety issues among pregnant women, and good effectiveness after two doses.

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.

INTRODUCTION

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.