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.
The risk of cholera outbreaks spreading rapidly and extensively is substantial. Case-area targeted interventions (CATI) are based on the premise that early detection can trigger a rapid, localised response in the high-risk radius around case-households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread, as opposed to relying on resource-intensive mass interventions. Current evidence supports intervention in a high-risk spatiotemporal zone of up to 200 m around case- households for 5 days after case presentation. Médecins Sans Frontières (MSF) started delivering CATI to people living within these high-risk rings during outbreaks in the Democratic Republic of the Congo in April 2022. We present the results of a prospective observational study designed to evaluate the CATI strategy, measuring effectiveness, feasibility, timeliness, and resource requirements, and we extract operational learnings.
METHODS
Between April 2022 and April 2023, MSF delivered the holistic CATI package in five cholera-affected regions. The package incorporated key interventions combining household-level water, sanitation, and hygiene measures, health promotion, antibiotic chemoprophylaxis, and single-dose oral cholera vaccination (OCV). We conducted a survey in each ring roughly 3 weeks after the intervention to estimate coverage and uptake of the different components. We measured effectiveness by comparing cholera incidence in the first 30 days between rings with different delays from primary case presentation to CATI implementation, using a Bayesian regression model and adjusting for covariates such as population density, age, and access to water and sanitation.
RESULTS
During the study, four MSF operational sections implemented 118 CATI rings in five sites. The median number of households per ring was 70, the median OCV coverage was 85%, and the median time from presentation of the primary case to CATI implementation and to vaccination was 2 days and 3 days, respectively. These characteristics varied widely across sites and between rings. No secondary cases were observed in 81 (78%) of 104 rings included in the analysis, and we noted a (non- significant) decreasing trend in the number of secondary cases with decreasing delay to CATI implementation, e.g. 1.3 cases [95% CrI 0.01–4.9] for CATI implementation starting within 5 days from primary case presentation, and 0.5 cases [0.03–2.0] for CATI starting within 2 days.
CONCLUSION
Our results show that rapid implementation of CATI with vaccination is feasible in complex contexts. The number of secondary cases was low when CATI was implemented promptly. This highly targeted approach may be an effective strategy to quickly protect people most at risk and is resource- efficient if implemented early to extinguish localised outbreaks before they require mass interventions.
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.
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