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.
In many ways, Marburg virus disease resembles the more well-known Ebola virus disease: The clinical syndrome is similar, management of outbreaks is similar, and the fear engendered in the population experiencing the outbreak is similar. However, diagnostics, therapeutics, and vaccines to manage patients and outbreaks are not similarly available. These have been developed but not yet approved, as outbreaks have not provided the opportunity to establish an evidence base for regulators to evaluate their use in humans. The history of outbreaks of Marburg virus disease suggests that this opportunity will not come, and so alternative pathways to regulatory approval are needed.
BACKGROUND
Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC’s Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD.
METHODS
This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak.
RESULTS
Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p<0.001). Similarly, time from symptom onset to admission was significantly shorter among EVD-suspected patients ultimately diagnosed as EVD-negative.
CONCLUSIONS
Since <5% of the EVD-suspected patients admitted were eventually diagnosed with EVD, there is a need for better screening to optimise resource utilization and outbreak control. Only one in seven EVD-suspected patients were admitted to a DTC first, as the DTCs were piloted in a limited and phased manner. However, there is a case to be made for considering decentralized care especially in remote and hard-to-reach areas in places like the DRC to facilitate early access to care, contain viral shedding by patients with EVD and ensure no disrupted provision of non-EVD services.
During the 2018–2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.
Outbreak alert systems can offset the severity of measles epidemics by minimising response delays. Existing systems, however, are often too sensitive to be practical when identifying areas for reactive interventions. To redress this challenge, we present a simple alternative system that combines a weekly and triweekly suspected case threshold. First evaluated in the DRC in 2022, here we extend the evaluation of this system to the context of Niger.
METHODS
A large number of threshold combinations were evaluated against indicators of cases captured by intervention and false alert risk. Combinations were evaluated against admin 2 level surveillance data from the DRC and Niger from 2015-2024. Performance was then compared to standard recommendations from the WHO and MSF.
RESULTS
The two example countries have distinct epidemic profiles, with the DRC exhibiting mas epidemics and Niger showing strong annual seasonality. In both settings, the proposed alternative alert system outperformed the existing WHO and MSF recommendation. The WHO recommendation, which is triggered by four suspected cases occuring within one month in a given locale (here, admin level 2), performs similarly to the proposed alternative when selecting the most sensitive of threshold combinations. The MSF recommendation, which is triggered by a raw increase in number of cases for three consecutive weeks, performed markedly worse, capturing 50% or less of cases. This poor performance is predominantly attributable to the high volatility of weekly measles surveillance data.
CONCLUSION
This analysis presents a simple evidence based alert system to improve measles outbreak response. It has been assessed in two countries, Niger and the DRC, and found to outperform standard recommendations. At present the system is available for use in both countries via their respective surveillance dashboards. Ongoing work is being conducted to evaluate the system in settings with additional epidemic profiles, including areas with low burden and areas with poor surveillance.
Diphtheria is an infection of the upper respiratory tract characterized by the production of an extracellular toxin. Individuals with incomplete immunization or low levels of antitoxin antibodies are particularly susceptible to infection. Specific treatment relies on Diphtheria Anti-Toxin (DAT) and the disease is preventable by active immunization. Since 2019, large outbreaks have been reported in WHO African Region, but 2023 has seen an unprecedented surge in diphtheria cases in West Africa, mainly Kano State, Nigeria.
METHODS
Médecins Sans Frontières (MSF) and Epicentre have been involved in response efforts but have faced several challenges due to limited hospital capacity and a global shortage of DAT. This led to the implementation of new solutions such as home-based care, adaptation of DAT dosage and strategic allocation of DAT stocks. Preliminary descriptive analysis shows the key figures from the 2023 diphtheria outbreak and summarizes critical insights from one year of MSF intervention in Kano.
RESULTS
MSF treated around 23 thousand individuals across 14 sites in five countries. Nearly half of these patients required hospitalization, with an overall case fatality rate (CFR) of 6%. The majority of patients were under 15 years of age, and most were female.
In Kano State, Nigeria, specifically, three main centres were established at the peak of the outbreak. MSF used adaptive strategies to deal with the constraints of the response, which were phased according to the number of cases and the availability of drugs. Centralised case management was used for severe cases, while a decentralised care model, including home-based care, was used for mild and close contacts. The primary centre, which remains operational, has received approximately 9 thousand patients.
Data indicate that the prompt administration of diphtheria antitoxin (DAT) may influence patient outcomes. Furthermore, an early immunization campaign could have potentially reduced the overall mortality rate associated with the epidemic.
CONCLUSION
The surge of diphtheria in West Africa highlighted numerous challenges in combating the disease in low-resource settings, particularly concerning the availability of diphtheria antitoxin (DAT). Further analyses are required to accurately assess the impact of home-based care and DAT dosage strategies. Scaling up global DAT production and enhancing routine vaccination programs could be crucial in preventing future outbreaks.