Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
The recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine is the only vaccine recommended for use to respond to Zaire ebolavirus outbreaks by SAGE. A single ring vaccination trial found the efficacy to be 100%; however, no estimates of real-world effectiveness have yet been published.
METHODS
We conducted a retrospective test-negative case-control analysis to estimate effectiveness of rVSV-ZEBOV vaccination against Ebola virus disease (EVD) during the 2018 - 2020 epidemic in the Democratic Republic of the Congo (DRC), using data on suspected cases collected at Ebola treatment centres. Missing data were imputed using multivariate imputation. Among those who reported contact with an Ebola case before symptom onset, each EVD-positive case was matched to one EVD-negative control by sex, age, health zone and month of symptom onset. Effectiveness was then estimated from the odds ratio of being vaccinated vs. unvaccinated among cases and controls, after adjusting for the matching factors.
RESULTS
The primary study population contained 309 cases and controls each, on average, of which between 11 and 23 cases (3.6– 7.4%) and between 48 and 80 controls (16 – 26%) were recorded as vaccinated at least ten days before symptom onset. We found rVSV-ZEBOV vaccination at least ten days before symptom onset was 84% effective against developing EVD (95% credible interval [70%, 92%]). There was no apparent difference in effectiveness by sex, age, or due to a change in vaccination protocol.
CONCLUSION
This study is the first to estimate real-world effectiveness of rVSV-ZEBOV vaccination EVD during the second largest EVD outbreak ever recorded. Our findings confirm that rVSV-ZEBOV vaccination is highly protective against developing EVD and support its reactive, targeted use in at-risk people during future outbreaks.
The rVSVΔG-ZEBOV-GP vaccine constitutes a valuable tool to control Ebola virus disease (EVD) outbreaks. This study aimed to assess the protective effect of the vaccine against death among patients with confirmed EVD.
METHODS
In this retrospective cohort analysis of patients with confirmed EVD admitted to Ebola health facilities in the Democratic Republic of the Congo between July 27, 2018, and April 27, 2020, we performed univariate and multivariate analyses to assess case fatality risk (CFR) and cycle threshold for nucleoprotein according to vaccination status, EVD-specific treatments, and other risk factors.
RESULTS
We analysed all 2279 patients with confirmed EVD. Vaccination significantly lowered CFR (vaccinated: 25% (106/423) vs not vaccinated: 56% (570/1015); p<0·0001). In adjusted analyses, vaccination significantly lowered the risk of death compared with no vaccination, with protection increasing as time elapsed from vaccination to symptom onset (vaccinated ≤2 days before onset: 27% [27/99], adjusted relative risk 0·56 [95% CI 0·36–0·82, p=0·0046]; 3–9 days before onset: 20% [28/139], 0·44 [0·29–0·65, p=0·0001]; ≥10 days before onset: 18% [12/68], 0·40 [0·21–0·69; p=0·0022]; vaccination date unknown: 33% [39/117], 0·69 [0·48–0·96; p=0·0341]; and vaccination status unknown: 52% [441/841], 0·80 [0·70–0·91, p=0·0011]).
Cycle threshold values were significantly higher—indicating lower viraemia— among patients who were vaccinated compared with those who were not vaccinated; the highest difference was observed among those vaccinated 21 days or longer before symptom onset (median 30·0 cycles [IQR 24·6–33·7]) compared with patients who were not vaccinated (21·4 cycles [18·4–25·9], p<0·0001).
CONCLUSION
To our knowledge, this is the largest observational study describing the protective effect of rVSVΔG-ZEBOV-GP vaccination against death among patients with confirmed EVD admitted to an Ebola health facility. Vaccination was protective against death for all patients, even when adjusted for EVD-specific treatment, age group, and time from symptom onset to admission.
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.