• Clinical and epidemiological performance of WHO Ebola case definitions: a systematic review and meta-analysis

      Caleo, G; Theocharaki, F; Lokuge, K; Weiss, HA; Inamdar, L; Grandesso, F; Danis, K; Pedalino, B; Kobinger, G; Sprecher, A; et al. (Elsevier, 2020-06-25)
      Background Ebola virus disease case definition is a crucial surveillance tool to detect suspected cases for referral and as a screening tool for clinicians to support admission and laboratory testing decisions at Ebola health facilities. We aimed to assess the performance of the WHO Ebola virus disease case definitions and other screening scores. Methods In this systematic review and meta-analysis, we searched PubMed, Scopus, Embase, and Web of Science for studies published in English between June 13, 1978, and Jan 14, 2020. We included studies that estimated the sensitivity and specificity of WHO Ebola virus disease case definitions, clinical and epidemiological characteristics (symptoms at admission and contact history), and predictive risk scores against the reference standard (laboratory-confirmed Ebola virus disease). Summary estimates of sensitivity and specificity were calculated using bivariate and hierarchical summary receiver operating characteristic (when four or more studies provided data) or random-effects meta-analysis (fewer than four studies provided data). Findings We identified 2493 publications, of which 14 studies from four countries (Sierra Leone, Guinea, Liberia, and Angola) were included in the analysis. 12 021 people with suspected disease were included, of whom 4874 were confirmed as positive for Ebola virus infection. Six studies explored the performance of WHO case definitions in non-paediatric populations, and in all of these studies, suspected and probable cases were combined and could not be disaggregated for analysis. The pooled sensitivity of the WHO Ebola virus disease case definitions from these studies was 81·5% (95% CI 74·1–87·2) and pooled specificity was 35·7% (28·5–43·6). History of contact or epidemiological link was a key predictor for the WHO case definitions (seven studies) and for risk scores (six studies). The most sensitive symptom was intense fatigue (79·0% [95% CI 74·4–83·0]), assessed in seven studies, and the least sensitive symptom was pain behind the eyes (1·0% [0·0–7·0]), assessed in three studies. The performance of fever as a symptom varied depending on the cutoff used to define fever. Interpretation WHO Ebola virus disease case definitions perform suboptimally to identify cases at both community level and during triage at Ebola health facilities. Inclusion of intense fatigue as a key symptom and contact history could improve the performance of case definitions, but implementation of these changes will require effective collaboration with, and trust of, affected communities.
    • Distribution of household disinfection kits during the 2014-2015 Ebola virus outbreak in Monrovia, Liberia: The MSF experience.

      Ali, E; Benedetti, G; Van den Bergh, R; Halford, A; Bawo, L; Massaquoi, M; Bellizzi, S; Maes, P (Public Library of Sciences, 2020-09-21)
      During the initial phase of the 2014-2016 Ebola virus disease (EVD) outbreak in Monrovia, Liberia, all hospitals' isolation capacities were overwhelmed by the sheer caseload. As a stop-gap measure to halt transmission, Medecins sans Frontieres (MSF) distributed household disinfection kits to those who were at high risk of EVD contamination. The kit contained chlorine and personal protective materials to be used for the care of a sick person or the handling of a dead body. This intervention was novel and controversial for MSF. This paper shed the light on this experience of distribution in Monrovia and assess if kits were properly used by recipients. Targeted distribution was conducted to those at high risk of EVD (relatives of confirmed EVD cases) and health staff. Mass distributions were also conducted to households in the most EVD affected urban districts. A health promotion strategy focused on the purpose and use of the kit was integrated into the distribution. Follow-up phone calls to recipients were conducted to enquire about the use of the kit. Overall, 65,609 kits were distributed between September and November 2014. A total of 1,386 recipients were reached by phone. A total of 60 cases of sickness and/or death occurred in households who received a kit. The majority of these (46, 10%) were in households of relatives of confirmed EVD cases. Overall, usage of the kits was documented in 56 out of 60 affected households. Out of the 1322 households that did not experience sickness and/or death after the distribution, 583 (44%) made use of elements of the kit, mainly (94%) chlorine for hand-washing. At the peak of an EVD outbreak, the distribution of household disinfection kits was feasible and kits were appropriately used by the majority of recipients. In similar circumstances in the future, the intervention should be considered.
    • Ebola

      Feldmann, H; Sprecher, A; Geisbert, TW (Massachusetts Medical Society, 2020-05-07)
    • Ebola and the eye

      Clare, G (London School of Hygiene and Tropical Medicine, International Centre for Eye Health, 2020-03-30)
    • Ensuring On-site Ebola Patient Monitoring and Follow-up: Development of a Laboratory Structure Embedded in an Ebola Treatment Center.

      Williams, A; Amand, M; Van den Bergh, R; De Clerck, H; Antierens, A; Chaillet, P (Cambridge University Press, 2019-12-01)
      The capacity to rapidly distinguish Ebola virus disease from other infectious diseases and to monitor biochemistry and viremia levels is crucial to the clinical management of suspected Ebola virus disease cases. This article describes the design and practical considerations of a laboratory straddling the high- and low-risk zones of an Ebola treatment center to produce timely diagnostic and clinical results for informed case management of Ebola virus disease in real-life conditions. This innovation may be of relevance for actors requiring flexible laboratory implementation in contexts of high-communicability, high-lethality disease outbreaks.
    • Humoral and cellular immune response induced by rVSVΔG-ZEBOV-GP vaccine among frontline workers during the 2013-2016 West Africa Ebola outbreak in Guinea

      Boum, Y; Juan-Giner, A; Hitchings, M; Soumah, A; Strecker, T; Sadjo, M; Cuthbertson, H; Hayes, P; Tchaton, M; Jemmy, JP; et al. (Elsevier, 2020-06-26)
      Background As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate in a sub-study to provide additional information on the immunogenicity of the vaccine. Methods We conducted an open‐label, non‐randomized, single-arm immunogenicity evaluation of one dose of rVSVΔG-ZEBOV-GP among healthy FLWs in Guinea. FLWs who refused vaccination were offered to participate as a control group. We followed participants for 84 days with a subset followed-up for 180 days. The primary endpoint was immune response, as measured by ELISA for ZEBOV-glycoprotein–specific antibodies (ELISA-GP) at 28 days. We also conducted neutralization, whole virion ELISA and enzyme-linked immunospot (ELISPOT) assay for cellular response. Results A total of 1172 participants received one dose of vaccine and were followed-up for 84 days, among them 114 participants were followed-up for 180 days. Additionally, 99 participants were included in the control group and followed up for 180 days. Overall, 86.4% (95% CI 84.1–88.4) of vaccinated participants seroresponded at 28 days post-vaccination (ELISA- GP) with 65% of these seroresponding at 14 days post-vaccination. Among those who seroresponded at 28 days, 90.7% (95% CI 82.0–95.4) were still seropositive at 180 days. The proportion of seropositivity in the unvaccinated group was 0.0% (95% CI 0.0–3.8) at 28 days and 5.4% (95% CI 2.1–13.1) at 180 days post-vaccination. We found weak correlation between ELISA-GP and neutralization at baseline but significant pairwise correlation at 28 days post-vaccination. Among samples analysed for cellular response, only 1 (2.2%) exhibited responses towards the Zaire Ebola glycoprotein (Ebola GP ≥ 10) at baseline, 10 (13.5%) at day 28 post-vaccination and 27 (48.2%) at Day 180. Conclusions We found one dose of rVSVΔG-ZEBOV-GP to be highly immunogenic at 28- and 180-days post vaccination among frontline workers in Guinea. We also found a cellular response that increased with time.
    • A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups

      Dodd, L; Follman, D; Proschan, M; Wang, J; Malvy, D; Horby, P; Gouel-Cheron, A; Ciglenecki, I; Davey, R; Lane, C; et al. (American Association for the Advancement of Science, 2019-11-27)
      Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.
    • New filovirus disease classification and nomenclature

      Kuhn, JH; Adachi, T; Adhikari, NKJ; Arribas, JR; Bah, IE; Bausch, DG; Bhadelia, N; Borchert, M; Brantsæter, AB; Brett-Major, DM; et al. (Nature Research, 2019-03-29)
      The recent large outbreak of Ebola virus disease (EVD) in Western Africa resulted in greatly increased accumulation of human genotypic, phenotypic and clinical data, and improved our understanding of the spectrum of clinical manifestations. As a result, the WHO disease classification of EVD underwent major revision.
    • The power of touch

      Dahl, EH (Elsevier, 2020-04-04)
    • Prior vaccination with rVSV-ZEBOV does not interfere with but improves efficacy of postexposure antibody treatment

      Cross, RW; Bornholdt, ZA; Prasad, AN; Geisbert, JB; Borisevich, V; Agans, KN; Deer, DJ; Melody, K; Fenton, KA; Feldmann, H; et al. (Nature Research, 2020-07-27)
      A replication-competent vesicular stomatitis virus vaccine expressing the Ebola virus (EBOV) glycoprotein (GP) (rVSV-ZEBOV) was successfully used during the 2013-16 EBOV epidemic. Additionally, chimeric and human monoclonal antibodies (mAb) against the EBOV GP have shown promise in animals and humans when administered therapeutically. Uncertainty exists regarding the efficacy of postexposure antibody treatments in the event of a known exposure of a recent rVSV-ZEBOV vaccinee. Here, we model a worst-case scenario using rhesus monkeys vaccinated or unvaccinated with the rVSV-ZEBOV vaccine. We demonstrate that animals challenged with a uniformly lethal dose of EBOV one day following vaccination, and then treated with the anti-EBOV GP mAb MIL77 starting 3 days postexposure show no evidence of clinical illness and survive challenge. In contrast, animals receiving only vaccination or only mAb-based therapy become ill, with decreased survival compared to animals vaccinated and subsequently treated with MIL77. These results suggest that rVSV-ZEBOV augments immunotherapy.
    • A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

      Mulangu, S; Grais, R; Dodd, L; Follmann, D; Proschan, M; Davey, R; Mukadi, D; Lusakibanza, M (2019-12-12)
      BACKGROUND Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase–polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.)
    • What can be learnt from Ebola about the dangers of the global health security approach?

      Roper, S (Transactions of the Royal Society, 2019-12-01)
      The current outbreak of Ebola that has been raging out of control for over 1 y in the Democratic Republic of Congo (DRC) has brought back painful memories from West Africa about the dangers of the global health security approach. Drawing on the author’s personal experience of working as a medic in both outbreaks, this article reflects on the challenges of responding to the disease inside a global health security framework. Insights and recommendations are made as to how the global health community can contribute towards gaining better control of Ebola both now and in the future.