Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model

Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976–2014). Using species distribution models, these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration, and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people; however, the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past.DOI: http://dx.doi.org/10.7554/eLife.04395.001

Ebola virus (EBOV), family Filoviridae, emerged in 1976 on the African continent. Since then it caused several outbreaks of viral hemorrhagic fever in humans with case fatality rates up to 90% and remains a serious Public Health concern and biothreat pathogen. The most pathogenic and best-studied species is Zaire ebolavirus (ZEBOV). EBOV encodes one viral surface glycoprotein (GP), which is essential for replication, a determinant of pathogenicity and an important immunogen. GP mediates viral entry through interaction with cellular surface molecules, which results in the uptake of virus particles via macropinocytosis. Later in this pathway endosomal acidification activates the cysteine proteases Cathepsin B and L (CatB, CatL), which have been shown to cleave ZEBOV-GP leading to subsequent exposure of the putative receptor-binding and fusion domain and productive infection. We studied the effect of CatB and CatL on in vitro and in vivo replication of EBOV. Similar to previous findings, our results show an effect of CatB, but not CatL, on ZEBOV entry into cultured cells. Interestingly, cell entry by other EBOV species (Bundibugyo, Côte d'Ivoire, Reston and Sudan ebolavirus) was independent of CatB or CatL as was EBOV replication in general. To investigate whether CatB and CatL have a role in vivo during infection, we utilized the mouse model for ZEBOV. Wild-type (control), catB−/− and catL−/− mice were equally susceptible to lethal challenge with mouse-adapted ZEBOV with no difference in virus replication and time to death. In conclusion, our results show that CatB and CatL activity is not required for EBOV replication. Furthermore, EBOV glycoprotein cleavage seems to be mediated by an array of proteases making targeted therapeutic approaches difficult.

Analyzing The Ebola ViruAnalyzing The Impact That The Ebola Virus Disease Has on Children

To the Editor: Three well-documented outbreaks of Ebola hemorrhagic fever occurred from 1996 through 2001 in Gabon in central Africa (1). All were caused by the highly pathogenic species Zaire ebolavirus, which is associated with an ≈80% case-fatality rate. The first outbreak hit Mayibout, a village in northeast Gabon in January and February 1996, causing 31 cases and 21 deaths. The first victims were children who helped carry and butcher a chimpanzee carcass found in the forest. The second outbreak lasted from October 1996 through March 1997 and occurred in the Booue region, about 150 km southwest of Mayibout, Gabon. The outbreak area was located along a trunk road and railroad track, and the infection spread to several villages around Booue, then to Libreville, the capital of Gabon, where 15 cases were recorded. The third outbreak occurred October 2001 through May 2002 in the Mekambo area, about 150 km from Mayibout in the east (2). This outbreak consisted of several independent chains of human transmission arising from infected animal carcasses, mainly chimpanzees and gorillas. It caused 65 cases and 53 deaths and coincided with major outbreaks in great apes that decimated wild populations (3,4). A total of 207 human cases were recorded during these 3 outbreaks; 149 persons died. Of the fatal and nonfatal cases 31 and 24, respectively, were confirmed by real-time reverse transcription–PCR, antigen detection, and immunoglobulin (Ig) G ELISA at Centre International de Recherches Medicales de Franceville (CIRMF) in Gabon. Because of the lack of available samples from survivors, little is known about the duration of IgG antibody response. However, studies of 20 survivors convalescing after the 1995 Kikwit outbreak in the Democratic Republic of the Congo (DRC) showed that Zaire ebolavirus IgG appeared 5 to 18 days after symptom onset and persisted at least 21 months (5,6). With the exception of 2 survivors sampled 10 years after the 1976 Yambuku outbreak in DRC (7), no data are available on Zaire ebolavirus IgG persistence beyond 21 months. Low seroprevalence rates of Ebola virus or Marburg virus found in surveys of patients in outbreak areas have been attributed to seroreversion (8–10). To investigate the persistence of Zaire ebolavirus IgG, we studied laboratory-confirmed survivors of the 3 outbreaks in Gabon. The study was approved by the Gabon Ministry of Health and by the traditional chief of each village, and written informed consent was obtained from each survivor. During 3 months of investigations in the different outbreak areas beginning in June 2007, we located 11, 3, and 6 survivors of the 2001 Mekambo, 1996 Booue, and 1996 Mayibout outbreaks, respectively. During home visits, the survivors underwent a brief medical consultation, malaria smears were taken, and basic medicines were provided to the villagers. We collected blood samples in EDTA tubes; plasma was separated by centrifugation in the field and stored in dry nitrogen until transfer to the CIRMF laboratory in Gabon, where it was stored at –80°C. ELISA was performed as previously described, using reagents provided by the Special Pathogens Branch, Centers for Disease Control and Prevention (Atlanta, GA, USA) (7). The optical density (OD) cut-off value (0.13) was calculated as the mean + 3 SD of adjusted OD values for 103 negative control serum samples obtained from Caucasian persons living in Europe. All 20 survivors had positive test results for Zaire ebolavirus IgG (Table). The adjusted OD values at a dilution of 1:1,600 ranged from 0.3 to 3.4 in the 9 survivors of the 1996 outbreaks and from 0.7 to 3.5 in the 11 survivors of the 2001 outbreak. Adjusted OD values determined during the symptomatic period and/or a few days to 1 month after recovery were available for some survivors (Table). Specific IgG appeared by day 5 after symptom onset, increased during the symptomatic period (as shown by higher titers on day 10), peaked by day 30 (2 weeks after recovery), then declined slowly over several years. Zaire ebolavirus IgG remained detectable, often at high levels, >11 years after the infection. Table Adjusted OD values in patients infected with Zaire ebolavirus during 3 outbreaks in Gabon, determined by testing at days 5, 10, and/or 30 after symptom onset and again in 2007 (7 or 11 years after recovery)* These long-lasting IgG antibody responses found in 20 survivors of 3 different Zaire ebolavirus outbreaks rule out the hypothesis that low Ebola virus (and Marburg virus) seroprevalence rates found in epidemic regions of Africa are due to rapid loss of specific IgG. Whether this immunity is sufficient to protect from recurrent infection remains undetermined. These findings show that IgG ELISA is suitable for epidemiologic and epizootiologic investigations of Ebola and that Zaire ebolavirus IgG is an excellent indicator of Zaire ebolavirus circulation in humans.

Ebola virus: a new concern, its virological characteristics, diagnosis, present condition, and treatment during the ongoing SARS-CoV-2 omicron variant - correspondence.

A reconstituted replication and transcription system for Ebola virus Reston and comparison with Ebola virus Zaire

Ebola hemorrhagic fever is a fatal infectious disease of humans and primates. The disease is caused by single-stranded RNA viruses belonging to the family Filoviridae. The Ebola virus started to emerge in 1976, in an outbreak that almost simultaneously attacked two countries, namely Zaire and Sudan. (1) Around 500 cases were reported, with a case fatality rate of 88% in Zaire and 53% in Sudan. Although occurring at the same time, the Ebola viruses in the two countries were of different species, by serologic criteria as well as by sequence analysis.(2) The following Ebola virus species have been found: Zaire ebolavirus, Sudan ebolavirus, Cote d’Ivoire ebolavirus, Reston ebolavirus, and Bundibugyo ebolavirus.(1) Since September 2014, more than 4000 confirmed cases of Ebola virus disease, with more than 2000 deaths, have been reported in West African countries, such as Guinea, Liberia, Nigeria, Senegal, and Sierra Leone.(3) The Ebola outbreak started in Guinea in Desember 2013.(4) Nine months after the occurrence of the first cases, there was a weekly increase in the number of reported cases and deaths. There is now a global warning for nations to be on the alert against the spread of the Ebola virus. Therefore the World Health Organization has declared the situation to be a public health emergency of international concern.(3) At the present time the Ebola outbreak is developing and spreading, so there are substantial challenges in controlling the outbreak, halting its transmission, and providing clinical services to Ebola virus patients. However, the detection of patients with Ebola infection requires adequate diagnostic facilities, accompanied by treatment clinics and medicines, so as to help in containing the disease. The Ebola virus infection is mainly spread by contact with body fluids of symptomatic patients, and its transmission can be prevented by early diagnosis, contact tracing, isolation of patients, patient care, and infection control.(4,5) Since it became known that two American healthcare workers in Liberia had become infected with the Ebola virus, the Ebola outbreak in West Africa has attracted much attention and caused anxiety in many countries.(7) This is not the first viral outbreak in West Africa that has caused concern in advanced countries. Between 1928-1929, a yellow fever outbreak in West Africa resulted in the deaths of prominent research workers from America, England, and Japan.(7) Although several ecological aspects of the virus are known, there is still much to be investigated in relation to its ecology. Fruit bats are thought to be one of the reservoirs of the Ebola virus, although other animals may also be susceptible to the Ebola virus and be able to infect humans.(6) It is thought that infection in humans first occur at the time of exposure to body fluids from animal reservoirs of the virus, or intermediate animal hosts.(1) A study conducted by Pourrut et al.(8) reported that 4% of bats in Gabon were positive for immunoglobulins to the Zaire ebolavirus. This seems to provide evidence of bats as carriers of Ebola viruses and as a source of Ebola infection. Furthermore, person-to-person transmission may also occur through direct contact with body fluids from the patients. The incubation period of Ebola virus disease is between 1 and 21 days. The signs and symptoms are acute fever, shivering, headache, and myalgia, followed by rashes, sore throat, nausea, vomiting, diarrhea, and abdominal pain.(1) Around half of the patients show signs of hemorrhage, such as hemorrhage of the nasal cavity, hematuria, gastrointestinal hemorrhage, and vaginal hemorrhage in women. Wamala et al.(1) report that around 59% of patients who die from Ebola virus have hemorrhages. The case fatality rate of Zaire ebolavirus and Sudan ebolavirus varies from 53%-90%.(1) The outbreak occurring in the Bundibugyo district, Uganda, in August – December 2007 showed three successive transmission cycles. Each transmission cycle lasted 6 weeks, with an interval of 3-11 days, and was marked by a typical peaking of the outbreak, followed by a gradual decline.(1) Frieden et al.(9) list three types of preventive interventions. The first is strict control of the infection in healthcare settings, because the greatest risk of transmission is not the obvious one from the patients, but from delayed detection and isolation. The second is education of local communities regarding habits that may spread the disease, and the third is to avoid consumption of raw meat of wild animals. The Ebola virus outbreak constitutes a serious warning that epidemics may occur anywhere and places every afflicted nation at risk. Therefore it is essential to institute measures to stop its spread and its future threat, which is a moral obligation of members of the health profession, whether academicians, researchers, or health ministry officials.

There are currently no widely accepted animal surveillance guidelines for human Ebola hemorrhagic fever (EHF) outbreak investigations to identify potential sources of Ebolavirus (EBOV) spillover into humans and other animals. Animal field surveillance during and following an outbreak has several purposes, from helping identify the specific animal source of a human case to guiding control activities by describing the spatial and temporal distribution of wild circulating EBOV, informing public health efforts, and contributing to broader EHF research questions. Since 1976, researchers have sampled over 10,000 individual vertebrates from areas associated with human EHF outbreaks and tested for EBOV or antibodies. Using field surveillance data associated with EHF outbreaks, this review provides guidance on animal sampling for resource-limited outbreak situations, target species, and in some cases which diagnostics should be prioritized to rapidly assess the presence of EBOV in animal reservoirs. In brief, EBOV detection was 32.7% (18/55) for carcasses (animals found dead) and 0.2% (13/5309) for live captured animals. Our review indicates that for the purposes of identifying potential sources of transmission from animals to humans and isolating suspected virus in an animal in outbreak situations, (1) surveillance of free-ranging non-human primate mortality and morbidity should be a priority, (2) any wildlife morbidity or mortality events should be investigated and may hold the most promise for locating virus or viral genome sequences, (3) surveillance of some bat species is worthwhile to isolate and detect evidence of exposure, and (4) morbidity, mortality, and serology studies of domestic animals should prioritize dogs and pigs and include testing for virus and previous exposure.

Background: The authors analysed the Ebola Virus Disease (EVD) outbreak in Guinea. They summarised the epidemic impact on the country’s health care system, its economy, education, domestic policies and its international cooperation.Methods:This was a descriptive study based on statistics, published by the World Health Organization (WHO) in the Ebola Situation Reports in response to the Ebola Hemorrhagic Fever (EHF) outbreak in West Africa.Results: It was found that of November 21st 2015, Guinea had 3351 confirmed cases of EVD and 453 probable cases, the disease had claimed the life of 2536 people with a fatality rate of 66.6%. The epidemic had an important impact on the country’s economy, education, domestic policies and international cooperation.Conclusions:The EVD outbreak in Guinea was one of the longest Ebola outbreaks in the world. It pointed out the weakness of the Guinean health system. This should be an opportunity to ensure that the country’s health system is strengthened. A robust surveillance measure to ensure the rapid detection of any reintroduction or re-emergence of EVD or other diseases of obligatory declaration should be reinforced.

Ebolavirus

Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV), and the Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa.IMPORTANCE The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens.

Ebola vaccination

BackgroundExperience from the Zaire Ebolavirus epidemic in the eastern Democratic Republic of the Congo (2018–2020) demonstrates that early initiation of essential critical care and administration of Zaire Ebolavirus specific monoclonal antibodies may be associated with improved outcomes among patients with Ebola virus disease (EVD).ObjectivesThis series describes 13 EVD patients and 276 patients with suspected EVD treated during a Zaire Ebolavirus outbreak in Guinea in 2021.MethodPatients with confirmed or suspected EVD were treated in two Ebola treatment centres (ETC) in the region of N’zérékoré. Data were reviewed from all patients with suspected or confirmed EVD hospitalised in these two ETCs during the outbreak (14 February 2021 – 19 June 2021). Ebola-specific monoclonal antibodies, were available 2 weeks after onset of the outbreak.ResultsNine of the 13 EVD patients (age range: 22–70 years) survived. The four EVD patients who died, including one pregnant woman, presented with multi-organ dysfunction and died within 48 h of admission. All eight patients who received Ebola-specific monoclonal antibodies survived. Four of the 13 EVD patients were health workers. Improvement of ETC design facilitated implementation of WHO-recommended ‘optimized supportive care for EVD’. In this context, pragmatic clinical training was integrated in routine ETC activities. Initial clinical manifestations of 13 confirmed EVD patients were similar to those of 276 patients with suspected, but subsequently non confirmed EVD. These patients suffered from other acute infections (e.g. malaria in 183 of 276 patients; 66%). Five of the 276 patients with suspected EVD died. One of these five patients had Lassa virus disease and a coronavirus disease 2019 (COVID-19) co-infection.ConclusionMultidisciplinary outbreak response teams can rapidly optimise ETC design. Trained clinical teams can provide WHO-recommended optimised supportive care, including safe administration of Ebola-specific monoclonal antibodies. Pragmatic training in essential critical care can be integrated in routine ETC activities.ContributionThis article describes clinical realities associated with implementation of WHO-recommended standards of ‘optimized supportive care’ and administration of Ebola virus specific treatments. In this context, the importance of essential design principles of ETCs is underlined, which allow continuous visual contact and verbal interaction of health workers and families with their patients. Elements that may contribute to further quality of care improvements for patients with confirmed or suspected EVD are discussed.

Will Ebola change the game? Ten essential reforms before the next pandemic. The report of the Harvard-LSHTM Independent Panel on the Global Response to Ebola