Chimeric human parainfluenza virus bearing the Ebola virus glycoprotein as the sole surface protein is immunogenic and highly protective against Ebola virus challenge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bukreyev, Alexander; Marzi, Andrea; Feldmann, Friederike

2009-01-20

We generated a new live-attenuated vaccine against Ebola virus (EBOV) based on a chimeric virus HPIV3/{delta}F-HN/EboGP that contains the EBOV glycoprotein (GP) as the sole transmembrane envelope protein combined with the internal proteins of human parainfluenza virus type 3 (HPIV3). Electron microscopy analysis of the virus particles showed that they have an envelope and surface spikes resembling those of EBOV and a particle size and shape resembling those of HPIV3. When HPIV3/{delta}F-HN/EboGP was inoculated via apical surface of an in vitro model of human ciliated airway epithelium, the virus was released from the apical surface; when applied to basolateral surface,more » the virus infected basolateral cells but did not spread through the tissue. Following intranasal (IN) inoculation of guinea pigs, scattered infected cells were detected in the lungs by immunohistochemistry, but infectious HPIV3/{delta}F-HN/EboGP could not be recovered from the lungs, blood, or other tissues. Despite the attenuation, the virus was highly immunogenic, and a single IN dose completely protected the animals against a highly lethal intraperitoneal challenge of guinea pig-adapted EBOV.« less

Ebola (Ebola Virus Disease): Treatment

MedlinePlus

... Guidance for Cleaning, Disinfection, and Waste Disposal in Commercial Passenger Aircraft Notes on the Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure Communication Resources Videos Audio Infographics & Illustrations Factsheets Posters Virus ...

Ebola (Ebola Virus Disease): Prevention

MedlinePlus

... Guidance for Cleaning, Disinfection, and Waste Disposal in Commercial Passenger Aircraft Notes on the Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure Communication Resources Videos Audio Infographics & Illustrations Factsheets Posters Virus ...

Ebola (Ebola Virus Disease): Transmission

MedlinePlus

... Guidance for Cleaning, Disinfection, and Waste Disposal in Commercial Passenger Aircraft Notes on the Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure Communication Resources Videos Audio Infographics & Illustrations Factsheets Posters Virus ...

Ebola (Ebola Virus Disease): Diagnosis

MedlinePlus

... Guidance for Cleaning, Disinfection, and Waste Disposal in Commercial Passenger Aircraft Notes on the Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure Communication Resources Videos Audio Infographics & Illustrations Factsheets Posters Virus ...

Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment.

PubMed

Sakurai, Yasuteru; Kolokoltsov, Andrey A; Chen, Cheng-Chang; Tidwell, Michael W; Bauta, William E; Klugbauer, Norbert; Grimm, Christian; Wahl-Schott, Christian; Biel, Martin; Davey, Robert A

2015-02-27

Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy. Copyright © 2015, American Association for the Advancement of Science.

Development of a broad-spectrum antiviral with activity against Ebola virus.

PubMed

Aman, M Javad; Kinch, Michael S; Warfield, Kelly; Warren, Travis; Yunus, Abdul; Enterlein, Sven; Stavale, Eric; Wang, Peifang; Chang, Shaojing; Tang, Qingsong; Porter, Kevin; Goldblatt, Michael; Bavari, Sina

2009-09-01

We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a common pathway utilized by different viruses. These findings suggest FGI-106 may provide an opportunity for targeting viral diseases.

Ebola virus host cell entry.

PubMed

Sakurai, Yasuteru

2015-01-01

Ebola virus is an enveloped virus with filamentous structure and causes a severe hemorrhagic fever in human and nonhuman primates. Host cell entry is the first essential step in the viral life cycle, which has been extensively studied as one of the therapeutic targets. A virus factor of cell entry is a surface glycoprotein (GP), which is an only essential viral protein in the step, as well as the unique particle structure. The virus also interacts with a lot of host factors to successfully enter host cells. Ebola virus at first binds to cell surface proteins and internalizes into cells, followed by trafficking through endosomal vesicles to intracellular acidic compartments. There, host proteases process GPs, which can interact with an intracellular receptor. Then, under an appropriate circumstance, viral and endosomal membranes are fused, which is enhanced by major structural changes of GPs, to complete host cell entry. Recently the basic research of Ebola virus infection mechanism has markedly progressed, largely contributed by identification of host factors and detailed structural analyses of GPs. This article highlights the mechanism of Ebola virus host cell entry, including recent findings.

Ebola Virus Persistence in Semen Ex Vivo.

PubMed

Fischer, Robert J; Judson, Seth; Miazgowicz, Kerri; Bushmaker, Trent; Munster, Vincent J

2016-02-01

On March 20, 2015, a case of Ebola virus disease was identified in Liberia that most likely was transmitted through sexual contact. We assessed the efficiency of detecting Ebola virus in semen samples by molecular diagnostics and the stability of Ebola virus in ex vivo semen under simulated tropical conditions.

Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice

PubMed Central

Konduru, Krishnamurthy; Bradfute, Steven B.; Jacques, Jerome; Manangeeswaran, Mohanraj; Nakamura, Siham; Morshed, Sufi; Wood, Steven C.; Bavari, Sina

2011-01-01

Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGP-Fc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use. PMID:21329775

An Ebola virus-centered knowledge base

PubMed Central

Kamdar, Maulik R.; Dumontier, Michel

2015-01-01

Ebola virus (EBOV), of the family Filoviridae viruses, is a NIAID category A, lethal human pathogen. It is responsible for causing Ebola virus disease (EVD) that is a severe hemorrhagic fever and has a cumulative death rate of 41% in the ongoing epidemic in West Africa. There is an ever-increasing need to consolidate and make available all the knowledge that we possess on EBOV, even if it is conflicting or incomplete. This would enable biomedical researchers to understand the molecular mechanisms underlying this disease and help develop tools for efficient diagnosis and effective treatment. In this article, we present our approach for the development of an Ebola virus-centered Knowledge Base (Ebola-KB) using Linked Data and Semantic Web Technologies. We retrieve and aggregate knowledge from several open data sources, web services and biomedical ontologies. This knowledge is transformed to RDF, linked to the Bio2RDF datasets and made available through a SPARQL 1.1 Endpoint. Ebola-KB can also be explored using an interactive Dashboard visualizing the different perspectives of this integrated knowledge. We showcase how different competency questions, asked by domain users researching the druggability of EBOV, can be formulated as SPARQL Queries or answered using the Ebola-KB Dashboard. Database URL: http://ebola.semanticscience.org. PMID:26055098

Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection.

PubMed

Qiu, Xiangguo; Fernando, Lisa; Melito, P Leno; Audet, Jonathan; Feldmann, Heinz; Kobinger, Gary; Alimonti, Judie B; Jones, Steven M

2012-01-01

Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 µg) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.

Frequently Asked Questions on Ebola Virus Disease

MedlinePlus

... kidney dialysis, blood transfusions, plasma replacement therapy. An experimental Ebola vaccine proved highly protective against Ebola virus ... Ebola. 13. Is there an Ebola vaccine? An experimental Ebola vaccine proved highly protective against the deadly ...

Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga.

PubMed

Chippaux, Jean-Philippe

2014-01-01

The tremendous outbreak of Ebola virus disease occurring in West Africa since the end of 2013 surprises by its remoteness from previous epidemics and dramatic extent. This review aims to describe the 27 manifestations of Ebola virus that arose after its discovery in 1976. It provides an update on research on the ecology of Ebola viruses, modes of contamination and human transmission of the disease that are mainly linked to close contact with an infected animal or a patient suffering from the disease. The recommendations to contain the epidemic and challenges to achieve it are reminded.

Possible sexual transmission of Ebola virus - Liberia, 2015.

PubMed

Christie, Athalia; Davies-Wayne, Gloria J; Cordier-Lassalle, Thierry; Cordier-Lasalle, Thierry; Blackley, David J; Laney, A Scott; Williams, Desmond E; Shinde, Shivam A; Badio, Moses; Lo, Terrence; Mate, Suzanne E; Ladner, Jason T; Wiley, Michael R; Kugelman, Jeffrey R; Palacios, Gustavo; Holbrook, Michael R; Janosko, Krisztina B; de Wit, Emmie; van Doremalen, Neeltje; Munster, Vincent J; Pettitt, James; Schoepp, Randal J; Verhenne, Leen; Evlampidou, Iro; Kollie, Karsor K; Sieh, Sonpon B; Gasasira, Alex; Bolay, Fatorma; Kateh, Francis N; Nyenswah, Tolbert G; De Cock, Kevin M

2015-05-08

On March 20, 2015, 30 days after the most recent confirmed Ebola Virus Disease (Ebola) patient in Liberia was isolated, Ebola was laboratory confirmed in a woman in Monrovia. The investigation identified only one epidemiologic link to Ebola: unprotected vaginal intercourse with a survivor. Published reports from previous outbreaks have demonstrated Ebola survivors can continue to harbor virus in immunologically privileged sites for a period of time after convalescence. Ebola virus has been isolated from semen as long as 82 days after symptom onset and viral RNA has been detected in semen up to 101 days after symptom onset. One instance of possible sexual transmission of Ebola has been reported, although the accompanying evidence was inconclusive. In addition, possible sexual transmission of Marburg virus, a filovirus related to Ebola, was documented in 1968. This report describes the investigation by the Government of Liberia and international response partners of the source of Liberia's latest Ebola case and discusses the public health implications of possible sexual transmission of Ebola virus. Based on information gathered in this investigation, CDC now recommends that contact with semen from male Ebola survivors be avoided until more information regarding the duration and infectiousness of viral shedding in body fluids is known. If male survivors have sex (oral, vaginal, or anal), a condom should be used correctly and consistently every time.

Viraemia and Ebola virus secretion in survivors of Ebola virus disease in Sierra Leone: a cross-sectional cohort study.

PubMed

Green, Edward; Hunt, Luke; Ross, J C Gareth; Nissen, Nina Marie; Curran, Tanya; Badhan, Anjna; Sutherland, Katherine A; Richards, Jade; Lee, James S; Allen, Samuel H; Laird, Steven; Blackman, Mandy; Collacott, Ian; Parker, Paul A; Walbridge, Andrew; Phillips, Rebecca; Sellu, Sia Jammie; Dama, Agnes; Sheriff, Alpha Karim; Zombo, Joseph; Ngegba, Doris; Wurie, Alieh H; Checchi, Francesco; Brooks, Timothy J

2016-09-01

In survivors of Ebola virus disease, clinical sequelae including uveitis, arthralgia, and fatigue are common and necessitate systematic follow-up. However, the infection risk to health-care providers is poorly defined. Here we report Ebola virus RT-PCR data for body site and fluid samples from a large cohort of Ebola virus survivors at clinic follow-up. In this cross-sectional cohort study, consecutive survivors of Ebola virus disease attending Kerry Town survivor clinic (Freetown, Sierra Leone), who had been discharged from the Kerry Town Ebola treatment unit, were invited to participate. We collected and tested axillary, blood, conjunctival, forehead, mouth, rectal, semen, urine, and vaginal specimens for presence of Ebola virus using RT-PCR. We regarded samples to be positive for Ebola virus disease if the cycle threshold was 40 or lower. We collected demographic data from survivors of their age, sex, time since discharge from the treatment unit, and length of acute admission in the Ebola treatment unit using anonymised standard forms. Between April 2, and June 16, 2015, of 151 survivors of Ebola virus disease invited to participate, 112 (74%) provided consent. The median age of participants was 21·5 years (IQR 14-31·5) with 34 (30%) participants younger than 16 years. 50 (45%) of 112 participants were male. We tested a total of 555 specimens: 103 from the axilla, 93 from blood, 92 from conjunctiva, 54 from forehead, 105 from mouth, 17 from the rectum, one from semen, 69 from urine, and 21 from the vagina. The median time from Ebola treatment unit discharge to specimen collection was 142 days (IQR 127-159). 15 participants had a total of 74 swabs taken less than 100 days from discharge. The semen sample from one participant tested positive for Ebola virus at 114 days after discharge from the treatment unit; specimens taken from the axilla, blood, conjunctiva, forehead, mouth, rectum, and urine of the same participant tested negative. All specimens from the

Vaccines against Ebola virus.

PubMed

Venkatraman, Navin; Silman, Daniel; Folegatti, Pedro M; Hill, Adrian V S

2017-08-02

We have just witnessed the largest and most devastating outbreak of Ebola virus disease, which highlighted the urgent need for development of an efficacious vaccine that could be used to curtail future outbreaks. Prior to 2014, there had been limited impetus worldwide to develop a vaccine since the virus was first discovered in 1976. Though too many lives were lost during this outbreak, it resulted in the significantly accelerated clinical development of a number of candidate vaccines through an extraordinary collaborative global effort coordinated by the World Health Organisation (WHO) and involving a number of companies, trial centres, funders, global stakeholders and agencies. We have acquired substantial safety and immunogenicity data on a number of vaccines in Caucasian and African populations. The rapid pace of events led to the initiation of the landmark efficacy trial testing the rVSV-vectored vaccine, which showed high level efficacy in an outbreak setting when deployed using an innovative ring vaccination strategy. Though the Public Health Emergency of International Concern (PHEIC) declared by the WHO has now been lifted, the global scientific community faces numerous challenges ahead to ensure that there is a licensed, deployable vaccine available for use in future outbreaks for at least the Zaire and Sudan strains of Ebola virus. There remain several unanswered questions on the durability of protection, mechanistic immunological correlates and preferred deployment strategies. This review outlines a brief history of the development of Ebola vaccines, the significant progress made since the scale of the outbreak became apparent, some lessons learnt and how they could shape future development of vaccines and the management of similar outbreaks. Copyright © 2017. Published by Elsevier Ltd.

Protection of Nonhuman Primates against Two Species of Ebola Virus Infection with a Single Complex Adenovirus Vector▿

PubMed Central

Pratt, William D.; Wang, Danher; Nichols, Donald K.; Luo, Min; Woraratanadharm, Jan; Dye, John M.; Holman, David H.; Dong, John Y.

2010-01-01

Ebola viruses are highly pathogenic viruses that cause outbreaks of hemorrhagic fever in humans and other primates. To meet the need for a vaccine against the several types of Ebola viruses that cause human diseases, we developed a multivalent vaccine candidate (EBO7) that expresses the glycoproteins of Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) in a single complex adenovirus-based vector (CAdVax). We evaluated our vaccine in nonhuman primates against the parenteral and aerosol routes of lethal challenge. EBO7 vaccine provided protection against both Ebola viruses by either route of infection. Significantly, protection against SEBOV given as an aerosol challenge, which has not previously been shown, could be achieved with a boosting vaccination. These results demonstrate the feasibility of creating a robust, multivalent Ebola virus vaccine that would be effective in the event of a natural virus outbreak or biological threat. PMID:20181765

Protection of nonhuman primates against two species of Ebola virus infection with a single complex adenovirus vector.

PubMed

Pratt, William D; Wang, Danher; Nichols, Donald K; Luo, Min; Woraratanadharm, Jan; Dye, John M; Holman, David H; Dong, John Y

2010-04-01

Ebola viruses are highly pathogenic viruses that cause outbreaks of hemorrhagic fever in humans and other primates. To meet the need for a vaccine against the several types of Ebola viruses that cause human diseases, we developed a multivalent vaccine candidate (EBO7) that expresses the glycoproteins of Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) in a single complex adenovirus-based vector (CAdVax). We evaluated our vaccine in nonhuman primates against the parenteral and aerosol routes of lethal challenge. EBO7 vaccine provided protection against both Ebola viruses by either route of infection. Significantly, protection against SEBOV given as an aerosol challenge, which has not previously been shown, could be achieved with a boosting vaccination. These results demonstrate the feasibility of creating a robust, multivalent Ebola virus vaccine that would be effective in the event of a natural virus outbreak or biological threat.

Ebola (Ebola Virus Disease): Signs and Symptoms

MedlinePlus

... Guidance for Cleaning, Disinfection, and Waste Disposal in Commercial Passenger Aircraft Notes on the Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure Communication Resources Videos Audio Infographics & Illustrations Factsheets Posters Virus ...

Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates.

PubMed

Marzi, Andrea; Engelmann, Flora; Feldmann, Friederike; Haberthur, Kristen; Shupert, W Lesley; Brining, Douglas; Scott, Dana P; Geisbert, Thomas W; Kawaoka, Yoshihiro; Katze, Michael G; Feldmann, Heinz; Messaoudi, Ilhem

2013-01-29

Ebola viruses cause hemorrhagic disease in humans and nonhuman primates with high fatality rates. These viruses pose a significant health concern worldwide due to the lack of approved therapeutics and vaccines as well as their potential misuse as bioterrorism agents. Although not licensed for human use, recombinant vesicular stomatitis virus (rVSV) expressing the filovirus glycoprotein (GP) has been shown to protect macaques from Ebola virus and Marburg virus infections, both prophylactically and postexposure in a homologous challenge setting. However, the immune mechanisms of protection conferred by this vaccine platform remain poorly understood. In this study, we set out to investigate the role of humoral versus cellular immunity in rVSV vaccine-mediated protection against lethal Zaire ebolavirus (ZEBOV) challenge. Groups of cynomolgus macaques were depleted of CD4+ T, CD8+ T, or CD20+ B cells before and during vaccination with rVSV/ZEBOV-GP. Unfortunately, CD20-depleted animals generated a robust IgG response. Therefore, an additional group of vaccinated animals were depleted of CD4+ T cells during challenge. All animals were subsequently challenged with a lethal dose of ZEBOV. Animals depleted of CD8+ T cells survived, suggesting a minimal role for CD8+ T cells in vaccine-mediated protection. Depletion of CD4+ T cells during vaccination caused a complete loss of glycoprotein-specific antibodies and abrogated vaccine protection. In contrast, depletion of CD4+ T cells during challenge resulted in survival of the animals, indicating a minimal role for CD4+ T-cell immunity in rVSV-mediated protection. Our results suggest that antibodies play a critical role in rVSV-mediated protection against ZEBOV.

An Ebola virus-centered knowledge base.

PubMed

Kamdar, Maulik R; Dumontier, Michel

2015-01-01

Ebola virus (EBOV), of the family Filoviridae viruses, is a NIAID category A, lethal human pathogen. It is responsible for causing Ebola virus disease (EVD) that is a severe hemorrhagic fever and has a cumulative death rate of 41% in the ongoing epidemic in West Africa. There is an ever-increasing need to consolidate and make available all the knowledge that we possess on EBOV, even if it is conflicting or incomplete. This would enable biomedical researchers to understand the molecular mechanisms underlying this disease and help develop tools for efficient diagnosis and effective treatment. In this article, we present our approach for the development of an Ebola virus-centered Knowledge Base (Ebola-KB) using Linked Data and Semantic Web Technologies. We retrieve and aggregate knowledge from several open data sources, web services and biomedical ontologies. This knowledge is transformed to RDF, linked to the Bio2RDF datasets and made available through a SPARQL 1.1 Endpoint. Ebola-KB can also be explored using an interactive Dashboard visualizing the different perspectives of this integrated knowledge. We showcase how different competency questions, asked by domain users researching the druggability of EBOV, can be formulated as SPARQL Queries or answered using the Ebola-KB Dashboard. © The Author(s) 2015. Published by Oxford University Press.

[Recent Advances in Vaccines and Drugs Against the Ebola Virus].

PubMed

Zhu, Xiang; Yao, Chenguang; Wei, Yanhong; Kou, Zheng; Hu, Kanghong

2015-05-01

The Ebola virus belongs to the Filovirus family, which causes Ebola hemorrhagic fever (mortality, 25%-90%). An outbreak of infection by the Ebola virus is sweeping across West Africa, leading to high mortality and worldwide panic. The Ebola virus has caused a serious threat to public health, so intensive scientific studies have been carried out. Several vaccines (e.g., rVSV-ZEBOV, ChAd3-ZEBOV) have been put into clinical trials and antiviral drugs (e.g., TKM-Ebola, ZMAPP) have been administered in the emergency setting to patients infected by the Ebola virus. Here, recent advances in vaccines and drugs against the Ebola virus are reviewed.

Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses.

PubMed

Geisbert, Thomas W; Daddario-Dicaprio, Kathleen M; Geisbert, Joan B; Reed, Douglas S; Feldmann, Friederike; Grolla, Allen; Ströher, Ute; Fritz, Elizabeth A; Hensley, Lisa E; Jones, Steven M; Feldmann, Heinz

2008-12-09

Considerable progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against Ebola and Marburg viruses. A vaccine based on recombinant vesicular stomatitis virus (VSV) seems to be particularly robust as it can also confer protection when administered as a postexposure treatment. While filoviruses are not thought to be transmitted by aerosol in nature the inhalation route is among the most likely portals of entry in the setting of a bioterrorist event. At present, all candidate filoviral vaccines have been evaluated against parenteral challenges but none have been tested against an aerosol exposure. Here, we evaluated our recombinant VSV-based Zaire ebolavirus (ZEBOV) and Marburg virus (MARV) vaccines against aerosol challenge in cynomolgus macaques. All monkeys vaccinated with a VSV vector expressing the glycoprotein of ZEBOV were completely protected against an aerosol exposure of ZEBOV. Likewise, all monkeys vaccinated with a VSV vector expressing the glycoprotein of MARV were completely protected against an aerosol exposure of MARV. All control animals challenged by the aerosol route with either ZEBOV or MARV succumbed. Interestingly, disease in control animals appeared to progress slower than previously seen in macaques exposed to comparable doses by intramuscular injection.

[Ebola and Marburg viruses: the humans strike back].

PubMed

Alazard-Dany, Nathalie; Ottmann Terrangle, Michèle; Volchkov, Viktor

2006-04-01

Ebola and Marburg viruses are the causative agents of rapidly progressive hemorrhagic fevers with high mortality rates. Pre- or post-exposure treatments against the diseases are currently not available for human use. In the field, establishment of strict quarantine measures preventing further virus transmission are still the only way to fight the infections. However, our knowledge of Ebola and Marburg viruses has markedly increased as a result of two recent discoveries discussed in this review. Chandran et al. have elucidated the mechanism by which Ebola GP is converted to a fusion-active form. Infectivity of Ebola virus was shown to be dependent on the cleavage of GP by cellular endosomal proteases, cathepsin B and L, thus opening new therapeutic approaches options. As for Jones SM et al., they have successfully vaccinated monkeys with recombinant vesicular stomatitis virus expressing Ebola or Marburg virus surface glycoprotein GP, a promising vaccine approach.

Ebola Virus Disease: A Review of Its Past and Present.

PubMed

Murray, Michael J

2015-09-01

Ebola virus, the virus responsible for Ebola virus disease, has spawned several epidemics during the past 38 years. In 2014, an Ebola epidemic spread from Africa to other continents, becoming a pandemic. The virus's relatively unique structure, its infectivity and lethality, the difficulty in stopping its spread, and the lack of an effective treatment captured the world's attention. This article provides a brief review of the known history of Ebola virus disease, its etiology, epidemiology, and pathophysiology and a review of the limited information on managing patients with Ebola virus disease.

Late Ebola virus relapse causing meningoencephalitis: a case report.

PubMed

Jacobs, Michael; Rodger, Alison; Bell, David J; Bhagani, Sanjay; Cropley, Ian; Filipe, Ana; Gifford, Robert J; Hopkins, Susan; Hughes, Joseph; Jabeen, Farrah; Johannessen, Ingolfur; Karageorgopoulos, Drosos; Lackenby, Angie; Lester, Rebecca; Liu, Rebecca S N; MacConnachie, Alisdair; Mahungu, Tabitha; Martin, Daniel; Marshall, Neal; Mepham, Stephen; Orton, Richard; Palmarini, Massimo; Patel, Monika; Perry, Colin; Peters, S Erica; Porter, Duncan; Ritchie, David; Ritchie, Neil D; Seaton, R Andrew; Sreenu, Vattipally B; Templeton, Kate; Warren, Simon; Wilkie, Gavin S; Zambon, Maria; Gopal, Robin; Thomson, Emma C

2016-07-30

There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2). A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors

Detection of Ebola Virus RNA through Aerosol Sampling of Animal Biosafety Level 4 Rooms Housing Challenged Nonhuman Primates

DTIC Science & Technology

2016-08-02

301- 619-4768(f). 1 2 3 4 5 6 7 8 Title: Detection of Ebola Virus RNA through Aerosol Sampling of Animal Biosafety Level 9 4...5 6 To whom it may concern, 7 8 My colleagues and I are submitting the attached manuscript, Detection of Ebola Virus 9 RNA through Aerosol...embedded in the texts. This is the first report demonstrating detection of Ebola virus 17 RNA from animal rooms housing infected nonhuman primates and

[Multiplex real-time PCR method for rapid detection of Marburg virus and Ebola virus].

PubMed

Yang, Yu; Bai, Lin; Hu, Kong-Xin; Yang, Zhi-Hong; Hu, Jian-Ping; Wang, Jing

2012-08-01

Marburg virus and Ebola virus are acute infections with high case fatality rates. A rapid, sensitive detection method was established to detect Marburg virus and Ebola virus by multiplex real-time fluorescence quantitative PCR. Designing primers and Taqman probes from highly conserved sequences of Marburg virus and Ebola virus through whole genome sequences alignment, Taqman probes labeled by FAM and Texas Red, the sensitivity of the multiplex real-time quantitative PCR assay was optimized by evaluating the different concentrations of primers and Probes. We have developed a real-time PCR method with the sensitivity of 30.5 copies/microl for Marburg virus positive plasmid and 28.6 copies/microl for Ebola virus positive plasmids, Japanese encephalitis virus, Yellow fever virus, Dengue virus were using to examine the specificity. The Multiplex real-time PCR assays provide a sensitive, reliable and efficient method to detect Marburg virus and Ebola virus simultaneously.

Ebola Virus Localization in the Macaque Reproductive Tract during Acute Ebola Virus Disease.

PubMed

Perry, Donna L; Huzella, Louis M; Bernbaum, John G; Holbrook, Michael R; Jahrling, Peter B; Hagen, Katie R; Schnell, Matthias J; Johnson, Reed F

2018-03-01

Sexual transmission of Ebola virus (EBOV) has been demonstrated more than a year after recovery from the acute phase of Ebola virus disease (EVD). The mechanisms underlying EBOV persistence and sexual transmission are not currently understood. Using the acute macaque model of EVD, we hypothesized EBOV would infect the reproductive tissues and sought to localize the infection in these tissues using immunohistochemistry and transmission electron microscopy. In four female and eight male macaques that succumbed to EVD between 6 and 9 days after EBOV challenge, we demonstrate widespread EBOV infection of the interstitial tissues and endothelium in the ovary, uterus, testis, seminal vesicle, epididymis, and prostate gland, with minimal associated tissue immune response or organ pathology. Given the widespread involvement of EBOV in the reproductive tracts of both male and female macaques, it is reasonable to surmise that our understanding of the mechanisms underlying sexual transmission of EVD and persistence of EBOV in immune-privileged sites would be facilitated by the development of a nonhuman primate model in which the macaques survived past the acute stage into convalescence. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Implementation of a study to examine the persistence of Ebola virus in the body fluids of Ebola virus disease survivors in Sierra Leone: Methodology and lessons learned

PubMed Central

Marrinan, Jaclyn E.; Sesay, Foday R.; Ervin, Elizabeth; Thorson, Anna E.; Xu, Wenbo; Ströher, Ute; Ongpin, Patricia; Abad, Neetu; Ariyarajah, Archchun; Malik, Tasneem; Liu, Hongtu; Ross, Christine; Durski, Kara N.; Gaillard, Philippe; Morgan, Oliver; Formenty, Pierre; Knust, Barbara; Broutet, Nathalie; Sahr, Foday

2017-01-01

Background The 2013–2016 West African Ebola virus disease epidemic was unprecedented in terms of the number of cases and survivors. Prior to this epidemic there was limited data available on the persistence of Ebola virus in survivors’ body fluids and the potential risk of transmission, including sexual transmission. Methodology/Principal findings Given the urgent need to determine the persistence of Ebola virus in survivors’ body fluids, an observational cohort study was designed and implemented during the epidemic response operation in Sierra Leone. This publication describes study implementation methodology and the key lessons learned. Challenges encountered during implementation included unforeseen duration of follow-up, complexity of interpreting and communicating laboratory results to survivors, and the urgency of translating research findings into public health practice. Strong community engagement helped rapidly implement the study during the epidemic. The study was conducted in two phases. The first phase was initiated within five months of initial protocol discussions and assessed persistence of Ebola virus in semen of 100 adult men. The second phase assessed the persistence of virus in multiple body fluids (semen or vaginal fluid, menstrual blood, breast milk, and urine, rectal fluid, sweat, saliva, tears), of 120 men and 120 women. Conclusion/Significance Data from this study informed national and global guidelines in real time and demonstrated the need to implement semen testing programs among Ebola virus disease survivors. The lessons learned and study tools developed accelerated the implementation of such programs in Ebola virus disease affected countries, and also informed studies examining persistence of Zika virus. Research is a vital component of the public health response to an epidemic of a poorly characterized disease. Adequate resources should be rapidly made available to answer critical research questions, in order to better inform

Implementation of a study to examine the persistence of Ebola virus in the body fluids of Ebola virus disease survivors in Sierra Leone: Methodology and lessons learned.

PubMed

Deen, Gibrilla Fadlu; McDonald, Suzanna L R; Marrinan, Jaclyn E; Sesay, Foday R; Ervin, Elizabeth; Thorson, Anna E; Xu, Wenbo; Ströher, Ute; Ongpin, Patricia; Abad, Neetu; Ariyarajah, Archchun; Malik, Tasneem; Liu, Hongtu; Ross, Christine; Durski, Kara N; Gaillard, Philippe; Morgan, Oliver; Formenty, Pierre; Knust, Barbara; Broutet, Nathalie; Sahr, Foday

2017-09-01

The 2013-2016 West African Ebola virus disease epidemic was unprecedented in terms of the number of cases and survivors. Prior to this epidemic there was limited data available on the persistence of Ebola virus in survivors' body fluids and the potential risk of transmission, including sexual transmission. Given the urgent need to determine the persistence of Ebola virus in survivors' body fluids, an observational cohort study was designed and implemented during the epidemic response operation in Sierra Leone. This publication describes study implementation methodology and the key lessons learned. Challenges encountered during implementation included unforeseen duration of follow-up, complexity of interpreting and communicating laboratory results to survivors, and the urgency of translating research findings into public health practice. Strong community engagement helped rapidly implement the study during the epidemic. The study was conducted in two phases. The first phase was initiated within five months of initial protocol discussions and assessed persistence of Ebola virus in semen of 100 adult men. The second phase assessed the persistence of virus in multiple body fluids (semen or vaginal fluid, menstrual blood, breast milk, and urine, rectal fluid, sweat, saliva, tears), of 120 men and 120 women. Data from this study informed national and global guidelines in real time and demonstrated the need to implement semen testing programs among Ebola virus disease survivors. The lessons learned and study tools developed accelerated the implementation of such programs in Ebola virus disease affected countries, and also informed studies examining persistence of Zika virus. Research is a vital component of the public health response to an epidemic of a poorly characterized disease. Adequate resources should be rapidly made available to answer critical research questions, in order to better inform response efforts.

Intradermal Vaccination With Adjuvanted Ebola Virus Soluble Glycoprotein Subunit Vaccine by Microneedle Patches Protects Mice Against Lethal Ebola Virus Challenge.

PubMed

Liu, Ying; Ye, Ling; Lin, Fang; Gomaa, Yasmine; Flyer, David; Carrion, Ricardo; Patterson, Jean L; Prausnitz, Mark R; Smith, Gale; Glenn, Gregory; Wu, Hua; Compans, Richard W; Yang, Chinglai

2018-06-08

In this study, we investigated immune responses induced by purified Ebola virus (EBOV) soluble glycoprotein (sGP) subunit vaccines via intradermal immunization with microneedle (MN) patches in comparison with intramuscular (IM) injection in mice. Our results showed that MN delivery of EBOV sGP was superior to IM injection in eliciting higher levels and longer lasting antibody responses against EBOV sGP and GP antigens. Moreover, sGP-specific immune responses induced by MN or IM immunizations were effectively augmented by formulating sGP with a saponin-based adjuvant, and they were shown to confer complete protection of mice against lethal mouse-adapted EBOV (MA-EBOV) challenge. In comparison, mice that received sGP without adjuvant by MN or IM immunizations succumbed to lethal MA-EBOV challenge. These results show that immunization with EBOV sGP subunit vaccines with adjuvant by MN patches, which have been shown to provide improved safety and thermal stability, is a promising approach to protect against EBOV infection.

Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections.

PubMed

Geisbert, Thomas W; Feldmann, Heinz

2011-11-01

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections.

Intramuscular Adeno-Associated Virus-Mediated Expression of Monoclonal Antibodies Provides 100% Protection Against Ebola Virus Infection in Mice.

PubMed

van Lieshout, Laura P; Soule, Geoff; Sorensen, Debra; Frost, Kathy L; He, Shihua; Tierney, Kevin; Safronetz, David; Booth, Stephanie A; Kobinger, Gary P; Qiu, Xiangguo; Wootton, Sarah K

2018-03-05

The 2013-2016 West Africa outbreak demonstrated the epidemic potential of Ebola virus and highlighted the need for counter strategies. Monoclonal antibody (mAb)-based therapies hold promise as treatment options for Ebola virus infections. However, production of clinical-grade mAbs is labor intensive, and immunity is short lived. Conversely, adeno-associated virus (AAV)-mediated mAb gene transfer provides the host with a genetic blueprint to manufacture mAbs in vivo, leading to steady release of antibody over many months. Here we demonstrate that AAV-mediated expression of nonneutralizing mAb 5D2 or 7C9 confers 100% protection against mouse-adapted Ebola virus infection, while neutralizing mAb 2G4 was 83% protective. A 2-component cocktail, AAV-2G4/AAV-5D2, provided complete protection when administered 7 days prior to challenge and was partially protective with a 3-day lead time. Finally, AAV-mAb therapies provided sustained protection from challenge 5 months following AAV administration. AAV-mAb may be a viable alternative strategy for vaccination against emerging infectious diseases.

Potent neutralizing monoclonal antibodies against Ebola virus infection

PubMed Central

Zhang, Qi; Gui, Miao; Niu, Xuefeng; He, Shihua; Wang, Ruoke; Feng, Yupeng; Kroeker, Andrea; Zuo, Yanan; Wang, Hua; Wang, Ying; Li, Jiade; Li, Chufang; Shi, Yi; Shi, Xuanling; Gao, George F.; Xiang, Ye; Qiu, Xiangguo; Chen, Ling; Zhang, Linqi

2016-01-01

Ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. Here we show isolation of three (Q206, Q314 and Q411) neutralizing monoclonal antibodies (mAbs) against the surface glycoprotein (GP) of Ebola virus identified in West Africa in 2014 through sequential immunization of Chinese rhesus macaques and antigen-specific single B cell sorting. These mAbs demonstrated potent neutralizing activities against both pseudo and live Ebola virus independent of complement. Biochemical, single particle EM, and mutagenesis analysis suggested Q206 and Q411 recognized novel epitopes in the head while Q314 targeted the glycan cap in the GP1 subunit. Q206 and Q411 appeared to influence GP binding to its receptor NPC1. Treatment with these mAbs provided partial but significant protection against disease in a mouse model of Ebola virus infection. These novel mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola virus infection. PMID:27181584

Potent neutralizing monoclonal antibodies against Ebola virus infection.

PubMed

Zhang, Qi; Gui, Miao; Niu, Xuefeng; He, Shihua; Wang, Ruoke; Feng, Yupeng; Kroeker, Andrea; Zuo, Yanan; Wang, Hua; Wang, Ying; Li, Jiade; Li, Chufang; Shi, Yi; Shi, Xuanling; Gao, George F; Xiang, Ye; Qiu, Xiangguo; Chen, Ling; Zhang, Linqi

2016-05-16

Ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. Here we show isolation of three (Q206, Q314 and Q411) neutralizing monoclonal antibodies (mAbs) against the surface glycoprotein (GP) of Ebola virus identified in West Africa in 2014 through sequential immunization of Chinese rhesus macaques and antigen-specific single B cell sorting. These mAbs demonstrated potent neutralizing activities against both pseudo and live Ebola virus independent of complement. Biochemical, single particle EM, and mutagenesis analysis suggested Q206 and Q411 recognized novel epitopes in the head while Q314 targeted the glycan cap in the GP1 subunit. Q206 and Q411 appeared to influence GP binding to its receptor NPC1. Treatment with these mAbs provided partial but significant protection against disease in a mouse model of Ebola virus infection. These novel mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola virus infection.

Plasmodium Parasitemia Associated With Increased Survival in Ebola Virus-Infected Patients.

PubMed

Rosenke, Kyle; Adjemian, Jennifer; Munster, Vincent J; Marzi, Andrea; Falzarano, Darryl; Onyango, Clayton O; Ochieng, Melvin; Juma, Bonventure; Fischer, Robert J; Prescott, Joseph B; Safronetz, David; Omballa, Victor; Owuor, Collins; Hoenen, Thomas; Groseth, Allison; Martellaro, Cynthia; van Doremalen, Neeltje; Zemtsova, Galina; Self, Joshua; Bushmaker, Trenton; McNally, Kristin; Rowe, Thomas; Emery, Shannon L; Feldmann, Friederike; Williamson, Brandi N; Best, Sonja M; Nyenswah, Tolbert G; Grolla, Allen; Strong, James E; Kobinger, Gary; Bolay, Fatorma K; Zoon, Kathryn C; Stassijns, Jorgen; Giuliani, Ruggero; de Smet, Martin; Nichol, Stuart T; Fields, Barry; Sprecher, Armand; Massaquoi, Moses; Feldmann, Heinz; de Wit, Emmie

2016-10-15

The ongoing Ebola outbreak in West Africa has resulted in 28 646 suspected, probable, and confirmed Ebola virus infections. Nevertheless, malaria remains a large public health burden in the region affected by the outbreak. A joint Centers for Disease Control and Prevention/National Institutes of Health diagnostic laboratory was established in Monrovia, Liberia, in August 2014, to provide laboratory diagnostics for Ebola virus. All blood samples from suspected Ebola virus-infected patients admitted to the Médecins Sans Frontières ELWA3 Ebola treatment unit in Monrovia were tested by quantitative real-time polymerase chain reaction for the presence of Ebola virus and Plasmodium species RNA. Clinical outcome in laboratory-confirmed Ebola virus-infected patients was analyzed as a function of age, sex, Ebola viremia, and Plasmodium species parasitemia. The case fatality rate of 1182 patients with laboratory-confirmed Ebola virus infections was 52%. The probability of surviving decreased with increasing age and decreased with increasing Ebola viral load. Ebola virus-infected patients were 20% more likely to survive when Plasmodium species parasitemia was detected, even after controlling for Ebola viral load and age; those with the highest levels of parasitemia had a survival rate of 83%. This effect was independent of treatment with antimalarials, as this was provided to all patients. Moreover, treatment with antimalarials did not affect survival in the Ebola virus mouse model. Plasmodium species parasitemia is associated with an increase in the probability of surviving Ebola virus infection. More research is needed to understand the molecular mechanism underlying this remarkable phenomenon and translate it into treatment options for Ebola virus infection. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

[Research progress of the molecule mechanisms of Ebola virus infection of cells].

PubMed

Shi, Ming; Shen, Yu-Qing

2013-01-01

Ebola virus can cause severe Ebola hemorrhagic fever. The mortality rate is 90 percent. Up till now, there is no effective vaccine or treatment of Ebola virus infection. Relaed researches on Ebola virus have become a hot topic in virology. The understanding of molecular mechanisms of Ebola virus infection of cells are important for the development of vaccine and anti-virus drugs. Therefore, this review summarized the recent research progress on the mechanisms of Ebola virus infection.

Antiviral effect of ranpirnase against Ebola virus.

PubMed

Hodge, Thomas; Draper, Ken; Brasel, Trevor; Freiberg, Alexander; Squiquera, Luis; Sidransky, David; Sulley, Jamie; Taxman, Debra J

2016-08-01

The recent epidemic of Ebola has intensified the need for the development of novel antiviral therapeutics that prolong and improve survival against deadly viral diseases. We sought to determine whether ranpirnase, an endoribonuclease from Rana pipiens with a demonstrated human safety profile in phase III oncology trials, can reduce titers of Ebola virus (EBOV) in infected cells, protect mice against mouse-adapted EBOV challenge, and reduce virus levels in infected mice. Our results demonstrate that 0.50 μg/ml ranpirnase is potently effective at reducing EBOV Zaire Kikwit infection in cultured Vero E6 cells (Selectivity Index 47.8-70.2). In a prophylactic study, a single intravenous dose of 0.1 mg/kg ranpirnase protected 70% of mice from progressive infection. Additionally, in a post-exposure prophylactic study, 100% of female mice survived infection after intraperitoneal administration of 0.1 mg/kg ranpirnase for ten days beginning 1 h post challenge. Most of the male counterparts were sacrificed due to weight loss by Study Day 8 or 9; however, the Clinical Activity/Behavior scores of these mice remained low and no significant microscopic pathologies could be detected in the kidneys, livers or spleens. Furthermore, live virus could not be detected in the sera of ranpirnase-treated mice by Study Day 8 or in the kidneys, livers or spleens by Study Day 12, and viral RNA levels declined exponentially by Study Day 12. Because ranpirnase is exceptionally stable and has a long track record of safe intravenous administration to humans, this drug provides a promising new candidate for clinical consideration in the treatment of Ebola virus disease alone or in combination with other therapeutics. Copyright © 2016 Elsevier B.V. All rights reserved.

Evidence-based guidelines for supportive care of patients with Ebola virus disease.

PubMed

Lamontagne, François; Fowler, Robert A; Adhikari, Neill K; Murthy, Srinivas; Brett-Major, David M; Jacobs, Michael; Uyeki, Timothy M; Vallenas, Constanza; Norris, Susan L; Fischer, William A; Fletcher, Thomas E; Levine, Adam C; Reed, Paul; Bausch, Daniel G; Gove, Sandy; Hall, Andrew; Shepherd, Susan; Siemieniuk, Reed A; Lamah, Marie-Claude; Kamara, Rashida; Nakyeyune, Phiona; Soka, Moses J; Edwin, Ama; Hazzan, Afeez A; Jacob, Shevin T; Elkarsany, Mubarak Mustafa; Adachi, Takuya; Benhadj, Lynda; Clément, Christophe; Crozier, Ian; Garcia, Armando; Hoffman, Steven J; Guyatt, Gordon H

2018-02-17

The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients' reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief. Copyright © 2018 Elsevier Ltd. All rights reserved.

Design of Fusion Proteins for Efficient and Soluble Production of Immunogenic Ebola Virus Glycoprotein in Escherichia coli.

PubMed

Ji, Yang; Lu, Yuan; Yan, Yishu; Liu, Xinxin; Su, Nan; Zhang, Chong; Bi, Shengli; Xing, Xin-Hui

2018-03-03

The Ebola hemorrhagic fever caused by Ebola virus is an extremely dangerous disease, and effective therapeutic agents are still lacking. Platforms for the efficient production of vaccines are crucial to ensure quick response against an Ebola virus outbreak. Ebola virus glycoprotein (EbolaGP) on the virion surface is responsible for membrane binding and virus entry, thus becoming the key target for vaccine development. However, heterologous expression of this protein still faces engineering challenges such as low production levels and insoluble aggregation. Here, the authors design and compare various fusion strategies, attaching great importance to the solubility-enhancing effect, and tag removal process. It is found that a C-terminal intein-based tag greatly enhances the solubility of EbolaGP and allows one-step chromatographic purification of the untagged EbolaGP through thiol-catalyzed self-cleavage. The purified untagged EbolaGP alone or with Freund's adjuvant are highly immunogenic, as confirmed in a mouse model. Consequently, the present study puts forward a new strategy for the efficient and soluble expression of untagged immunogenic EbolaGP. The intein-based protein fusion approach may be of importance for the large-scale production of Ebola virus subunit vaccine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of therapeutics for treatment of Ebola virus infection.

PubMed

Li, Haoyang; Ying, Tianlei; Yu, Fei; Lu, Lu; Jiang, Shibo

2015-02-01

Ebola virus infection can cause Ebola virus disease (EVD). Patients usually show severe symptoms, and the fatality rate can reach up to 90%. No licensed medicine is available. In this review, development of therapeutics for treatment of Ebola virus infection and EVD will be discussed. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study.

PubMed

Sissoko, Daouda; Duraffour, Sophie; Kerber, Romy; Kolie, Jacques Seraphin; Beavogui, Abdoul Habib; Camara, Alseny-Modet; Colin, Géraldine; Rieger, Toni; Oestereich, Lisa; Pályi, Bernadett; Wurr, Stephanie; Guedj, Jeremie; Nguyen, Thi Huyen Tram; Eggo, Rosalind M; Watson, Conall H; Edmunds, W John; Bore, Joseph Akoi; Koundouno, Fara Raymond; Cabeza-Cabrerizo, Mar; Carter, Lisa L; Kafetzopoulou, Liana Eleni; Kuisma, Eeva; Michel, Janine; Patrono, Livia Victoria; Rickett, Natasha Y; Singethan, Katrin; Rudolf, Martin; Lander, Angelika; Pallasch, Elisa; Bockholt, Sabrina; Rodríguez, Estefanía; Di Caro, Antonino; Wölfel, Roman; Gabriel, Martin; Gurry, Céline; Formenty, Pierre; Keïta, Sakoba; Malvy, Denis; Carroll, Miles W; Anglaret, Xavier; Günther, Stephan

2017-01-01

By January, 2016, all known transmission chains of the Ebola virus disease (EVD) outbreak in west Africa had been stopped. However, there is concern about persistence of Ebola virus in the reproductive tract of men who have survived EVD. We aimed to use biostatistical modelling to describe the dynamics of Ebola virus RNA load in seminal fluid, including clearance parameters. In this longitudinal study, we recruited men who had been discharged from three Ebola treatment units in Guinea between January and July, 2015. Participants provided samples of seminal fluid at follow-up every 3-6 weeks, which we tested for Ebola virus RNA using quantitative real-time RT-PCR. Representative specimens from eight participants were then inoculated into immunodeficient mice to test for infectivity. We used a linear mixed-effect model to analyse the dynamics of virus persistence in seminal fluid over time. We enrolled 26 participants and tested 130 seminal fluid specimens; median follow up was 197 days (IQR 187-209 days) after enrolment, which corresponded to 255 days (228-287) after disease onset. Ebola virus RNA was detected in 86 semen specimens from 19 (73%) participants. Median duration of Ebola virus RNA detection was 158 days after onset (73-181; maximum 407 days at end of follow-up). Mathematical modelling of the quantitative time-series data showed a mean clearance rate of Ebola virus RNA from seminal fluid of -0·58 log units per month, although the clearance kinetic varied greatly between participants. Using our biostatistical model, we predict that 50% and 90% of male survivors clear Ebola virus RNA from seminal fluid at 115 days (90% prediction interval 72-160) and 294 days (212-399) after disease onset, respectively. We also predicted that the number of men positive for Ebola virus RNA in affected countries would decrease from about 50 in January 2016, to fewer than 1 person by July, 2016. Infectious virus was detected in 15 of 26 (58%) specimens tested in mice. Time

Characterization of Ebola virus entry by using pseudotyped viruses: identification of receptor-deficient cell lines.

PubMed

Wool-Lewis, R J; Bates, P

1998-04-01

Studies analyzing Ebola virus replication have been severely hampered by the extreme pathogenicity of this virus. To permit analysis of the host range and function of the Ebola virus glycoprotein (Ebo-GP), we have developed a system for pseudotyping these glycoproteins into murine leukemia virus (MLV). This pseudotyped virus, MLV(Ebola), can be readily concentrated to titers which exceed 5 x 10(6) infectious units/ml and is effectively neutralized by antibodies specific for Ebo-GP. Analysis of MLV(Ebola) infection revealed that the host range conferred by Ebo-GP is very broad, extending to cells of a variety of species. Notably, all lymphoid cell lines tested were completely resistant to infection; we speculate that this is due to the absence of a cellular receptor for Ebo-GP on B and T cells. The generation of high-titer MLV(Ebola) pseudotypes will be useful for the analysis of immune responses to Ebola virus infection, development of neutralizing antibodies, analysis of glycoprotein function, and isolation of the cellular receptor(s) for the Ebola virus.

Anti-Ebola therapies based on monoclonal antibodies: Current state and challenges ahead

PubMed Central

González-González, E; Alvarez, MM; Márquez-Ipiña, AR; Santiago, G Trujillo-de; Rodríguez-Martínez, LM; Annabi, N; Khademhosseini, A

2017-01-01

The 2014 Ebola outbreak, the largest recorded, took us largely unprepared, with no available vaccine or specific treatment. In this context, the World Health Organization (WHO) declared that the humanitarian use of experimental therapies against Ebola Virus (EBOV) is ethical. In particular, an experimental treatment consisting of a cocktail of three monoclonal antibodies (mAbs) produced in tobacco plants and specifically directed to the Ebola virus glycoprotein (GP) was tested in humans, apparently with good results. Several mAbs with high affinity to the GP have been described. This review discusses our current knowledge on this topic. Particular emphasis is devoted to those mAbs that have been assayed in animal models or humans as possible therapies against Ebola. Engineering aspects and challenges for the production of anti-Ebola mAbs are also briefly discussed; current platforms for the design and production of full-length mAbs are cumbersome and costly. PMID:26611830

Unusual Ebola Virus Chain of Transmission, Conakry, Guinea, 2014-2015.

PubMed

Keita, Mory; Duraffour, Sophie; Loman, Nicholas J; Rambaut, Andrew; Diallo, Boubacar; Magassouba, Nfaly; Carroll, Miles W; Quick, Joshua; Sall, Amadou A; Glynn, Judith R; Formenty, Pierre; Subissi, Lorenzo; Faye, Ousmane

2016-12-01

In October 2015, a new case of Ebola virus disease in Guinea was detected. Case investigation, serology, and whole-genome sequencing indicated possible transmission of the virus from an Ebola virus disease survivor to another person and then to the case-patient reported here. This transmission chain over 11 months suggests slow Ebola virus evolution.

ISCB Ebola Award for Important Future Research on the Computational Biology of Ebola Virus

PubMed Central

Karp, Peter D.; Berger, Bonnie; Kovats, Diane; Lengauer, Thomas; Linial, Michal; Sabeti, Pardis; Hide, Winston; Rost, Burkhard

2015-01-01

Speed is of the essence in combating Ebola; thus, computational approaches should form a significant component of Ebola research. As for the development of any modern drug, computational biology is uniquely positioned to contribute through comparative analysis of the genome sequences of Ebola strains as well as 3-D protein modeling. Other computational approaches to Ebola may include large-scale docking studies of Ebola proteins with human proteins and with small-molecule libraries, computational modeling of the spread of the virus, computational mining of the Ebola literature, and creation of a curated Ebola database. Taken together, such computational efforts could significantly accelerate traditional scientific approaches. In recognition of the need for important and immediate solutions from the field of computational biology against Ebola, the International Society for Computational Biology (ISCB) announces a prize for an important computational advance in fighting the Ebola virus. ISCB will confer the ISCB Fight against Ebola Award, along with a prize of US$2,000, at its July 2016 annual meeting (ISCB Intelligent Systems for Molecular Biology (ISMB) 2016, Orlando, Florida). PMID:26097686

ISCB Ebola Award for Important Future Research on the Computational Biology of Ebola Virus.

PubMed

Karp, Peter D; Berger, Bonnie; Kovats, Diane; Lengauer, Thomas; Linial, Michal; Sabeti, Pardis; Hide, Winston; Rost, Burkhard

2015-01-01

Speed is of the essence in combating Ebola; thus, computational approaches should form a significant component of Ebola research. As for the development of any modern drug, computational biology is uniquely positioned to contribute through comparative analysis of the genome sequences of Ebola strains as well as 3-D protein modeling. Other computational approaches to Ebola may include large-scale docking studies of Ebola proteins with human proteins and with small-molecule libraries, computational modeling of the spread of the virus, computational mining of the Ebola literature, and creation of a curated Ebola database. Taken together, such computational efforts could significantly accelerate traditional scientific approaches. In recognition of the need for important and immediate solutions from the field of computational biology against Ebola, the International Society for Computational Biology (ISCB) announces a prize for an important computational advance in fighting the Ebola virus. ISCB will confer the ISCB Fight against Ebola Award, along with a prize of US$2,000, at its July 2016 annual meeting (ISCB Intelligent Systems for Molecular Biology (ISMB) 2016, Orlando, Florida).

Musculoskeletal manifestations of Ebola virus.

PubMed

Amissah-Arthur, Maame B; Poller, Bozena; Tunbridge, Anne; Adebajo, Adewale

2018-01-01

The 2014 West African Ebola virus disease outbreak shocked the world as it swept through the region leaving Guinea, Liberia and Sierra Leone struggling to gain control. As the largest Ebola virus disease outbreak to date, there are more survivors in its wake than ever before, with a spectrum of health problems requiring management. Here we review various musculoskeletal manifestations of the virus that can occur both during and after the infection, and consider possible pathogenesis. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Characteristics of Filoviridae: Marburg and Ebola Viruses

NASA Astrophysics Data System (ADS)

Beer, Brigitte; Kurth, Reinhard; Bukreyev, Alexander

Filoviruses are enveloped, nonsegmented negative-stranded RNA viruses. The two species, Marburg and Ebola virus, are serologically, biochemically, and genetically distinct. Marburg virus was first isolated during an outbreak in Europe in 1967, and Ebola virus emerged in 1976 as the causative agent of two simultaneous outbreaks in southern Sudan and northern Zaire. Although the main route of infection is known to be person-to-person transmission by intimate contact, the natural reservoir for filoviruses still remains a mystery.

Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges.

PubMed

Grant-Klein, Rebecca J; Altamura, Louis A; Badger, Catherine V; Bounds, Callie E; Van Deusen, Nicole M; Kwilas, Steven A; Vu, Hong A; Warfield, Kelly L; Hooper, Jay W; Hannaman, Drew; Dupuy, Lesley C; Schmaljohn, Connie S

2015-01-01

Cynomolgus macaques were vaccinated by intramuscular electroporation with DNA plasmids expressing codon-optimized glycoprotein (GP) genes of Ebola virus (EBOV) or Marburg virus (MARV) or a combination of codon-optimized GP DNA vaccines for EBOV, MARV, Sudan virus and Ravn virus. When measured by ELISA, the individual vaccines elicited slightly higher IgG responses to EBOV or MARV than did the combination vaccines. No significant differences in immune responses of macaques given the individual or combination vaccines were measured by pseudovirion neutralization or IFN-γ ELISpot assays. Both the MARV and mixed vaccines were able to protect macaques from lethal MARV challenge (5/6 vs. 6/6). In contrast, a greater proportion of macaques vaccinated with the EBOV vaccine survived lethal EBOV challenge in comparison to those that received the mixed vaccine (5/6 vs. 1/6). EBOV challenge survivors had significantly higher pre-challenge neutralizing antibody titers than those that succumbed.

Ebola virus disease: from epidemiology to prophylaxis.

PubMed

Liu, Wen Bin; Li, Zi Xiong; Du, Yan; Cao, Guang Wen

2015-01-01

The outbreak of Ebola virus disease (EVD) continues to spread through West Africa. Since the first report of EVD in March 2014, the number of cases has increased rapidly, with the fatality rate of >50%. The most prevalent Ebola virus belongs to the species of Zaire ebolavirus, with a fatality rate as high as 90%. Although there were cases introduced into other continents, Africa is the endemic area where fruit bats and apes are suspected to be Ebola virus carriers. The virus might be transmitted from the host animals to humans if humans consume raw or not fully cooked and contaminated meats. However, human-to-human transmission via close contact is the major route of current outbreaks. EVD can occur during any season and affect people of any race and age group. Direct contact with body fluids of EVD patients or living in contaminated environments greatly increases the risk of being infected. Transmission via aerosol less likely, but transmission via virus-containing droplets is possible in humans. Thus, health care providers are facing danger of getting Ebola virus infection. To date, vaccines, drugs and/or therapies to prevent Ebola virus infection or treat EVD are limited. Medical workers should follow the current standard prophylactic procedures. The military can orchestrate efficient care to mass EVD patients. Although it is necessary to speed up the pace of developing effective vaccine and therapeutics for the prevention and treatment of EVD, public health prevention and management should be important issue at present to control the spread of this disease cost-effectively.

Kunjin Virus Replicon-Based Vaccines Expressing Ebola Virus Glycoprotein GP Protect the Guinea Pig Against Lethal Ebola Virus Infection

PubMed Central

Reynard, O.; Mokhonov, V.; Mokhonova, E.; Leung, J.; Page, A.; Mateo, M.; Pyankova, O.; Georges-Courbot, M. C.; Raoul, H.; Khromykh, A. A.

2011-01-01

Pre- or postexposure treatments against the filoviral hemorrhagic fevers are currently not available for human use. We evaluated, in a guinea pig model, the immunogenic potential of Kunjin virus (KUN)–derived replicons as a vaccine candidate against Ebola virus (EBOV). Virus like particles (VLPs) containing KUN replicons expressing EBOV wild-type glycoprotein GP, membrane anchor-truncated GP (GP/Ctr), and mutated GP (D637L) with enhanced shedding capacity were generated and assayed for their protective efficacy. Immunization with KUN VLPs expressing full-length wild-type and D637L-mutated GPs but not membrane anchor–truncated GP induced dose-dependent protection against a challenge of a lethal dose of recombinant guinea pig-adapted EBOV. The surviving animals showed complete clearance of the virus. Our results demonstrate the potential for KUN replicon vectors as vaccine candidates against EBOV infection. PMID:21987742

Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine.

PubMed

Richardson, Jason S; Yao, Michel K; Tran, Kaylie N; Croyle, Maria A; Strong, James E; Feldmann, Heinz; Kobinger, Gary P

2009-01-01

The Ebola virus is transmitted by direct contact with bodily fluids of infected individuals, eliciting death rates as high as 90% among infected humans. Currently, replication defective adenovirus-based Ebola vaccine is being studied in a phase I clinical trial. Another Ebola vaccine, based on an attenuated vesicular stomatitis virus has shown efficacy in post-exposure treatment of nonhuman primates to Ebola infection. In this report, we modified the common recombinant adenovirus serotype 5-based Ebola vaccine expressing the wild-type ZEBOV glycoprotein sequence from a CMV promoter (Ad-CMVZGP). The immune response elicited by this improved expression cassette vector (Ad-CAGoptZGP) and its ability to afford protection against lethal ZEBOV challenge in mice was compared to the standard Ad-CMVZGP vector. Ad-CMVZGP was previously shown to protect mice, guinea pigs and nonhuman primates from an otherwise lethal challenge of Zaire ebolavirus. The antigenic expression cassette of this vector was improved through codon optimization, inclusion of a consensus Kozak sequence and reconfiguration of a CAG promoter (Ad-CAGoptZGP). Expression of GP from Ad-CAGoptZGP was substantially higher than from Ad-CMVZGP. Ad-CAGoptZGP significantly improved T and B cell responses at doses 10 to 100-fold lower than that needed with Ad-CMVZGP. Additionally, Ad-CAGoptZGP afforded full protections in mice against lethal challenge at a dose 100 times lower than the dose required for Ad-CMVZGP. Finally, Ad-CAGoptZGP induced full protection to mice when given 30 minutes post-challenge. We describe an improved adenovirus-based Ebola vaccine capable of affording post-exposure protection against lethal challenge in mice. The molecular modifications of the new improved vaccine also translated in the induction of significantly enhanced immune responses and complete protection at a dose 100 times lower than with the previous generation adenovirus-based Ebola vaccine. Understanding and improving the

Changes associated with Ebola virus adaptation to novel species.

PubMed

Pappalardo, Morena; Reddin, Ian G; Cantoni, Diego; Rossman, Jeremy S; Michaelis, Martin; Wass, Mark N

2017-07-01

Ebola viruses are not pathogenic but can be adapted to replicate and cause disease in rodents. Here, we used a structural bioinformatics approach to analyze the mutations associated with Ebola virus adaptation to rodents to elucidate the determinants of host-specific Ebola virus pathogenicity. We identified 33 different mutations associated with Ebola virus adaptation to rodents in the proteins GP, NP, L, VP24 and VP35. Only VP24, GP and NP were consistently found mutated in rodent-adapted Ebola virus strains. Fewer than five mutations in these genes seem to be required for the adaptation of Ebola viruses to a new species. The role of mutations in GP and NP is not clear. However, three VP24 mutations located in the protein interface with karyopherin α5 may enable VP24 to inhibit karyopherins and subsequently the host interferon response. Three further VP24 mutations change hydrogen bonding or cause conformational changes. Hence, there is evidence that few mutations including crucial mutations in VP24 enable Ebola virus adaptation to new hosts. Since Reston virus, the only non-human pathogenic Ebolavirus species circulates in pigs in Asia, this raises concerns that few mutations may result in novel human pathogenic Ebolaviruses. m.n.wass@kent.ac.uk , m.michaelis@kent.ac.uk or j.s.rossman@kent.ac.uk. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Acceptability and Willingness-to-Pay for a Hypothetical Ebola Virus Vaccine in Nigeria

PubMed Central

Ughasoro, Maduka Donatus; Esangbedo, Dorothy Omono; Tagbo, Beckie Nnenna; Mejeha, Ijeoma Chigozie

2015-01-01

Background Ebola virus disease is a highly virulent and transmissible disease. The largest recorded fatality from Ebola virus disease epidemic is ongoing in a few countries in West Africa, and this poses a health risk to the entire population of the world because arresting the transmission has been challenging. Vaccination is considered a key intervention that is capable of arresting further spread of the disease and preventing future outbreak. However, no vaccine has yet been approved for public use, although various recombinant vaccines are undergoing trials and approval for public use is imminent. Therefore, this study aimed to determine the acceptability of and willingness-to-pay for Ebola virus vaccine by the public. Methods The study was a community-based cross-sectional qualitative and quantitative interventional study conducted in two communities, each in two states in Nigeria. An interviewer-administered questionnaire was used to collect information on respondents’ knowledge of the Ebola virus, the ways to prevent the disease, and their preventive practices, as well as their acceptability of and willingness-to-pay for a hypothetical vaccine against Ebola virus disease. The association between acceptability of the vaccine and other independent variables were evaluated using multivariate regression analysis. Results Ebola virus disease was considered to be a very serious disease by 38.5% of the 582 respondents (224/582), prior to receiving health education on Ebola virus and its vaccine. Eighty percent (80%) accepted to be vaccinated with Ebola vaccine. However, among those that accepted to be vaccinated, most would only accept after observing the outcome on others who have received the vaccine. More than 87.5% was willing to pay for the vaccine, although 55.2% was of the opinion that the vaccine should be provided free of charge. Conclusion The level of acceptability of Ebola virus vaccine among respondents was impressive (though conditional), as well as

Spatiotemporal Fluctuations and Triggers of Ebola Virus Spillover

PubMed Central

Park, Andrew W.; Kramer, Andrew M.; Han, Barbara A.; Alexander, Laura W.; Drake, John M.

2017-01-01

Because the natural reservoir of Ebola virus remains unclear and disease outbreaks in humans have occurred only sporadically over a large region, forecasting when and where Ebola spillovers are most likely to occur constitutes a continuing and urgent public health challenge. We developed a statistical modeling approach that associates 37 human or great ape Ebola spillovers since 1982 with spatiotemporally dynamic covariates including vegetative cover, human population size, and absolute and relative rainfall over 3 decades across sub-Saharan Africa. Our model (area under the curve 0.80 on test data) shows that spillover intensity is highest during transitions between wet and dry seasons; overall, high seasonal intensity occurs over much of tropical Africa; and spillover intensity is greatest at high (>1,000/km2) and very low (<100/km2) human population densities compared with intermediate levels. These results suggest strong seasonality in Ebola spillover from wild reservoirs and indicate particular times and regions for targeted surveillance. PMID:28221131

Spatiotemporal Fluctuations and Triggers of Ebola Virus Spillover.

PubMed

Schmidt, John Paul; Park, Andrew W; Kramer, Andrew M; Han, Barbara A; Alexander, Laura W; Drake, John M

2017-03-01

Because the natural reservoir of Ebola virus remains unclear and disease outbreaks in humans have occurred only sporadically over a large region, forecasting when and where Ebola spillovers are most likely to occur constitutes a continuing and urgent public health challenge. We developed a statistical modeling approach that associates 37 human or great ape Ebola spillovers since 1982 with spatiotemporally dynamic covariates including vegetative cover, human population size, and absolute and relative rainfall over 3 decades across sub-Saharan Africa. Our model (area under the curve 0.80 on test data) shows that spillover intensity is highest during transitions between wet and dry seasons; overall, high seasonal intensity occurs over much of tropical Africa; and spillover intensity is greatest at high (>1,000/km 2 ) and very low (<100/km 2 ) human population densities compared with intermediate levels. These results suggest strong seasonality in Ebola spillover from wild reservoirs and indicate particular times and regions for targeted surveillance.

Ebola virus vaccines: an overview of current approaches

PubMed Central

Marzi, Andrea; Feldmann, Heinz

2016-01-01

Ebola hemorrhagic fever is one of the most fatal viral diseases worldwide affecting humans and nonhuman primates. Although infections only occur frequently in Central Africa, the virus has the potential to spread globally and is classified as a category A pathogen that could be misused as a bioterrorism agent. As of today there is no vaccine or treatment licensed to counteract Ebola virus infections. DNA, subunit and several viral vector approaches, replicating and non-replicating, have been tested as potential vaccine platforms and their protective efficacy has been evaluated in nonhuman primate models for Ebola virus infections, which closely resemble disease progression in humans. Though these vaccine platforms seem to confer protection through different mechanisms, several of them are efficacious against lethal disease in nonhuman primates attesting that vaccination against Ebola virus infections is feasible. PMID:24575870

Ebola virus: A gap in drug design and discovery - experimental and computational perspective.

PubMed

Balmith, Marissa; Faya, Mbuso; Soliman, Mahmoud E S

2017-03-01

The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the Ebola virus. © 2016 John Wiley & Sons A/S.

Reidentification of Ebola Virus E718 and ME as Ebola Virus/H.sapiens-tc/COD/1976/Yambuku-Ecran.

PubMed

Kuhn, Jens H; Lofts, Loreen L; Kugelman, Jeffrey R; Smither, Sophie J; Lever, Mark S; van der Groen, Guido; Johnson, Karl M; Radoshitzky, Sheli R; Bavari, Sina; Jahrling, Peter B; Towner, Jonathan S; Nichol, Stuart T; Palacios, Gustavo

2014-11-20

Ebola virus (EBOV) was discovered in 1976 around Yambuku, Zaire. A lack of nomenclature standards resulted in a variety of designations for each isolate, leading to confusion in the literature and databases. We sequenced the genome of isolate E718/ME/Ecran and unified the various designations under Ebola virus/H.sapiens-tc/COD/1976/Yambuku-Ecran. Copyright © 2014 Kuhn et al.

Human Ebola virus infection results in substantial immune activation.

PubMed

McElroy, Anita K; Akondy, Rama S; Davis, Carl W; Ellebedy, Ali H; Mehta, Aneesh K; Kraft, Colleen S; Lyon, G Marshall; Ribner, Bruce S; Varkey, Jay; Sidney, John; Sette, Alessandro; Campbell, Shelley; Ströher, Ute; Damon, Inger; Nichol, Stuart T; Spiropoulou, Christina F; Ahmed, Rafi

2015-04-14

Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10-50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1-2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients' discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.

Unusual Ebola Virus Chain of Transmission, Conakry, Guinea, 2014–2015

PubMed Central

Keita, Mory; Duraffour, Sophie; Loman, Nicholas J.; Rambaut, Andrew; Diallo, Boubacar; Magassouba, Nfaly; Carroll, Miles W.; Quick, Joshua; Sall, Amadou A.; Glynn, Judith R.; Formenty, Pierre; Faye, Ousmane

2016-01-01

In October 2015, a new case of Ebola virus disease in Guinea was detected. Case investigation, serology, and whole-genome sequencing indicated possible transmission of the virus from an Ebola virus disease survivor to another person and then to the case-patient reported here. This transmission chain over 11 months suggests slow Ebola virus evolution. PMID:27869596

Ebola Virus Shedding and Transmission: Review of Current Evidence.

PubMed

Vetter, Pauline; Fischer, William A; Schibler, Manuel; Jacobs, Michael; Bausch, Daniel G; Kaiser, Laurent

2016-10-15

 The magnitude of the 2013-2016 Ebola virus disease outbreak in West Africa was unprecedented, with >28 500 reported cases and >11 000 deaths. Understanding the key elements of Ebola virus transmission is necessary to implement adequate infection prevention and control measures to protect healthcare workers and halt transmission in the community.  We performed an extensive PubMed literature review encompassing the period from discovery of Ebola virus, in 1976, until 1 June 2016 to evaluate the evidence on modes of Ebola virus shedding and transmission.  Ebola virus has been isolated by cell culture from blood, saliva, urine, aqueous humor, semen, and breast milk from infected or convalescent patients. Ebola virus RNA has been noted in the following body fluids days or months after onset of illness: saliva (22 days), conjunctiva/tears (28 days), stool (29 days), vaginal fluid (33 days), sweat (44 days), urine (64 days), amniotic fluid (38 days), aqueous humor (101 days), cerebrospinal fluid (9 months), breast milk (16 months [preliminary data]), and semen (18 months). Nevertheless, the only documented cases of secondary transmission from recovered patients have been through sexual transmission. We did not find strong evidence supporting respiratory or fomite-associated transmission. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Role of natural killer cells in innate protection against lethal ebola virus infection.

PubMed

Warfield, Kelly L; Perkins, Jeremy G; Swenson, Dana L; Deal, Emily M; Bosio, Catharine M; Aman, M Javad; Yokoyama, Wayne M; Young, Howard A; Bavari, Sina

2004-07-19

Ebola virus is a highly lethal human pathogen and is rapidly driving many wild primate populations toward extinction. Several lines of evidence suggest that innate, nonspecific host factors are potentially critical for survival after Ebola virus infection. Here, we show that nonreplicating Ebola virus-like particles (VLPs), containing the glycoprotein (GP) and matrix protein virus protein (VP)40, administered 1-3 d before Ebola virus infection rapidly induced protective immunity. VLP injection enhanced the numbers of natural killer (NK) cells in lymphoid tissues. In contrast to live Ebola virus, VLP treatment of NK cells enhanced cytokine secretion and cytolytic activity against NK-sensitive targets. Unlike wild-type mice, treatment of NK-deficient or -depleted mice with VLPs had no protective effect against Ebola virus infection and NK cells treated with VLPs protected against Ebola virus infection when adoptively transferred to naive mice. The mechanism of NK cell-mediated protection clearly depended on perforin, but not interferon-gamma secretion. Particles containing only VP40 were sufficient to induce NK cell responses and provide protection from infection in the absence of the viral GP. These findings revealed a decisive role for NK cells during lethal Ebola virus infection. This work should open new doors for better understanding of Ebola virus pathogenesis and direct the development of immunotherapeutics, which target the innate immune system, for treatment of Ebola virus infection.

DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs.

PubMed

Cashman, Kathleen A; Wilkinson, Eric R; Wollen, Suzanne E; Shamblin, Joshua D; Zelko, Justine M; Bearss, Jeremy J; Zeng, Xiankun; Broderick, Kate E; Schmaljohn, Connie S

2017-12-02

We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 µg of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinated guinea pigs succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed-infection environment.

DNA vaccines elicit durable protective immunity against individual or simultaneous infections with Lassa and Ebola viruses in guinea pigs

PubMed Central

Cashman, Kathleen A.; Wilkinson, Eric R.; Wollen, Suzanne E.; Shamblin, Joshua D.; Zelko, Justine M.; Bearss, Jeremy J.; Zeng, Xiankun; Broderick, Kate E.; Schmaljohn, Connie S.

2017-01-01

ABSTRACT We previously developed optimized DNA vaccines against both Lassa fever and Ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. In this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 µg of each DNA vaccine or a mock vaccine at discrete sites by intradermal electroporation. Five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of Lassa virus, Ebola virus, or a combination of both viruses simultaneously. None of the vaccinated guinea pigs, regardless of challenge virus and including the coinfected group, displayed weight loss, fever or other disease signs, and all survived to the study endpoint. All of the mock-vaccinated guinea pigs that were infected with Lassa virus, and all but one of the EBOV-infected mock-vaccinated guinea pigs succumbed. In order to determine if the dual-agent vaccination strategy could protect against both viruses if exposures were temporally separated, we held the surviving vaccinates in BSL-4 for approximately 120 days to perform a cross-challenge experiment in which guinea pigs originally infected with Lassa virus received a lethal dose of Ebola virus and those originally infected with Ebola virus were infected with a lethal dose of Lassa virus. All guinea pigs remained healthy and survived to the study endpoint. This study clearly demonstrates that DNA vaccines against Lassa and Ebola viruses can elicit protective immunity against both individual virus exposures as well as in a mixed-infection environment. PMID:29135337

Effectively Communicating the Uncertainties Surrounding Ebola Virus Transmission.

PubMed

Kilianski, Andy; Evans, Nicholas G

2015-10-01

The current Ebola virus outbreak has highlighted the uncertainties surrounding many aspects of Ebola virus virology, including routes of transmission. The scientific community played a leading role during the outbreak-potentially, the largest of its kind-as many of the questions surrounding ebolaviruses have only been interrogated in the laboratory. Scientists provided an invaluable resource for clinicians, public health officials, policy makers, and the lay public in understanding the progress of Ebola virus disease and the continuing outbreak. Not all of the scientific communication, however, was accurate or effective. There were multiple instances of published articles during the height of the outbreak containing potentially misleading scientific language that spurred media overreaction and potentially jeopardized preparedness and policy decisions at critical points. Here, we use articles declaring the potential for airborne transmission of Ebola virus as a case study in the inaccurate reporting of basic science, and we provide recommendations for improving the communication about unknown aspects of disease during public health crises.

Ebola virus outbreaks in Africa: past and present.

PubMed

Muyembe-Tamfum, J J; Mulangu, S; Masumu, Justin; Kayembe, J M; Kemp, A; Paweska, Janusz T

2012-06-20

Ebola haemorrhagic fever (EHF) is a zoonosis affecting both human and non-human primates (NHP). Outbreaks in Africa occur mainly in the Congo and Nile basins. The first outbreaks of EHF occurred nearly simultaneously in 1976 in the Democratic Republic of the Congo (DRC, former Zaire) and Sudan with very high case fatality rates of 88% and 53%, respectively. The two outbreaks were caused by two distinct species of Ebola virus named Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV). The source of transmission remains unknown. After a long period of silence (1980-1993), EHF outbreaks in Africa caused by the two species erupted with increased frequency and new species were discovered, namely Côte d'Ivoire ebolavirus (CIEBOV) in 1994 in the Ivory Coast and Bundibugyo ebolavirus (BEBOV) in 2007 in Uganda. The re-emergence of EHF outbreaks in Gabon and Republic of the Congo were concomitant with an increase in mortality amongst gorillas and chimpanzees infected with ZEBOV. The human outbreaks were related to multiple, unrelated index cases who had contact with dead gorillas or chimpanzees. However, in areas where NHP were rare or absent, as in Kikwit (DRC) in 1995, Mweka (DRC) in 2007, Gulu (Uganda) in 2000 and Yambio (Sudan) in 2004, the hunting and eating of fruit bats may have resulted in the primary transmission of Ebola virus to humans. Human-to-human transmission is associated with direct contact with body fluids or tissues from an infected subject or contaminated objects. Despite several, often heroic field studies, the epidemiology and ecology of Ebola virus, including identification of its natural reservoir hosts, remains a formidable challenge for public health and scientific communities.

Structure of an Antibody in Complex with Its Mucin Domain Linear Epitope That Is Protective against Ebola Virus

PubMed Central

Olal, Daniel; Kuehne, Ana I.; Bale, Shridhar; Halfmann, Peter; Hashiguchi, Takao; Fusco, Marnie L.; Lee, Jeffrey E.; King, Liam B.; Kawaoka, Yoshihiro; Dye, John M.

2012-01-01

Antibody 14G7 is protective against lethal Ebola virus challenge and recognizes a distinct linear epitope in the prominent mucin-like domain of the Ebola virus glycoprotein GP. The structure of 14G7 in complex with its linear peptide epitope has now been determined to 2.8 Å. The structure shows that this GP sequence forms a tandem β-hairpin structure that binds deeply into a cleft in the antibody-combining site. A key threonine at the apex of one turn is critical for antibody interaction and is conserved among all Ebola viruses. This work provides further insight into the mechanism of protection by antibodies that target the protruding, highly accessible mucin-like domain of Ebola virus and the structural framework for understanding and characterizing candidate immunotherapeutics. PMID:22171276

Structure of an antibody in complex with its mucin domain linear epitope that is protective against Ebola virus.

PubMed

Olal, Daniel; Kuehne, Ana I; Bale, Shridhar; Halfmann, Peter; Hashiguchi, Takao; Fusco, Marnie L; Lee, Jeffrey E; King, Liam B; Kawaoka, Yoshihiro; Dye, John M; Saphire, Erica Ollmann

2012-03-01

Antibody 14G7 is protective against lethal Ebola virus challenge and recognizes a distinct linear epitope in the prominent mucin-like domain of the Ebola virus glycoprotein GP. The structure of 14G7 in complex with its linear peptide epitope has now been determined to 2.8 Å. The structure shows that this GP sequence forms a tandem β-hairpin structure that binds deeply into a cleft in the antibody-combining site. A key threonine at the apex of one turn is critical for antibody interaction and is conserved among all Ebola viruses. This work provides further insight into the mechanism of protection by antibodies that target the protruding, highly accessible mucin-like domain of Ebola virus and the structural framework for understanding and characterizing candidate immunotherapeutics.

Immunopathology of highly virulent pathogens: insights from Ebola virus.

PubMed

Zampieri, Carisa A; Sullivan, Nancy J; Nabel, Gary J

2007-11-01

Ebola virus is a highly virulent pathogen capable of inducing a frequently lethal hemorrhagic fever syndrome. Accumulating evidence indicates that the virus actively subverts both innate and adaptive immune responses and triggers harmful inflammatory responses as it inflicts direct tissue damage. The host immune system is ultimately overwhelmed by a combination of inflammatory factors and virus-induced cell damage, particularly in the liver and vasculature, often leading to death from septic shock. We summarize the mechanisms of immune dysregulation and virus-mediated cell damage in Ebola virus-infected patients. Future approaches to prevention and treatment of infection will be guided by answers to unresolved questions about interspecies transmission, molecular mechanisms of pathogenesis, and protective adaptive and innate immune responses to Ebola virus.

A multiagent filovirus DNA vaccine delivered by intramuscular electroporation completely protects mice from ebola and Marburg virus challenge.

PubMed

Grant-Klein, Rebecca J; Van Deusen, Nicole M; Badger, Catherine V; Hannaman, Drew; Dupuy, Lesley C; Schmaljohn, Connie S

2012-11-01

We evaluated the immunogenicity and protective efficacy of DNA vaccines expressing the codon-optimized envelope glycoprotein genes of Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus (Musoke and Ravn). Intramuscular or intradermal delivery of the vaccines in BALB/c mice was performed using the TriGrid™ electroporation device. Mice that received DNA vaccines against the individual viruses developed robust glycoprotein-specific antibody titers as determined by ELISA and survived lethal viral challenge with no display of clinical signs of infection. Survival curve analysis revealed there was a statistically significant increase in survival compared to the control groups for both the Ebola and Ravn virus challenges. These data suggest that further analysis of the immune responses generated in the mice and additional protection studies in nonhuman primates are warranted.

Suramin is a potent inhibitor of Chikungunya and Ebola virus cell entry.

PubMed

Henß, Lisa; Beck, Simon; Weidner, Tatjana; Biedenkopf, Nadine; Sliva, Katja; Weber, Christopher; Becker, Stephan; Schnierle, Barbara S

2016-08-31

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes high fever, rash, and recurrent arthritis in humans. It has efficiently adapted to Aedes albopictus, which also inhabits temperate regions and currently causes large outbreaks in the Caribbean and Latin America. Ebola virus (EBOV) is a member of the filovirus family. It causes the Ebola virus disease (EDV), formerly known as Ebola hemorrhagic fever in humans and has a mortality rate of up to 70 %. The last outbreak in Western Africa was the largest in history and has caused approximately 25,000 cases and 10,000 deaths. For both viral infections no specific treatment or licensed vaccine is currently available. The bis-hexasulfonated naphthylurea, suramin, is used as a treatment for trypanosome-caused African river blindness. As a competitive inhibitor of heparin, suramin has been described to have anti-viral activity. We tested the activity of suramin during CHIKV or Ebola virus infection, using CHIKV and Ebola envelope glycoprotein pseudotyped lentiviral vectors and wild-type CHIKV and Ebola virus. Suramin efficiently inhibited CHIKV and Ebola envelope-mediated gene transfer while vesicular stomatitis virus G protein pseudotyped vectors were only marginally affected. In addition, suramin was able to inhibit wild-type CHIKV and Ebola virus replication in vitro. Inhibition occurred at early time points during CHIKV infection. Suramin, also known as Germanin or Bayer-205, is a market-authorized drug, however shows significant side effects, which probably prevents its use as a CHIKV drug, but due to the high lethality of Ebola virus infections, suramin might be valuable against Ebola infections.

Elimination of Ebola Virus Transmission in Liberia - September 3, 2015.

PubMed

Bawo, Luke; Fallah, Mosoka; Kateh, Francis; Nagbe, Thomas; Clement, Peter; Gasasira, Alex; Mahmoud, Nuha; Musa, Emmanuel; Lo, Terrence Q; Pillai, Satish K; Seeman, Sara; Sunshine, Brittany J; Weidle, Paul J; Nyensweh, Tolbert

2015-09-11

Following 42 days since the last Ebola virus disease (Ebola) patient was discharged from a Liberian Ebola treatment unit (ETU), September 3, 2015, marks the second time in a 4-month period that the World Health Organization (WHO) has declared Liberia free of Ebola virus transmission (1). The first confirmed Ebola cases in West Africa were identified in southeastern Guinea on March 23, 2014, and within 1 week, cases were identified and confirmed in Liberia (1). Since then, Liberia has reported 5,036 confirmed and probable Ebola cases and 4,808 Ebola-related deaths. The epidemic in Liberia peaked in late summer and early fall of 2014, when more than 200 confirmed and probable cases were reported each week .

Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea.

PubMed

Savini, Hélène; Janvier, Frédéric; Karkowski, Ludovic; Billhot, Magali; Aletti, Marc; Bordes, Julien; Koulibaly, Fassou; Cordier, Pierre-Yves; Cournac, Jean-Marie; Maugey, Nancy; Gagnon, Nicolas; Cotte, Jean; Cambon, Audrey; Mac Nab, Christine; Moroge, Sophie; Rousseau, Claire; Foissaud, Vincent; De Greslan, Thierry; Granier, Hervé; Cellarier, Gilles; Valade, Eric; Kraemer, Philippe; Alla, Philippe; Mérens, Audrey; Sagui, Emmanuel; Carmoi, Thierry; Rapp, Christophe

2017-08-01

We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014-2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred.

Development of risk reduction behavioral counseling for Ebola virus disease survivors enrolled in the Sierra Leone Ebola Virus Persistence Study, 2015-2016.

PubMed

Abad, Neetu; Malik, Tasneem; Ariyarajah, Archchun; Ongpin, Patricia; Hogben, Matthew; McDonald, Suzanna L R; Marrinan, Jaclyn; Massaquoi, Thomas; Thorson, Anna; Ervin, Elizabeth; Bernstein, Kyle; Ross, Christine; Liu, William J; Kroeger, Karen; Durski, Kara N; Broutet, Nathalie; Knust, Barbara; Deen, Gibrilla F

2017-09-01

During the 2014-2016 West Africa Ebola Virus Disease (EVD) epidemic, the public health community had concerns that sexual transmission of the Ebola virus (EBOV) from EVD survivors was a risk, due to EBOV persistence in body fluids of EVD survivors, particularly semen. The Sierra Leone Ebola Virus Persistence Study was initiated to investigate this risk by assessing EBOV persistence in numerous body fluids of EVD survivors and providing risk reduction counseling based on test results for semen, vaginal fluid, menstrual blood, urine, rectal fluid, sweat, tears, saliva, and breast milk. This publication describes implementation of the counseling protocol and the key lessons learned. The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol was developed from a framework used to prevent transmission of HIV and other sexually transmitted infections. The framework helped to identify barriers to risk reduction and facilitated the development of a personalized risk-reduction plan, particularly around condom use and abstinence. Pre-test and post-test counseling sessions included risk reduction guidance, and post-test counseling was based on the participants' individual test results. The behavioral counseling protocol enabled study staff to translate the study's body fluid test results into individualized information for study participants. The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol provided guidance to mitigate the risk of EBOV transmission from EVD survivors. It has since been shared with and adapted by other EVD survivor body fluid testing programs and studies in Ebola-affected countries.

Investigating Ebola virus pathogenicity using molecular dynamics.

PubMed

Pappalardo, Morena; Collu, Francesca; Macpherson, James; Michaelis, Martin; Fraternali, Franca; Wass, Mark N

2017-08-11

Ebolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks. Four Ebolavirus species cause severe disease associated with high mortality in humans. Reston viruses are the only Ebolaviruses that do not cause disease in humans. Conserved amino acid changes in the Reston virus protein VP24 compared to VP24 of other Ebolaviruses have been suggested to alter VP24 binding to host cell karyopherins resulting in impaired inhibition of interferon signalling, which may explain the difference in human pathogenicity. Here we used protein structural analysis and molecular dynamics to further elucidate the interaction between VP24 and KPNA5. As a control experiment, we compared the interaction of wild-type and R137A-mutant (known to affect KPNA5 binding) Ebola virus VP24 with KPNA5. Results confirmed that the R137A mutation weakens direct VP24-KPNA5 binding and enables water molecules to penetrate at the interface. Similarly, Reston virus VP24 displayed a weaker interaction with KPNA5 than Ebola virus VP24, which is likely to reduce the ability of Reston virus VP24 to prevent host cell interferon signalling. Our results provide novel molecular detail on the interaction of Reston virus VP24 and Ebola virus VP24 with human KPNA5. The results indicate a weaker interaction of Reston virus VP24 with KPNA5 than Ebola virus VP24, which is probably associated with a decreased ability to interfere with the host cell interferon response. Hence, our study provides further evidence that VP24 is a key player in determining Ebolavirus pathogenicity.

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks.

PubMed

Haque, Azizul; Hober, Didier; Blondiaux, Joel

2015-10-01

Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

PubMed Central

Hober, Didier; Blondiaux, Joel

2015-01-01

Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients. PMID:26248374

Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea

PubMed Central

Janvier, Frédéric; Karkowski, Ludovic; Billhot, Magali; Aletti, Marc; Bordes, Julien; Koulibaly, Fassou; Cordier, Pierre-Yves; Cournac, Jean-Marie; Maugey, Nancy; Gagnon, Nicolas; Cotte, Jean; Cambon, Audrey; Mac Nab, Christine; Moroge, Sophie; Rousseau, Claire; Foissaud, Vincent; De Greslan, Thierry; Granier, Hervé; Cellarier, Gilles; Valade, Eric; Kraemer, Philippe; Alla, Philippe; Mérens, Audrey; Sagui, Emmanuel; Carmoi, Thierry; Rapp, Christophe

2017-01-01

We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014−2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred. PMID:28726614

Ebola virus disease: What clinicians in the United States need to know

PubMed Central

Fischer, William A.; Uyeki, Timothy M.; Tauxe, Robert V.

2015-01-01

In March 2014 the World Health Organization was notified of an outbreak of Ebola virus disease (EVD) in the forest region of Guinea. Over the subsequent 8 months, this outbreak has become the most devastating Ebola epidemic in history with 21,296 infections and 8,429 deaths. The recent introduction of Ebola into noncontiguous countries including the United States from infected travelers highlights the importance of preparedness of all healthcare providers. Early identification and rapid isolation of patients suspected of being infected with Ebola virus is critical to limiting the spread of this virus. Additionally, enhanced understanding of Ebola case definitions, clinical presentation, treatment and infection control strategies will improve the ability of healthcare providers to safe care for patients with Ebola virus disease. PMID:26116335

The Drug Targets and Antiviral Molecules for Treatment of Ebola Virus Infection.

PubMed

Wu, Wenjiao; Liu, Shuwen

2017-01-01

Ebola virus (EBOV) is a highly pathogenic virus causing severe hemorrhagic fever with a high case fatality rate of 50% - 90% in humans. Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. As with the increase of outbreaks, a significant effort has been made to develop promising countermeasures for the prevention and treatment of Ebola virus infection. In this review, development of therapeutics and potential inhibitors for Ebola virus infection will be discussed.

Development of risk reduction behavioral counseling for Ebola virus disease survivors enrolled in the Sierra Leone Ebola Virus Persistence Study, 2015-2016

PubMed Central

Malik, Tasneem; Ariyarajah, Archchun; Ongpin, Patricia; Hogben, Matthew; McDonald, Suzanna L. R.; Marrinan, Jaclyn; Massaquoi, Thomas; Thorson, Anna; Ervin, Elizabeth; Bernstein, Kyle; Ross, Christine; Liu, William J.; Kroeger, Karen; Durski, Kara N.; Broutet, Nathalie; Knust, Barbara; Deen, Gibrilla F.

2017-01-01

Background During the 2014–2016 West Africa Ebola Virus Disease (EVD) epidemic, the public health community had concerns that sexual transmission of the Ebola virus (EBOV) from EVD survivors was a risk, due to EBOV persistence in body fluids of EVD survivors, particularly semen. The Sierra Leone Ebola Virus Persistence Study was initiated to investigate this risk by assessing EBOV persistence in numerous body fluids of EVD survivors and providing risk reduction counseling based on test results for semen, vaginal fluid, menstrual blood, urine, rectal fluid, sweat, tears, saliva, and breast milk. This publication describes implementation of the counseling protocol and the key lessons learned. Methodology/Principal findings The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol was developed from a framework used to prevent transmission of HIV and other sexually transmitted infections. The framework helped to identify barriers to risk reduction and facilitated the development of a personalized risk-reduction plan, particularly around condom use and abstinence. Pre-test and post-test counseling sessions included risk reduction guidance, and post-test counseling was based on the participants’ individual test results. The behavioral counseling protocol enabled study staff to translate the study’s body fluid test results into individualized information for study participants. Conclusions/Significance The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol provided guidance to mitigate the risk of EBOV transmission from EVD survivors. It has since been shared with and adapted by other EVD survivor body fluid testing programs and studies in Ebola-affected countries. PMID:28892490

Ebola Virus Disease (The Killer Virus): Another Threat to Humans and Bioterrorism: Brief Review and Recent Updates

PubMed Central

Sharma, Sarang; Dutta, Shubha Ranjan; Dudeja, Pooja; Sharma, Vivek

2015-01-01

Ebola virus disease (EVD) described as “one of the world’s most virulent diseases” by WHO was popularly known as Ebola haemorrhagic fever in the past. It is usually considered a severe and deadly illness when humans are concerned. EVD outbreaks have shown to have a very high fatality rate ranging from 50 - 90% with a reported occurrence primarily seen near the tropical rainforests of remote villages in Central and West Africa. The virus is transmitted to people from wild animals and within the human community through human-to-human contact. Natural host for Ebola virus is not yet conclusively identified but the most probable host appears to be the fruit bats of the Pteropodidae family. Five subspecies of Ebola virus are recognized till date, with Zaire Ebola virus being the most aggressive of all varieties and recording up to 90% mortality. All Ebola forms are highly contagious and hence have been classed as Category A Priority Pathogens by WHO. Severely ill patients warrant intensive support therapy. Medical workers working in affected areas need to undertake extensive measures to prevent contracting the disease. Till date, no particular anti-viral therapy has demonstrated effectiveness in Ebola virus infection. Also, no vaccine for use in humans is yet approved by the regulatory bodies. If Ebola was actually misused as a biological weapon, it could be a serious threat. Idea behind this article is to briefly review the history and present recent updates on Ebola virus, its pathogenesis and possible hopes for treatment. PMID:26266139

Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

PubMed Central

Messaoudi, Ilhem; Amarasinghe, Gaya K.; Basler, Christopher F.

2016-01-01

Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people. The Ebola virus epidemic in West Africa, which was first recognized in early 2014, highlights the threat posed by these deadly viruses. Filovirus disease is characterized by uncontrolled virus replication and the activation of damaging host pathways. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon (IFN) response, which allows high levels of replication. Here we review the mechanisms deployed by filoviruses to block host innate immunity and discuss aspects of virus replication that promote disease. PMID:26439085

Study of the pathogenesis of Ebola fever in laboratory animals with different sensitivity to this virus.

PubMed

Chepurnov, A A; Dadaeva, A A; Kolesnikov, S I

2001-12-01

Pathophysiological parameters were compared in animals with different sensitivity to Ebola virus infected with this virus. Analysis of the results showed the differences in immune reactions underlying the difference between Ebola-sensitive and Ebola-resistant animals. No neutrophil activation in response to Ebola virus injection was noted in Ebola-sensitive animal. Phagocytic activity of neutrophils in these animals inversely correlated with animal sensitivity to Ebola virus. Animal susceptibility to Ebola virus directly correlated with the decrease in the number of circulating T and B cells. We conclude that the immune system plays the key role in animal susceptibility and resistance to Ebola virus.

What is Ebola?

PubMed

Stein, R A

2015-01-01

On 23 March 2014, the World Health Organization first announced a new Ebola virus outbreak that started in December 2013 in the eastern part of the Republic of Guinea. Human infections shortly emerged in Liberia, Sierra Leone, and Nigeria. On 30 September 2014, the Centers for Disease Control and Prevention confirmed through laboratory testing the first Ebola virus infection diagnosed in the USA, in a patient who travelled from West Africa to Texas. On 6 October 2014, the first human infection occurring outside of Africa was reported, in a Spanish nurse who treated two priests, both of whom died, and on 23 October 2014, the first human infection was reported in New York City. To date, the 2014 Ebola virus outbreak is the longest, largest, and most persistent one since 1976, when the virus was first identified in humans, and the number of human cases exceeded, as of mid-September 2014, the cumulative number of infections from all the previous outbreaks. The early clinical presentation overlaps with other infectious diseases, opening differential diagnosis difficulties. Understanding the transmission routes and identifying the natural reservoir of the virus are additional challenges in studying Ebola hemorrhagic fever outbreaks. Ebola virus is as much a public health challenge for developing countries as it is for the developed world, and previous outbreaks underscored that the relative contribution of the risk factors may differ among outbreaks. The implementation of effective preparedness plans is contingent on integrating teachings from previous Ebola virus outbreaks with those from the current outbreak and with lessons provided by other infectious diseases, along with developing a multifaceted inter-disciplinary and cross-disciplinary framework that should be established and shaped by biomedical as well as sociopolitical sciences. © 2014 John Wiley & Sons Ltd.

Health workers perceptions and attitude about Ghana's preparedness towards preventing, containing, and managing Ebola Virus Disease.

PubMed

Adongo, Philip Baba; Tabong, Philip Teg-Nefaah; Asampong, Emmanuel; Ansong, Joana; Robalo, Magda; Adanu, Richard M

2017-04-12

Ebola virus is highly infectious and the disease can be very fatal. The World Health Organization has declared the 2014-2015 Ebola Virus Disease outbreak a Public Health Emergency of International Concern. In response to this, preparations were made in various health facilities and entry points across Ghana. This study explored health workers perceptions, and attitude about Ghana's preparedness towards preventing and containing Ebola Virus Disease. We conducted a qualitative study in five (5) of the ten (10) regions in Ghana. Five focus group discussions (N = 44) were conducted among nurses; one in each region. In addition, ten (10) health workers (2 in each region) who are members of regional Ebola Virus Disease task force were recruited and interviewed. In the Greater Accra, Volta and Western regions that have ports, six (6) port health officials: two in each of these regions were also interviewed. The interviews were recorded digitally and transcribed verbatim. Thematic content analysis was used to analyze the transcripts with the aid of NVivo 10 software. The results of this study showed that Ghanaian health workers perceived the screening at various ports as important and ongoing but felt that the screenings at in-land ports were being undermined by the use of unapproved routes. Training of health workers was also being carried out in all the regions, however, there was a general perception among 33 out of 44 nurses that majority of health workers have not received training on Ebola Virus Disease prevention and management. Logistical challenges were also reported as some health facilities did not have adequate Personal Protective Equipment. In facilities where equipment was available, they were stored in places which are not easily accessible to health workers at all times of the day. Human resource preparation was also perceived to be a challenge as health workers (38/44 of nurses) generally expressed fear and unwillingness to work in Ebola treatment

Disinfection of Ebola Virus in Sterilized Municipal Wastewater

PubMed Central

Fischer, Robert J.; Casson, Leonard W.; de Carvalho, Nathalia Aquino; Haas, Charles N.; Munster, Vincent J.

2017-01-01

Concerns have been raised regarding handling of Ebola virus contaminated wastewater, as well as the adequacy of proposed disinfection approaches. In the current study, we investigate the inactivation of Ebola virus in sterilized domestic wastewater utilizing sodium hypochlorite addition and pH adjustment. No viral inactivation was observed in the one-hour tests without sodium hypochlorite addition or pH adjustment. No virus was recovered after 20 seconds (i.e. 4.2 log10 unit inactivation to detection limit) following the addition of 5 and 10 mg L-1 sodium hypochlorite, which resulted in immediate free chlorine residuals of 0.52 and 1.11 mg L-1, respectively. The addition of 1 mg L-1 sodium hypochlorite resulted in an immediate free chlorine residual of 0.16 mg L-1, which inactivated 3.5 log10 units of Ebola virus in 20 seconds. Further inactivation was not evident due to the rapid consumption of the chlorine residual. Elevating the pH to 11.2 was found to significantly increase viral decay over ambient conditions. These results indicate the high susceptibility of the enveloped Ebola virus to disinfection in the presence of free chlorine in municipal wastewater; however, we caution that extension to more complex matrices (e.g. bodily fluids) will require additional verification. PMID:28146555

Disinfection of Ebola Virus in Sterilized Municipal Wastewater.

PubMed

Bibby, Kyle; Fischer, Robert J; Casson, Leonard W; de Carvalho, Nathalia Aquino; Haas, Charles N; Munster, Vincent J

2017-02-01

Concerns have been raised regarding handling of Ebola virus contaminated wastewater, as well as the adequacy of proposed disinfection approaches. In the current study, we investigate the inactivation of Ebola virus in sterilized domestic wastewater utilizing sodium hypochlorite addition and pH adjustment. No viral inactivation was observed in the one-hour tests without sodium hypochlorite addition or pH adjustment. No virus was recovered after 20 seconds (i.e. 4.2 log10 unit inactivation to detection limit) following the addition of 5 and 10 mg L-1 sodium hypochlorite, which resulted in immediate free chlorine residuals of 0.52 and 1.11 mg L-1, respectively. The addition of 1 mg L-1 sodium hypochlorite resulted in an immediate free chlorine residual of 0.16 mg L-1, which inactivated 3.5 log10 units of Ebola virus in 20 seconds. Further inactivation was not evident due to the rapid consumption of the chlorine residual. Elevating the pH to 11.2 was found to significantly increase viral decay over ambient conditions. These results indicate the high susceptibility of the enveloped Ebola virus to disinfection in the presence of free chlorine in municipal wastewater; however, we caution that extension to more complex matrices (e.g. bodily fluids) will require additional verification.

Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease.

PubMed

Chancellor, John R; Padmanabhan, Sriranjani P; Greenough, Thomas C; Sacra, Richard; Ellison, Richard T; Madoff, Lawrence C; Droms, Rebecca J; Hinkle, David M; Asdourian, George K; Finberg, Robert W; Stroher, Ute; Uyeki, Timothy M; Cerón, Olga M

2016-02-01

We report a case of probable Zaire Ebola virus-related ophthalmologic complications in a physician from the United States who contracted Ebola virus disease in Liberia. Uveitis, immune activation, and nonspecific increase in antibody titers developed during convalescence. This case highlights immune phenomena that could complicate management of Ebola virus disease-related uveitis during convalescence.

The Ebola contagion and forecasting virus: evidence from four African countries.

PubMed

Nadhem, Selmi; Nejib, Hachicha D

2015-12-01

This paper is focused on examining the number of deaths' increases participation in the propagating the Ebola virus during the period ranging from March to October 2014. An application of the MGARCH-DCC model regressions on four countries has led to discover that the finding that human contact play a significant role in transmitting the Ebola virus. Our findings also reveal that Guinea has already suffered from a spread-like virus originating from Sierra Lione and Liberia. Noteworthy also, other countries are now liable to such a risk; for instance, Nigeria is a country vulnerable to the propagation of this virus. Consequently, we undertake to conduct our forecasts for EGARCH model estimates implements; which has estimated a decrease in the Ebola virus incurred number of deadly Ebola virus over the two months following the November and December.

THE STRENGTHS, WEAKNESSES, OPPORTUNITIES, AND THREATS (SWOTs) ANALYSES OF THE EBOLA VIRUS - PAPER RETRACTED.

PubMed

Babalola, Michael Oluyemi

2016-01-01

Owing to the extreme virulence and case fatality rate of ebola virus disease (EVD), there had been so much furore, panic and public health emergency about the possible pandemic from the recent West African outbreak of the disease, with attendant handful research, both in the past and most recently. The magnitude of the epidemic of ebola virus disease has prompted global interest and urgency in the discovery of measures to mitigate the impact of the disease. Researchers in the academia and the industry were pressured to only focus on the development of effective and safe ebola virus vaccines, without consideration of the other aspects to this virus, which may influence the success or otherwise of a potential vaccine. The objective of this review was to adopt the SWOT concept to elucidate the biological Strengths, Weaknesses, Opportunities, and Threats to Ebola virus as a pathogen, with a view to understanding and devising holistic strategies at combating and overcoming the scourge of EVD. This systematic review and narrative synthesis utilized Medline, PubMed, Google and other databases to select about 150 publications on ebola and ebola virus disease using text word searches to generate the specific terms. Relevant publications were reviewed and compared, findings were synthesized using a narrative method and summarized qualitatively. Some of the identified strengths of ebola virus include: Ebola virus is an RNA virus with inherent capability to mutate, reassort and recombine to generate mutant or reassortant virulent strains; Ebola virus has a broad cellular tropism; Natural Reservoir of ebola virus is unconfirmed but fruit bats, arthropods, and plants are hypothesized; Ebola virus primarily targets and selectively destroys the immune system; Ebola viruses possess accessory proteins that inhibits the host' immune responses; Secreted glycoprotein (sGP), a truncated soluble protein that triggers immune activation and increased vascular permeability is uniquely

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model.

PubMed

Cooper, Timothy K; Huzella, Louis; Johnson, Joshua C; Rojas, Oscar; Yellayi, Sri; Sun, Mei G; Bavari, Sina; Bonilla, Amanda; Hart, Randy; Jahrling, Peter B; Kuhn, Jens H; Zeng, Xiankun

2018-01-19

Survivors of Ebola virus infection may become subclinically infected, but whether animal models recapitulate this complication is unclear. Using histology in combination with immunohistochemistry and in situ hybridization in a retrospective review of a guinea pig confirmation-of-virulence study, we demonstrate for the first time Ebola virus infection in hepatic oval cells, the endocardium and stroma of the atrioventricular valves and chordae tendinae, satellite cells of peripheral ganglia, neurofibroblasts and Schwann cells of peripheral nerves and ganglia, smooth muscle cells of the uterine myometrium and vaginal wall, acini of the parotid salivary glands, thyroid follicular cells, adrenal medullary cells, pancreatic islet cells, endometrial glandular and surface epithelium, and the epithelium of the vagina, penis and, prepuce. These findings indicate that standard animal models for Ebola virus disease are not as well-described as previously thought and may serve as a stepping stone for future identification of potential sites of virus persistence.

Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors.

PubMed

Anantpadma, Manu; Kouznetsova, Jennifer; Wang, Hang; Huang, Ruili; Kolokoltsov, Andrey; Guha, Rajarshi; Lindstrom, Aaron R; Shtanko, Olena; Simeonov, Anton; Maloney, David J; Maury, Wendy; LaCount, Douglas J; Jadhav, Ajit; Davey, Robert A

2016-08-01

Filoviruses are highly infectious, and no FDA-approved drug therapy for filovirus infection is available. Most work to find a treatment has involved only a few strains of Ebola virus and testing of relatively small drug libraries or compounds that have shown efficacy against other virus types. Here we report the findings of a high-throughput screening of 319,855 small molecules from the Molecular Libraries Small Molecule Repository library for their activities against Marburg virus and Ebola virus. Nine of the most potent, novel compounds that blocked infection by both viruses were analyzed in detail for their mechanisms of action. The compounds inhibited known key steps in the Ebola virus infection mechanism by blocking either cell surface attachment, macropinocytosis-mediated uptake, or endosomal trafficking. To date, very few specific inhibitors of macropinocytosis have been reported. The 2 novel macropinocytosis inhibitors are more potent inhibitors of Ebola virus infection and less toxic than ethylisopropylamiloride, one commonly accepted macropinocytosis inhibitor. Each compound blocked infection of primary human macrophages, indicating their potential to be developed as new antifiloviral therapies. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A Single Dose of Modified Vaccinia Ankara expressing Ebola Virus Like Particles Protects Nonhuman Primates from Lethal Ebola Virus Challenge.

PubMed

Domi, Arban; Feldmann, Friederike; Basu, Rahul; McCurley, Nathanael; Shifflett, Kyle; Emanuel, Jackson; Hellerstein, Michael S; Guirakhoo, Farshad; Orlandi, Chiara; Flinko, Robin; Lewis, George K; Hanley, Patrick W; Feldmann, Heinz; Robinson, Harriet L; Marzi, Andrea

2018-01-16

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013-2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.

Ebola Virus Disease Candidate Vaccines Under Evaluation in Clinical Trials

PubMed Central

Martins, Karen A.; Jahrling, Peter B.; Bavari, Sina; Kuhn, Jens H.

2016-01-01

Summary Filoviruses are the etiological agents of two human illnesses: Ebola virus disease and Marburg virus disease. Until 2013, medical countermeasure development against these afflictions was limited to only a few research institutes worldwide as both infections were considered exotic due to very low case numbers. Together with the high case-fatality rate of both diseases, evaluation of any candidate countermeasure in properly controlled clinical trials seemed impossible. However, in 2013, Ebola virus was identified as the etiological agent of a large disease outbreak in Western Africa including almost 30,000 infections and more than 11,000 deaths, including case exportations to Europe and North America. These large case numbers resulted in medical countermeasure development against Ebola virus disease becoming a global public-health priority. This review summarizes the status quo of candidate vaccines against Ebola virus disease, with a focus on those that are currently under evaluation in clinical trials. PMID:27160784

Ebola virus: immune mechanisms of protection and vaccine development.

PubMed

Nyamathi, Adeline M; Fahey, John L; Sands, Heather; Casillas, Adrian M

2003-04-01

Vaccination is one of our most powerful antiviral strategies. Despite the emergence of deadly viruses such as Ebola virus, vaccination efforts have focused mainly on childhood communicable diseases. Although Ebola virus was once believed to be limited to isolated outbreaks in distant lands, forces of globalization potentiate outbreaks anywhere in the world through incidental transmission. Moreover, since this virus has already been transformed into weapon-grade material, the potential exists for it to be used as a biological weapon with catastrophic consequences for any population vulnerable to attack. Ebola hemorrhagic fever (EHF) is a syndrome that can rapidly lead to death within days of symptom onset. The disease directly affects the immune system and vascular bed, with correspondingly high mortality rates. Patients with severe disease produce dangerously high levels of inflammatory cytokines, which destroy normal tissue and microcirculation, leading to profound capillary leakage, renal failure, and disseminated intravascular coagulation. Vaccine development has been fraught with obstacles, primarily of a biosafety nature. Case reports of acutely ill patients with EHF showing improvement with the transfusion of convalescent plasma are at odds with animal studies demonstrating further viral replication with the same treatment. Using mRNA extracted from bone marrow of Ebola survivors, human monoclonal antibodies against Ebola virus surface protein have been experimentally produced and now raise the hope for the development of a safe vaccine.

The VP35 protein of Ebola virus impairs dendritic cell maturation induced by virus and lipopolysaccharide.

PubMed

Jin, Huali; Yan, Zhipeng; Prabhakar, Bellur S; Feng, Zongdi; Ma, Yijie; Verpooten, Dustin; Ganesh, Balaji; He, Bin

2010-02-01

Ebola virus causes rapidly progressive haemorrhagic fever, which is associated with severe immuosuppression. In infected dendritic cells (DCs), Ebola virus replicates efficiently and inhibits DC maturation without inducing cytokine expression, leading to impaired T-cell proliferation. However, the underlying mechanism remains unclear. In this study, we report that Ebola virus VP35 impairs the maturation of mouse DCs. When expressed in mouse immature DCs, Ebola virus VP35 prevents virus-stimulated expression of CD40, CD80, CD86 and major histocompatibility complex class II. Further, it suppresses the induction of cytokines such as interleukin (IL)-6, IL-12, tumour necrosis factor alpha and alpha/beta interferon (IFN-alpha/beta). Notably, Ebola VP35 attenuates the ability of DCs to stimulate the activation of CD4(+) T cells. Addition of type I IFN to mouse DCs only partially reverses the inhibitory effects of VP35. Moreover, VP35 perturbs mouse DC functions induced by lipopolysaccharide, an agonist of Toll-like receptor 4. Deletion of the amino terminus abolishes its activity, whereas a mutation in the RNA binding motif has no effect. Our work highlights a critical role of VP35 in viral interference in DC function with resultant deficiency in T-cell function, which may contribute to the profound virulence of Ebola virus infection.

Statistical considerations for a trial of Ebola virus disease therapeutics.

PubMed

Proschan, Michael A; Dodd, Lori E; Price, Dionne

2016-02-01

The 2014 West African outbreak of Ebola virus ravaged Liberia, Sierra Leone, and Guinea, causing hemorrhagic fever and death. The need to identify effective therapeutics was acute. The usual drug development paradigm of phase I, followed by phase II, and then phase III trials would take too long. These and other factors led to the design of a clinical trial of Ebola virus disease therapeutics that differs from more conventional clinical trial designs. This article describes the Ebola virus disease medical countermeasures trial design and the thinking behind it. © The Author(s) 2016.

Ebola crisis of 2014: are current strategies enough to meet the long-run challenges ahead?

PubMed

Gimm, Gilbert; Nichols, Len M

2015-05-01

The outbreak of the Ebola virus disease (EVD) in 2014 mobilized international efforts to contain a global health crisis. The emergence of the deadly virus in the United States and Europe among health care workers intensified fears of a worldwide epidemic. Market incentives for pharmaceutical firms to allocate their research and development resources toward Ebola treatments were weak because the limited number of EVD cases were previously confined to rural areas of West Africa. We discuss 3 policy recommendations to address the long-term challenges of EVD in an interconnected world.

Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus.

PubMed

Messaoudi, Ilhem; Amarasinghe, Gaya K; Basler, Christopher F

2015-11-01

Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirus pathogenesis.

Tobacco against Ebola virus disease.

PubMed

Budzianowski, Jaromir

2015-01-01

The Ebola virus disease (EVD), formerly known as a hemorrhagic fever and discovered in 1976, is dangerous, highly infectious disease with very high mortality. There are no licensed therapeutics against EVD, although a range of medicines and therapies are currently being evaluated. During the 2014 Ebola outbreak, an experimental drug named ZMapp was administered on an emergency basis to seven patients of which five were recovered. Currently, since February 2015, ZMapp is tested in clinical trials. ZMapp is a mixture (named a cocktail) of three chimaeric monoclonal antibodies (mAbs) of IgG class, which bind to three different epitopes on Ebola surface glycoprotein (GP). ZMapp was created by systematic selection of antibodies from two other three-component cocktails--MB-003 and ZMab the components of which were produced by rapid transient expression method in tobacco species of Australian origin--Nicotiana benthamiana. The ZMapp antibodies of pharmaceutical grade are manufactured in green-house grown N.benthamiana according to the cGMP (current Good Manufacturing Practice), using RAMP platform (Rapid Antibody Manufacturing Platform) and MagnICON system, which utilizes transient expression by magnifection method using viral vectors delivered to plant tissue by a bacterium--Agrobacterium tumefaciens. The applied glycosylation mutant of N.benthamiana (delta XTFT) synthesizes human-like, biantennary N-glycans, with terminal N-acetylglucoseamine and without typical of plants, immunogenic sugar epitopes-beta1,2-linked xylose and alpha1,3-linked fucose. Due to an absence of fucose on N-glycans attached to the Fc domains, the plant-produced anti-Ebola mAbs elicited significantly stronger antibody-dependent cellular cytotoxicity (ADCC) than the analogous anti-Ebola mAbs with fucosylated (alpha1,6-linked fucose) N-glycans produced in a mammalian CHO cell line--the basic expression system for the industrial production of recombinant therapeutical glycoproteins. As far as a

Post-exposure treatments for Ebola and Marburg virus infections.

PubMed

Cross, Robert W; Mire, Chad E; Feldmann, Heinz; Geisbert, Thomas W

2018-06-01

The filoviruses - Ebola virus and Marburg virus - cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively.

Why has the Ebola outbreak in West Africa been so challenging to control?

PubMed Central

Semalulu, T; Wong, G; Kobinger, G; Huston, P

2014-01-01

West Africa is in the midst of the largest Ebola outbreak ever; there have been over 1000 deaths and many new cases are reported each day. The World Health Organization (WHO) declared it an outbreak in March 2014 and on August 6, 2014 the WHO declared the outbreak a public health emergency of international concern. Based on the number of deaths and total number of cases reported to the WHO as of August 11, 2014, the current outbreak has an overall mortality rate of 55%. Outbreak control measures against Ebola virus disease are effective. Why then, has this outbreak been so challenging to control? Ebola is transmitted through bodily fluids and immediately attacks the immune system, then progressively attacks the major organs and the lining of blood vessels. Sierra Leone, Guinea and Liberia are small countries that have limited resources to respond to prolonged outbreaks, especially in rural areas. This has been made more challenging by the fact that health care workers are at risk of contracting Ebola virus disease. Treatment to date has been supportive, not curative and outbreak control strategies have been met with distrust due to fear and misinformation. However, important progress is being made. The international response to Ebola is gaining momentum, communication strategies have been developed to address the fear and mistrust, and promising treatments are under development, including a combination of three monoclonal antibodies that has been administered to two American Ebola infected health care workers. The National Microbiology Laboratory of the Public Health Agency of Canada (PHAC) has been supporting laboratory diagnostic efforts in West Africa and PHAC has been working with the provinces and territories and key stakeholders to ensure Canada is prepared for a potential Ebola importation. PMID:29769855

Why has the Ebola outbreak in West Africa been so challenging to control?

PubMed

Semalulu, T; Wong, G; Kobinger, G; Huston, P

2014-08-14

West Africa is in the midst of the largest Ebola outbreak ever; there have been over 1000 deaths and many new cases are reported each day. The World Health Organization (WHO) declared it an outbreak in March 2014 and on August 6, 2014 the WHO declared the outbreak a public health emergency of international concern. Based on the number of deaths and total number of cases reported to the WHO as of August 11, 2014, the current outbreak has an overall mortality rate of 55%. Outbreak control measures against Ebola virus disease are effective. Why then, has this outbreak been so challenging to control? Ebola is transmitted through bodily fluids and immediately attacks the immune system, then progressively attacks the major organs and the lining of blood vessels. Sierra Leone, Guinea and Liberia are small countries that have limited resources to respond to prolonged outbreaks, especially in rural areas. This has been made more challenging by the fact that health care workers are at risk of contracting Ebola virus disease. Treatment to date has been supportive, not curative and outbreak control strategies have been met with distrust due to fear and misinformation. However, important progress is being made. The international response to Ebola is gaining momentum, communication strategies have been developed to address the fear and mistrust, and promising treatments are under development, including a combination of three monoclonal antibodies that has been administered to two American Ebola infected health care workers. The National Microbiology Laboratory of the Public Health Agency of Canada (PHAC) has been supporting laboratory diagnostic efforts in West Africa and PHAC has been working with the provinces and territories and key stakeholders to ensure Canada is prepared for a potential Ebola importation.

Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus

PubMed Central

Matassov, Demetrius; Marzi, Andrea; Latham, Terri; Xu, Rong; Ota-Setlik, Ayuko; Feldmann, Friederike; Geisbert, Joan B.; Mire, Chad E.; Hamm, Stefan; Nowak, Becky; Egan, Michael A.; Geisbert, Thomas W.; Eldridge, John H.; Feldmann, Heinz; Clarke, David K.

2015-01-01

Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7–9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines. PMID:26109675

Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection.

PubMed

Swenson, Dana L; Warfield, Kelly L; Warren, Travis K; Lovejoy, Candace; Hassinger, Jed N; Ruthel, Gordon; Blouch, Robert E; Moulton, Hong M; Weller, Dwight D; Iversen, Patrick L; Bavari, Sina

2009-05-01

Phosphorodiamidate morpholino oligomers (PMOs) are uncharged nucleic acid-like molecules designed to inactivate the expression of specific genes via the antisense-based steric hindrance of mRNA translation. PMOs have been successful at knocking out viral gene expression and replication in the case of acute viral infections in animal models and have been well tolerated in human clinical trials. We propose that antisense PMOs represent a promising class of therapeutic agents that may be useful for combating filoviral infections. We have previously shown that mice treated with a PMO whose sequence is complementary to a region spanning the start codon of VP24 mRNA were protected against lethal Ebola virus challenge. In the present study, we report on the abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection. Additionally, structure-activity relationship evaluations were conducted to assess the enhancement of antiviral efficacy associated with PMO chemical modifications that included conjugation with peptides of various lengths and compositions, positioning of conjugated peptides to either the 5' or the 3' terminus, and the conferring of charge modifications by the addition of piperazine moieties. Conjugation with arginine-rich peptides greatly enhanced the antiviral efficacy of VP24-specific PMOs in infected cells and mice during lethal Ebola virus challenge.

Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus.

PubMed

Glynn, Judith R; Bower, Hilary; Johnson, Sembia; Houlihan, Catherine F; Montesano, Carla; Scott, Janet T; Semple, Malcolm G; Bangura, Mohammed S; Kamara, Alie Joshua; Kamara, Osman; Mansaray, Saidu H; Sesay, Daniel; Turay, Cecilia; Dicks, Steven; Wadoum, Raoul E Guetiya; Colizzi, Vittorio; Checchi, Francesco; Samuel, Dhan; Tedder, Richard S

2017-06-01

The frequency of asymptomatic infection with Ebola virus is unclear: previous estimates vary and there is no standard test. Asymptomatic infection with Ebola virus could contribute to population immunity, reducing spread. If people with asymptomatic infection are infectious it could explain re-emergences of Ebola virus disease (EVD) without known contact. We validated a new oral fluid anti-glycoprotein IgG capture assay among survivors from Kerry Town Ebola Treatment Centre and controls from communities unaffected by EVD in Sierra Leone. We then assessed the seroprevalence of antibodies to Ebola virus in a cross-sectional study of household contacts of the survivors. All household members were interviewed. Two reactive tests were required for a positive result, with a third test to resolve any discrepancies. The assay had a specificity of 100% (95% CI 98·9-100; 339 of 339 controls tested negative) and sensitivity of 95·9% (89·8-98·9; 93 of 97 PCR-confirmed survivors tested positive). Of household contacts not diagnosed with EVD, 47·6% (229 of 481) had high level exposure (direct contact with a corpse, body fluids, or a case with diarrhoea, vomiting, or bleeding). Among the contacts, 12·0% (95% CI 6·1-20·4; 11 of 92) with symptoms at the time other household members had EVD, and 2·6% (1·2-4·7; 10 of 388) with no symptoms tested positive. Among asymptomatic contacts, seropositivity was weakly correlated with exposure level. This new highly specific and sensitive assay showed asymptomatic infection with Ebola virus was uncommon despite high exposure. The low prevalence suggests asymptomatic infection contributes little to herd immunity in Ebola, and even if infectious, would account for few transmissions. Wellcome Trust ERAES Programme, Save the Children. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

Inappropriate bradycardia in Ebola virus disease.

PubMed

Cellarier, G; Bordes, J; De Greslan, T; Karkowski, L; Gagnon, N; Billhot, M; Cournac, J-M; Rousseau, C; Mac Nab, C; Dubrous, P

2016-08-01

As part of French assistance for the outbreak of Ebola virus disease in west Africa, a military treatment center for infected healthcare workers was deployed in Conakry, Guinea. Although some cases of bradycardia have been reported since the first Ebola outbreak, they have never been documented to our knowledge. We studied heart rhythm in patients with Ebola virus disease to analyze inappropriate bradycardia and discuss its mechanism. Nine patients who tested positive for Ebola were admitted in March 2015. Baseline clinical data were noted at admission and twice a day during follow-up, and laboratory analyses (with troponin testing) were performed. At admission, patients had no or moderate tachycardia (pulse = 82 ± 27 bpm). Among them, a 32-year-old midwife admitted on her fourth day of symptoms had marked bradycardia: 43 bpm. ECG showed sinus bradycardia with no conduction disturbances or repolarization anomalies; findings were similar for the three other patients with bradycardia (< 60 bpm). During follow-up, her pulse gradually increased, as it did for the other three; all four recovered. Despite several factors likely to promote tachycardia, we observed no or only moderate tachycardia in all patients with Ebola. In our study, ECG recorded sinus rhythm, without significant node dysfunction or atrioventricular block. In the absence of any evidence of myocarditis, we discuss the possibility of a central nervous system cause, associated with encephalitis. We observed relative or marked bradycardia in our patients infected with Ebola. We hypothesize that its causal mechanism was encephalitis.

Recombinant Vesicular Stomatitis Virus–Based Vaccines Against Ebola and Marburg Virus Infections

PubMed Central

Feldmann, Heinz

2011-01-01

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections. PMID:21987744

Nucleoprotein-based indirect enzyme-linked immunosorbent assay (indirect ELISA) for detecting antibodies specific to Ebola virus and Marbug virus.

PubMed

Huang, Yi; Zhu, Youjie; Yang, Mengshi; Zhang, Zhenqing; Song, Donglin; Yuan, Zhiming

2014-12-01

Full-length nucleoproteins from Ebola and Marburg viruses were expressed as His-tagged recombinant proteins in Escherichia coli and nucleoprotein-based enzyme-linked immunosorbent assays (ELISAs) were established for the detection of antibodies specific to Ebola and Marburg viruses. The ELISAs were evaluated by testing antisera collected from rabbit immunized with Ebola and Marburg virus nucleoproteins. Although little cross-reactivity of antibodies was observed in anti-Ebola virus nucleoprotein rabbit antisera, the highest reactions to immunoglobulin G (IgG) were uniformly detected against the nucleoprotein antigens of homologous viruses. We further evaluated the ELISA's ability to detect antibodies to Ebola and Marburg viruses using human sera samples collected from individuals passing through the Guangdong port of entry. With a threshold set at the mean plus three standard deviations of average optical densities of sera tested, the ELISA systems using these two recombinant nucleoproteins have good sensitivity and specificity. These results demonstrate the usefulness of ELISA for diagnostics as well as ecological and serosurvey studies of Ebola and Marburg virus infection.

THE STRENGTHS, WEAKNESSES, OPPORTUNITIES, AND THREATS (SWOTs) ANALYSES OF THE EBOLA VIRUS – PAPER RETRACTED

PubMed Central

Babalola, Michael Oluyemi

2016-01-01

Background: Owing to the extreme virulence and case fatality rate of ebola virus disease (EVD), there had been so much furore, panic and public health emergency about the possible pandemic from the recent West African outbreak of the disease, with attendant handful research, both in the past and most recently. The magnitude of the epidemic of ebola virus disease has prompted global interest and urgency in the discovery of measures to mitigate the impact of the disease. Researchers in the academia and the industry were pressured to only focus on the development of effective and safe ebola virus vaccines, without consideration of the other aspects to this virus, which may influence the success or otherwise of a potential vaccine. The objective of this review was to adopt the SWOT concept to elucidate the biological Strengths, Weaknesses, Opportunities, and Threats to Ebola virus as a pathogen, with a view to understanding and devising holistic strategies at combating and overcoming the scourge of EVD. Method: This systematic review and narrative synthesis utilized Medline, PubMed, Google and other databases to select about 150 publications on ebola and ebola virus disease using text word searches to generate the specific terms. Relevant publications were reviewed and compared, findings were synthesized using a narrative method and summarized qualitatively. Results: Some of the identified strengths of ebola virus include: Ebola virus is an RNA virus with inherent capability to mutate, reassort and recombine to generate mutant or reassortant virulent strains; Ebola virus has a broad cellular tropism; Natural Reservoir of ebola virus is unconfirmed but fruit bats, arthropods, and plants are hypothesized; Ebola virus primarily targets and selectively destroys the immune system; Ebola viruses possess accessory proteins that inhibits the host’ immune responses; Secreted glycoprotein (sGP), a truncated soluble protein that triggers immune activation and increased vascular

Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Messaoudi, Ilhem; Amarasinghe, Gaya K.; Basler, Christopher F.

Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirusmore » pathogenesis.« less

Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.

PubMed

Geisbert, Thomas W; Geisbert, Joan B; Leung, Anders; Daddario-DiCaprio, Kathleen M; Hensley, Lisa E; Grolla, Allen; Feldmann, Heinz

2009-07-01

The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (VSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman primates against Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Marburgvirus (MARV). In this study, 11 cynomolgus monkeys were vaccinated with a blended vaccine consisting of equal parts of the vaccine vectors VSVDeltaG/SEBOVGP, VSVDeltaG/ZEBOVGP, and VSVDeltaG/MARVGP. Four weeks later, three of these animals were challenged with MARV, three with CIEBOV, three with ZEBOV, and two with SEBOV. Three control animals were vaccinated with VSV vectors encoding a nonfilovirus GP and challenged with SEBOV, ZEBOV, and MARV, respectively, and five unvaccinated control animals were challenged with CIEBOV. Importantly, none of the macaques vaccinated with the blended vaccine succumbed to a filovirus challenge. As expected, an experimental control animal vaccinated with VSVDeltaG/ZEBOVGP and challenged with SEBOV succumbed, as did the positive controls challenged with SEBOV, ZEBOV, and MARV, respectively. All five control animals challenged with CIEBOV became severely ill, and three of the animals succumbed on days 12, 12, and 14, respectively. The two animals that survived CIEBOV infection were protected from subsequent challenge with either SEBOV or ZEBOV, suggesting that immunity to CIEBOV may be protective against other species of Ebola virus. In conclusion, we developed an immunization scheme based on a single-injection vaccine that protects nonhuman primates against lethal challenge with representative strains of all human pathogenic

Pathology of experimental Ebola virus infection in African green monkeys. Involvement of fibroblastic reticular cells.

PubMed

Davis, K J; Anderson, A O; Geisbert, T W; Steele, K E; Geisbert, J B; Vogel, P; Connolly, B M; Huggins, J W; Jahrling, P B; Jaax, N K

1997-08-01

Ebola virus has been responsible for explosive lethal outbreaks of hemorrhagic fever in both humans and nonhuman primates. Previous studies showed a predilection of Ebola virus for cells of the mononuclear phagocyte system and endothelial cells. To examine the distribution of lesions and Ebola virus antigen in the tissues of six adult male African green monkeys (Cercopithecus aethiops) that died 6 to 7 days after intraperitoneal inoculation of Ebola-Zaire (Mayinga) virus. Tissues were examined histologically, immunohistochemically, and ultrastructurally. A major novel finding of this study was that fibroblastic reticular cells were immunohistochemically and ultrastructurally identified as targets of Ebola virus infection. The role of Ebola virus-infected fibroblastic reticular cells in the pathogenesis of Ebola hemorrhagic fever warrants further investigation. This is especially important because of recent observations indicating that fibroblastic reticular cells, along with the reticular fibers they produce, maximize the efficiency of the immune response.

Mechanisms of immunity in post-exposure vaccination against Ebola virus infection.

PubMed

Bradfute, Steven B; Anthony, Scott M; Stuthman, Kelly S; Ayithan, Natarajan; Tailor, Prafullakumar; Shaia, Carl I; Bray, Mike; Ozato, Keiko; Bavari, Sina

2015-01-01

Ebolaviruses can cause severe hemorrhagic fever that is characterized by rapid viral replication, coagulopathy, inflammation, and high lethality rates. Although there is no clinically proven vaccine or treatment for Ebola virus infection, a virus-like particle (VLP) vaccine is effective in mice, guinea pigs, and non-human primates when given pre-infection. In this work, we report that VLPs protect Ebola virus-infected mice when given 24 hours post-infection. Analysis of cytokine expression in serum revealed a decrease in pro-inflammatory cytokine and chemokine levels in mice given VLPs post-exposure compared to infected, untreated mice. Using knockout mice, we show that VLP-mediated post-exposure protection requires perforin, B cells, macrophages, conventional dendritic cells (cDCs), and either CD4+ or CD8+ T cells. Protection was Ebola virus-specific, as marburgvirus VLPs did not protect Ebola virus-infected mice. Increased antibody production in VLP-treated mice correlated with protection, and macrophages were required for this increased production. However, NK cells, IFN-gamma, and TNF-alpha were not required for post-exposure-mediated protection. These data suggest that a non-replicating Ebola virus vaccine can provide post-exposure protection and that the mechanisms of immune protection in this setting require both increased antibody production and generation of cytotoxic T cells.

Analytical Performance Characteristics of the Cepheid GeneXpert Ebola Assay for the Detection of Ebola Virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pinsky, Benjamin A.; Sahoo, Malaya K.; Sandlund, Johanna

The recently developed Xpert® Ebola Assay is a novel nucleic acid amplification test for simplified detection of Ebola virus (EBOV) in whole blood and buccal swab samples. The assay targets sequences in two EBOV genes, lowering the risk for new variants to escape detection in the test. The objective of this report is to present analytical characteristics of the Xpert® Ebola Assay on whole blood samples. Our study evaluated the assay’s analytical sensitivity, analytical specificity, inclusivity and exclusivity performance in whole blood specimens. EBOV RNA, inactivated EBOV, and infectious EBOV were used as targets. The dynamic range of the assay,more » the inactivation of virus, and specimen stability were also evaluated. The lower limit of detection (LoD) for the assay using inactivated virus was estimated to be 73 copies/mL (95% CI: 51–97 copies/mL). The LoD for infectious virus was estimated to be 1 plaque-forming unit/mL, and for RNA to be 232 copies/mL (95% CI 163–302 copies/mL). The assay correctly identified five different Ebola viruses, Yambuku-Mayinga, Makona-C07, Yambuku-Ecran, Gabon-Ilembe, and Kikwit-956210, and correctly excluded all non-EBOV isolates tested. The conditions used by Xpert® Ebola for inactivation of infectious virus reduced EBOV titer by ≥6 logs. In conclusion, we found the Xpert® Ebola Assay to have high analytical sensitivity and specificity for the detection of EBOV in whole blood. It offers ease of use, fast turnaround time, and remote monitoring. The test has an efficient viral inactivation protocol, fulfills inclusivity and exclusivity criteria, and has specimen stability characteristics consistent with the need for decentralized testing. The simplicity of the assay should enable testing in a wide variety of laboratory settings, including remote laboratories that are not capable of performing highly complex nucleic acid amplification tests, and during outbreaks where time to detection is critical.« less

Analytical Performance Characteristics of the Cepheid GeneXpert Ebola Assay for the Detection of Ebola Virus

PubMed Central

Pinsky, Benjamin A.; Sahoo, Malaya K.; Sandlund, Johanna; Kleman, Marika; Kulkarni, Medha; Grufman, Per; Nygren, Malin; Kwiatkowski, Robert; Baron, Ellen Jo; Tenover, Fred; Denison, Blake; Higuchi, Russell; Van Atta, Reuel; Beer, Neil Reginald; Carrillo, Alda Celena; Naraghi-Arani, Pejman; Mire, Chad E.; Ranadheera, Charlene; Grolla, Allen; Lagerqvist, Nina; Persing, David H.

2015-01-01

Background The recently developed Xpert® Ebola Assay is a novel nucleic acid amplification test for simplified detection of Ebola virus (EBOV) in whole blood and buccal swab samples. The assay targets sequences in two EBOV genes, lowering the risk for new variants to escape detection in the test. The objective of this report is to present analytical characteristics of the Xpert® Ebola Assay on whole blood samples. Methods and Findings This study evaluated the assay’s analytical sensitivity, analytical specificity, inclusivity and exclusivity performance in whole blood specimens. EBOV RNA, inactivated EBOV, and infectious EBOV were used as targets. The dynamic range of the assay, the inactivation of virus, and specimen stability were also evaluated. The lower limit of detection (LoD) for the assay using inactivated virus was estimated to be 73 copies/mL (95% CI: 51–97 copies/mL). The LoD for infectious virus was estimated to be 1 plaque-forming unit/mL, and for RNA to be 232 copies/mL (95% CI 163–302 copies/mL). The assay correctly identified five different Ebola viruses, Yambuku-Mayinga, Makona-C07, Yambuku-Ecran, Gabon-Ilembe, and Kikwit-956210, and correctly excluded all non-EBOV isolates tested. The conditions used by Xpert® Ebola for inactivation of infectious virus reduced EBOV titer by ≥6 logs. Conclusion In summary, we found the Xpert® Ebola Assay to have high analytical sensitivity and specificity for the detection of EBOV in whole blood. It offers ease of use, fast turnaround time, and remote monitoring. The test has an efficient viral inactivation protocol, fulfills inclusivity and exclusivity criteria, and has specimen stability characteristics consistent with the need for decentralized testing. The simplicity of the assay should enable testing in a wide variety of laboratory settings, including remote laboratories that are not capable of performing highly complex nucleic acid amplification tests, and during outbreaks where time to detection

Analytical Performance Characteristics of the Cepheid GeneXpert Ebola Assay for the Detection of Ebola Virus

DOE PAGES

Pinsky, Benjamin A.; Sahoo, Malaya K.; Sandlund, Johanna; ...

2015-11-12

The recently developed Xpert® Ebola Assay is a novel nucleic acid amplification test for simplified detection of Ebola virus (EBOV) in whole blood and buccal swab samples. The assay targets sequences in two EBOV genes, lowering the risk for new variants to escape detection in the test. The objective of this report is to present analytical characteristics of the Xpert® Ebola Assay on whole blood samples. Our study evaluated the assay’s analytical sensitivity, analytical specificity, inclusivity and exclusivity performance in whole blood specimens. EBOV RNA, inactivated EBOV, and infectious EBOV were used as targets. The dynamic range of the assay,more » the inactivation of virus, and specimen stability were also evaluated. The lower limit of detection (LoD) for the assay using inactivated virus was estimated to be 73 copies/mL (95% CI: 51–97 copies/mL). The LoD for infectious virus was estimated to be 1 plaque-forming unit/mL, and for RNA to be 232 copies/mL (95% CI 163–302 copies/mL). The assay correctly identified five different Ebola viruses, Yambuku-Mayinga, Makona-C07, Yambuku-Ecran, Gabon-Ilembe, and Kikwit-956210, and correctly excluded all non-EBOV isolates tested. The conditions used by Xpert® Ebola for inactivation of infectious virus reduced EBOV titer by ≥6 logs. In conclusion, we found the Xpert® Ebola Assay to have high analytical sensitivity and specificity for the detection of EBOV in whole blood. It offers ease of use, fast turnaround time, and remote monitoring. The test has an efficient viral inactivation protocol, fulfills inclusivity and exclusivity criteria, and has specimen stability characteristics consistent with the need for decentralized testing. The simplicity of the assay should enable testing in a wide variety of laboratory settings, including remote laboratories that are not capable of performing highly complex nucleic acid amplification tests, and during outbreaks where time to detection is critical.« less

Emergence of Vaccine-Derived Polioviruses during Ebola Virus Disease Outbreak, Guinea, 2014-2015.

PubMed

Fernandez-Garcia, Maria Dolores; Majumdar, Manasi; Kebe, Ousmane; Fall, Aichatou D; Kone, Moussa; Kande, Mouctar; Dabo, Moustapha; Sylla, Mohamed Salif; Sompare, Djenou; Howard, Wayne; Faye, Ousmane; Martin, Javier; Ndiaye, Kader

2018-01-01

During the 2014-2015 outbreak of Ebola virus disease in Guinea, 13 type 2 circulating vaccine-derived polioviruses (cVDPVs) were isolated from 6 polio patients and 7 healthy contacts. To clarify the genetic properties of cVDPVs and their emergence, we combined epidemiologic and virologic data for polio cases in Guinea. Deviation of public health resources to the Ebola outbreak disrupted polio vaccination programs and surveillance activities, which fueled the spread of neurovirulent VDPVs in an area of low vaccination coverage and immunity. Genetic properties of cVDPVs were consistent with their capacity to cause paralytic disease in humans and capacity for sustained person-to-person transmission. Circulation ceased when coverage of oral polio vaccine increased. A polio outbreak in the context of the Ebola virus disease outbreak highlights the need to consider risks for polio emergence and spread during complex emergencies and urges awareness of the challenges in polio surveillance, vaccination, and diagnosis.

Ebola RNA Persistence in Semen of Ebola Virus Disease Survivors - Final Report.

PubMed

Deen, Gibrilla F; Broutet, Nathalie; Xu, Wenbo; Knust, Barbara; Sesay, Foday R; McDonald, Suzanna L R; Ervin, Elizabeth; Marrinan, Jaclyn E; Gaillard, Philippe; Habib, Ndema; Liu, Hongtu; Liu, William; Thorson, Anna E; Yamba, Francis; Massaquoi, Thomas A; James, Faustin; Ariyarajah, Archchun; Ross, Christine; Bernstein, Kyle; Coursier, Antoine; Klena, John; Carino, Marylin; Wurie, Alie H; Zhang, Yong; Dumbuya, Marion S; Abad, Neetu; Idriss, Baimba; Wi, Teodora; Bennett, Sarah D; Davies, Tina; Ebrahim, Faiqa K; Meites, Elissa; Naidoo, Dhamari; Smith, Samuel J; Ongpin, Patricia; Malik, Tasneem; Banerjee, Anshu; Erickson, Bobbie R; Liu, Yongjian; Liu, Yang; Xu, Ke; Brault, Aaron; Durski, Kara N; Winter, Jörn; Sealy, Tara; Nichol, Stuart T; Lamunu, Margaret; Bangura, James; Landoulsi, Sihem; Jambai, Amara; Morgan, Oliver; Wu, Guizhen; Liang, Mifang; Su, Qiudong; Lan, Yu; Hao, Yanzhe; Formenty, Pierre; Ströher, Ute; Sahr, Foday

2017-10-12

Ebola virus has been detected in the semen of men after their recovery from Ebola virus disease (EVD). We report the presence of Ebola virus RNA in semen in a cohort of survivors of EVD in Sierra Leone. We enrolled a convenience sample of 220 adult male survivors of EVD in Sierra Leone, at various times after discharge from an Ebola treatment unit (ETU), in two phases (100 participants were in phase 1, and 120 in phase 2). Semen specimens obtained at baseline were tested by means of a quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay with the use of the target sequences of NP and VP40 (in phase 1) or NP and GP (in phase 2). This study did not evaluate directly the risk of sexual transmission of EVD. Of 210 participants who provided an initial semen specimen for analysis, 57 (27%) had positive results on quantitative RT-PCR. Ebola virus RNA was detected in the semen of all 7 men with a specimen obtained within 3 months after ETU discharge, in 26 of 42 (62%) with a specimen obtained at 4 to 6 months, in 15 of 60 (25%) with a specimen obtained at 7 to 9 months, in 4 of 26 (15%) with a specimen obtained at 10 to 12 months, in 4 of 38 (11%) with a specimen obtained at 13 to 15 months, in 1 of 25 (4%) with a specimen obtained at 16 to 18 months, and in no men with a specimen obtained at 19 months or later. Among the 46 participants with a positive result in phase 1, the median baseline cycle-threshold values (higher values indicate lower RNA values) for the NP and VP40 targets were lower within 3 months after ETU discharge (32.4 and 31.3, respectively; in 7 men) than at 4 to 6 months (34.3 and 33.1; in 25), at 7 to 9 months (37.4 and 36.6; in 13), and at 10 to 12 months (37.7 and 36.9; in 1). In phase 2, a total of 11 participants had positive results for NP and GP targets (samples obtained at 4.1 to 15.7 months after ETU discharge); cycle-threshold values ranged from 32.7 to 38.0 for NP and from 31.1 to 37.7 for GP. These data showed the long

Anti-Ebola therapies based on monoclonal antibodies: current state and challenges ahead.

PubMed

González-González, Everardo; Alvarez, Mario Moisés; Márquez-Ipiña, Alan Roberto; Trujillo-de Santiago, Grissel; Rodríguez-Martínez, Luis Mario; Annabi, Nasim; Khademhosseini, Ali

2017-02-01

The 2014 Ebola outbreak, the largest recorded, took us largely unprepared, with no available vaccine or specific treatment. In this context, the World Health Organization declared that the humanitarian use of experimental therapies against Ebola Virus (EBOV) is ethical. In particular, an experimental treatment consisting of a cocktail of three monoclonal antibodies (mAbs) produced in tobacco plants and specifically directed to the EBOV glycoprotein (GP) was tested in humans, apparently with good results. Several mAbs with high affinity to the GP have been described. This review discusses our current knowledge on this topic. Particular emphasis is devoted to those mAbs that have been assayed in animal models or humans as possible therapies against Ebola. Engineering aspects and challenges for the production of anti-Ebola mAbs are also briefly discussed; current platforms for the design and production of full-length mAbs are cumbersome and costly.

Unique human immune signature of Ebola virus disease in Guinea.

PubMed

Ruibal, Paula; Oestereich, Lisa; Lüdtke, Anja; Becker-Ziaja, Beate; Wozniak, David M; Kerber, Romy; Korva, Miša; Cabeza-Cabrerizo, Mar; Bore, Joseph A; Koundouno, Fara Raymond; Duraffour, Sophie; Weller, Romy; Thorenz, Anja; Cimini, Eleonora; Viola, Domenico; Agrati, Chiara; Repits, Johanna; Afrough, Babak; Cowley, Lauren A; Ngabo, Didier; Hinzmann, Julia; Mertens, Marc; Vitoriano, Inês; Logue, Christopher H; Boettcher, Jan Peter; Pallasch, Elisa; Sachse, Andreas; Bah, Amadou; Nitzsche, Katja; Kuisma, Eeva; Michel, Janine; Holm, Tobias; Zekeng, Elsa-Gayle; García-Dorival, Isabel; Wölfel, Roman; Stoecker, Kilian; Fleischmann, Erna; Strecker, Thomas; Di Caro, Antonino; Avšič-Županc, Tatjana; Kurth, Andreas; Meschi, Silvia; Mély, Stephane; Newman, Edmund; Bocquin, Anne; Kis, Zoltan; Kelterbaum, Anne; Molkenthin, Peter; Carletti, Fabrizio; Portmann, Jasmine; Wolff, Svenja; Castilletti, Concetta; Schudt, Gordian; Fizet, Alexandra; Ottowell, Lisa J; Herker, Eva; Jacobs, Thomas; Kretschmer, Birte; Severi, Ettore; Ouedraogo, Nobila; Lago, Mar; Negredo, Anabel; Franco, Leticia; Anda, Pedro; Schmiedel, Stefan; Kreuels, Benno; Wichmann, Dominic; Addo, Marylyn M; Lohse, Ansgar W; De Clerck, Hilde; Nanclares, Carolina; Jonckheere, Sylvie; Van Herp, Michel; Sprecher, Armand; Xiaojiang, Gao; Carrington, Mary; Miranda, Osvaldo; Castro, Carlos M; Gabriel, Martin; Drury, Patrick; Formenty, Pierre; Diallo, Boubacar; Koivogui, Lamine; Magassouba, N'Faly; Carroll, Miles W; Günther, Stephan; Muñoz-Fontela, César

2016-05-05

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.

Message from the ISCB: ISCB Ebola award for important future research on the computational biology of Ebola virus.

PubMed

Karp, Peter D; Berger, Bonnie; Kovats, Diane; Lengauer, Thomas; Linial, Michal; Sabeti, Pardis; Hide, Winston; Rost, Burkhard

2015-02-15

Speed is of the essence in combating Ebola; thus, computational approaches should form a significant component of Ebola research. As for the development of any modern drug, computational biology is uniquely positioned to contribute through comparative analysis of the genome sequences of Ebola strains and three-dimensional protein modeling. Other computational approaches to Ebola may include large-scale docking studies of Ebola proteins with human proteins and with small-molecule libraries, computational modeling of the spread of the virus, computational mining of the Ebola literature and creation of a curated Ebola database. Taken together, such computational efforts could significantly accelerate traditional scientific approaches. In recognition of the need for important and immediate solutions from the field of computational biology against Ebola, the International Society for Computational Biology (ISCB) announces a prize for an important computational advance in fighting the Ebola virus. ISCB will confer the ISCB Fight against Ebola Award, along with a prize of US$2000, at its July 2016 annual meeting (ISCB Intelligent Systems for Molecular Biology 2016, Orlando, FL). dkovats@iscb.org or rost@in.tum.de. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Community Knowledge, Attitudes, and Practices Regarding Ebola Virus Disease - Five Counties, Liberia, September-October, 2014.

PubMed

Kobayashi, Miwako; Beer, Karlyn D; Bjork, Adam; Chatham-Stephens, Kevin; Cherry, Cara C; Arzoaquoi, Sampson; Frank, Wilmot; Kumeh, Odell; Sieka, Joseph; Yeiah, Adolphus; Painter, Julia E; Yoder, Jonathan S; Flannery, Brendan; Mahoney, Frank; Nyenswah, Tolbert G

2015-07-10

As of July 1, 2015, Guinea, Liberia, and Sierra Leone have reported a total of 27,443 confirmed, probable, and suspected Ebola virus disease (Ebola) cases and 11,220 deaths. Guinea and Sierra Leone have yet to interrupt transmission of Ebola virus. In January, 2016, Liberia successfully achieved Ebola transmission-free status, with no new Ebola cases occurring during a 42-day period; however, new Ebola cases were reported beginning June 29, 2015. Local cultural practices and beliefs have posed challenges to disease control, and therefore, targeted, timely health messages are needed to address practices and misperceptions that might hinder efforts to stop the spread of Ebola. As early as September 2014, Ebola spread to most counties in Liberia. To assess Ebola-related knowledge, attitudes, and practices (KAP) in the community, CDC epidemiologists who were deployed to the counties (field team), carried out a survey conducted by local trained interviewers. The survey was conducted in September and October 2014 in five counties in Liberia with varying cumulative incidence of Ebola cases. Survey results indicated several findings. First, basic awareness of Ebola was high across all surveyed populations (median correct responses = 16 of 17 questions on knowledge of Ebola transmission; range = 2-17). Second, knowledge and understanding of Ebola symptoms were incomplete (e.g., 61% of respondents said they would know if they had Ebola symptoms). Finally, certain fears about the disease were present: >90% of respondents indicated a fear of Ebola patients, >40% a fear of cured patients, and >50% a fear of treatment units (expressions of this last fear were greater in counties with lower Ebola incidence). This survey, which was conducted at a time when case counts were rapidly increasing in Liberia, indicated limited knowledge of Ebola symptoms and widespread fear of Ebola treatment units despite awareness of communication messages. Continued efforts are needed to address

Ebola Virus Disease in Children, Sierra Leone, 2014–2015

PubMed Central

Naveed, Asad; Wing, Kevin; Gbessay, Musa; Ross, J.C.G.; Checchi, Francesco; Youkee, Daniel; Jalloh, Mohammed Boie; Baion, David; Mustapha, Ayeshatu; Jah, Hawanatu; Lako, Sandra; Oza, Shefali; Boufkhed, Sabah; Feury, Reynold; Bielicki, Julia A.; Gibb, Diana M.; Klein, Nigel; Sahr, Foday; Yeung, Shunmay

2016-01-01

Little is known about potentially modifiable factors in Ebola virus disease in children. We undertook a retrospective cohort study of children <13 years old admitted to 11 Ebola holding units in the Western Area, Sierra Leone, during 2014–2015 to identify factors affecting outcome. Primary outcome was death or discharge after transfer to Ebola treatment centers. All 309 Ebola virus–positive children 2 days–12 years old were included; outcomes were available for 282 (91%). Case-fatality was 57%, and 55% of deaths occurred in Ebola holding units. Blood test results showed hypoglycemia and hepatic/renal dysfunction. Death occurred swiftly (median 3 days after admission) and was associated with younger age and diarrhea. Despite triangulation of information from multiple sources, data availability was limited, and we identified no modifiable factors substantially affecting death. In future Ebola virus disease epidemics, robust, rapid data collection is vital to determine effectiveness of interventions for children. PMID:27649367

Evaluating the frequency of asymptomatic Ebola virus infection.

PubMed

Mbala, Placide; Baguelin, Marc; Ngay, Ipos; Rosello, Alicia; Mulembakani, Prime; Demiris, Nikolaos; Edmunds, W John; Muyembe, Jean-Jacques

2017-05-26

The potential for asymptomatic infection from Ebola viruses has long been questioned. Knowing the proportion of infections that are asymptomatic substantially changes the predictions made by mathematical models and alters the corresponding decisions based upon these models. To assess the degree of asymptomatic infection occurring during an Ebola virus disease (EVD) outbreak, we carried out a serological survey in the Djera district of the Equateur province of the Democratic Republic of the Congo affected by an Ebola outbreak in 2014. We sampled all asymptomatic residents ( n = 182) of 48 households where at least one case of EVD was detected. To control for potential background seroprevalence of Ebola antibodies in the population, we also sampled 188 individuals from 92 households in an unaffected area with a similar demographic background. We tested the sera collected for anti-Ebola IgG and IgM antibodies at four different dilutions. We then developed a mixture model to estimate the likely number of asymptomatic patients who developed IgM and IgG responses to Ebola antigens in both groups. While we detected an association between medium to high titres and age, we did not detect any evidence of increased asymptomatic infection in the individuals who resided in the same household as cases.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'. © 2017 The Author(s).

Rapid Bedside Inactivation of Ebola Virus for Safe Nucleic Acid Tests.

PubMed

Rosenstierne, Maiken Worsøe; Karlberg, Helen; Bragstad, Karoline; Lindegren, Gunnel; Stoltz, Malin Lundahl; Salata, Cristiano; Kran, Anne-Marte Bakken; Dudman, Susanne Gjeruldsen; Mirazimi, Ali; Fomsgaard, Anders

2016-10-01

Rapid bedside inactivation of Ebola virus would be a solution for the safety of medical and technical staff, risk containment, sample transport, and high-throughput or rapid diagnostic testing during an outbreak. We show that the commercially available Magna Pure lysis/binding buffer used for nucleic acid extraction inactivates Ebola virus. A rapid bedside inactivation method for nucleic acid tests is obtained by simply adding Magna Pure lysis/binding buffer directly into vacuum blood collection EDTA tubes using a thin needle and syringe prior to sampling. The ready-to-use inactivation vacuum tubes are stable for more than 4 months, and Ebola virus RNA is preserved in the Magna Pure lysis/binding buffer for at least 5 weeks independent of the storage temperature. We also show that Ebola virus RNA can be manually extracted from Magna Pure lysis/binding buffer-inactivated samples using the QIAamp viral RNA minikit. We present an easy and convenient method for bedside inactivation using available blood collection vacuum tubes and reagents. We propose to use this simple method for fast, safe, and easy bedside inactivation of Ebola virus for safe transport and routine nucleic acid detection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Proportion of Deaths and Clinical Features in Bundibugyo Ebola Virus Infection, Uganda

PubMed Central

Farnon, Eileen C.; Wamala, Joseph; Okware, Sam; Cannon, Deborah L.; Reed, Zachary; Towner, Jonathan S.; Tappero, Jordan W.; Lutwama, Julius; Downing, Robert; Nichol, Stuart T.; Ksiazek, Thomas G.; Rollin, Pierre E.

2010-01-01

The first known Ebola hemorrhagic fever (EHF) outbreak caused by Bundibugyo Ebola virus occurred in Bundibugyo District, Uganda, in 2007. Fifty-six cases of EHF were laboratory confirmed. Although signs and symptoms were largely nonspecific and similar to those of EHF outbreaks caused by Zaire and Sudan Ebola viruses, proportion of deaths among those infected was lower (≈40%). PMID:21122234

Ebola haemorrhagic fever virus: pathogenesis, immune responses, potential prevention.

PubMed

Marcinkiewicz, Janusz; Bryniarski, Krzysztof; Nazimek, Katarzyna

2014-01-01

Ebola zoonotic RNA filovirus represents human most virulent and lethal pathogens, which induces acute hemorrhagic fever and death within few days in a range of 60-90% of symptomatic individuals. Last outbreak in 2014 in West Africa caused panic that Ebola epidemic can be spread to other continents. Number of deaths in late December reached almost 8,000 individuals out of more than 20,000 symptomatic patients. It seems that only a coordinated international response could counteract the further spread of Ebola. Major innate immunity mechanisms against Ebola are associated with the production of interferons, that are inhibited by viral proteins. Activation of host NK cells was recognized as a leading immune function responsible for recovery of infected people. Uncontrolled cell infection by Ebola leads to an impairment of immunity with cytokine storm, coagulopathy, systemic bleeding, multi-organ failure and death. Tested prevention strategies to induce antiviral immunity include: i. recombinant virus formulations (vaccines); ii. cocktail of monoclonal antibodies (serotherapy); iii. alternative RNA-interference-based antiviral methods. Maintaining the highest standards of aseptic and antiseptic precautions is equally important. Present brief review summarizes a current knowledge concerning pathogenesis of Ebola hemorrhagic disease and the virus interaction with the immune system and discusses recent advances in prevention of Ebola infection by vaccination and serotherapy.

[Research of Human-mouse Chimeric Antibodies Against Ebola Virus Nucleoprotein].

PubMed

Zhou, Rongping; Sun, Lina; Liu, Yang; Wu, Wei; Li, Chuan; Liang, Mifang; Qiu, Peihong

2016-01-01

The Ebola virus is highly infectious and can result in death in ≤ 90% of infected subjects. Detection of the Ebola virus and diagnosis of infection are extremely important for epidemic control. Presently, Chinese laboratories detect the nucleic acids of the Ebola virus by real-time reverse transcription-polymerase chain reaction (RT-PCR). However, such detection takes a relatively long time and necessitates skilled personnel and expensive equipment. Enzyme-linked immunosorbent assay (ELISA) of serum is simple, easy to operate, and can be used to ascertain if a patient is infected with the Ebola virus as well as the degree of infection. Hence, ELISA can be used in epidemiological investigations and is a strong complement to detection of nucleic acids. Cases of Ebola hemorrhagic fever have not been documented in China, so quality-control material for positive serology is needed. Construction and expression of human-mouse chimeric antibodies against the nucleoprotein of the Ebola virus was carried out. Genes encoding variable heavy (VH) and variable light (VL) chains were extracted and amplified from murine hybridoma cells. Genes encoding the VH and VL chains of monoclonal antibodies were amplified by RT-PCR. According to sequence analyses, a primer was designed to amplify functional sequences relative to VH and VL chain. The eukaryotic expression vector HL51-14 carrying some human antibody heavy chain- and light chain-constant regions was used. IgG antibodies were obtained by transient transfection of 293T cells. Subsequently, immunological detection and immunological identification were identified by ELISA, immunofluorescence assay, and western blotting. These results showed that we constructed and purified two human- mouse chimeric antibodies.

Ebola virus disease: Biological and diagnostic evolution from 2014 to 2017.

PubMed

Mérens, A; Bigaillon, C; Delaune, D

2018-03-01

The Ebola virus disease outbreak observed in West Africa from March 2014 to June 2016 has led to many fundamental and applied research works. Knowledge of this virus has substantially increased. Treatment of many patients in epidemic countries and a few imported cases in developed countries led to developing new diagnostic methods and to adapt laboratory organization and biosafety precautions to perform conventional biological analyses. Clinical and biological monitoring of patients infected with Ebola virus disease helped to determine severity criteria and bad prognosis markers. It also contributed to showing the possibility of viral sanctuaries in patients and the risk of transmission after recovery. After a summary of recent knowledge of environmental and clinical viral persistence, we aimed to present new diagnostic methods and other biological tests that led to highlighting the pathophysiological consequences of Ebola virus disease and its prognostic markers. We also aimed to describe our lab experience in the care of Ebola virus-infected patients, especially technical and logistical changes between 2014 and 2017. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Productive Replication of Ebola Virus Is Regulated by the c-Abl1 Tyrosine Kinase

PubMed Central

García, Mayra; Cooper, Arik; Shi, Wei; Bornmann, William; Carrion, Ricardo; Kalman, Daniel; Nabel, Gary J.

2016-01-01

Ebola virus causes a fulminant infection in humans resulting in diffuse bleeding, vascular instability, hypotensive shock, and often death. Because of its high mortality and ease of transmission from human to human, Ebola virus remains a biological threat for which effective preventive and therapeutic interventions are needed. An understanding of the mechanisms of Ebola virus pathogenesis is critical for developing antiviral therapeutics. Here, we report that productive replication of Ebola virus is modulated by the c-Abl1 tyrosine kinase. Release of Ebola virus–like particles (VLPs) in a cell culture cotransfection system was inhibited by c-Abl1–specific small interfering RNA (siRNA) or by Abl-specific kinase inhibitors and required tyrosine phosphorylation of the Ebola matrix protein VP40. Expression of c-Abl1 stimulated an increase in phosphorylation of tyrosine 13 (Y13) of VP40, and mutation of Y13 to alanine decreased the release of Ebola VLPs. Productive replication of the highly pathogenic Ebola virus Zaire strain was inhibited by c-Abl1–specific siRNAs or by the Abl-family inhibitor nilotinib by up to four orders of magnitude. These data indicate that c-Abl1 regulates budding or release of filoviruses through a mechanism involving phosphorylation of VP40. This step of the virus life cycle therefore may represent a target for antiviral therapy. PMID:22378924

Challenges in responding to the ebola epidemic - four rural counties, Liberia, August-November 2014.

PubMed

Summers, Aimee; Nyenswah, Tolbert G; Montgomery, Joel M; Neatherlin, John; Tappero, Jordan W; T, Nyenswah; M, Fahnbulleh; M, Massaquoi

2014-12-19

The first cases of Ebola virus disease (Ebola) in West Africa were identified in Guinea on March 22, 2014. On March 30, the first Liberian case was identified in Foya Town, Lofa County, near the Guinean border. Because the majority of early cases occurred in Lofa and Montserrado counties, resources were concentrated in these counties during the first several months of the response, and these counties have seen signs of successful disease control. By October 2014, the epidemic had reached all 15 counties of Liberia. During August 27-September 10, 2014, CDC in collaboration with the Liberian Ministry of Health and Social Welfare assessed county Ebola response plans in four rural counties (Grand Cape Mount, Grand Bassa, Rivercess, and Sinoe, to identify county-specific challenges in executing their Ebola response plans, and to provide recommendations and training to enhance control efforts. Assessments were conducted through interviews with county health teams and health care providers and visits to health care facilities. At the time of assessment, county health teams reported lacking adequate training in core Ebola response strategies and reported facing many challenges because of poor transportation and communication networks. Development of communication and transportation network strategies for communities with limited access to roads and limited means of communication in addition to adequate training in Ebola response strategies is critical for successful management of Ebola in remote areas.

Review of Ebola virus infections in domestic animals.

PubMed

Weingartl, H M; Nfon, C; Kobinger, G

2013-01-01

Ebola viruses (EBOV; genus Ebolavirus, family Filoviridae) cause often fatal, hemorrhagic fever in several species of simian primates including human. While fruit bats are considered a natural reservoir, the involvement of other species in the EBOV transmission cycle is unclear, especially for domesticated animals. Dogs and pigs are so far the only domestic animals identified as species that can be infected with EBOV. In 2009 Reston-EBOV was the first EBOV reported to infect swine with indicated transmission to humans; and a survey in Gabon found over 30% seroprevalence for EBOV in dogs during the Ebola outbreak in 2001-2002. While infections in dogs appear to be asymptomatic, pigs experimentally infected with EBOV can develop clinical disease, depending on the virus species and possibly the age of the infected animals. In the experimental settings, pigs can transmit Zaire-Ebola virus to naive pigs and macaques; however, their role during Ebola outbreaks in Africa needs to be clarified. Attempts at virus and antibody detection require as a prerequisite validation of viral RNA and antibody detection methods especially for pigs, as well as the development of a sampling strategy. Significant issues about disease development remain to be resolved for EBOV. Evaluation of current human vaccine candidates or development of veterinary vaccines de novo for EBOV might need to be considered, especially if pigs or dogs are implicated in the transmission of an African species of EBOV to humans.

Ebola Virus: a Clear and Present Danger

PubMed Central

2014-01-01

An epidemic of Ebola virus disease is occurring in Western Africa on a scale not seen before, particularly in the countries of Guinea, Liberia, and Sierra Leone. The continued spread is facilitated by insufficient medical facilities, poor sanitation, travel, and unsafe burial practices. Several patients diagnosed with Ebola virus disease in Africa have been evacuated to the United States for treatment, and several other patients have been diagnosed in the United States. It is important for laboratories to be aware of available tests, especially those granted emergency use authorization, as hospitals prepare protocols for the diagnosis and management of high-risk patients. PMID:25392362

Elucidating variations in the nucleotide sequence of Ebola virus associated with increasing pathogenicity.

PubMed

Dowall, Stuart D; Matthews, David A; Garcia-Dorival, Isabel; Taylor, Irene; Kenny, John; Hertz-Fowler, Christiane; Hall, Neil; Corbin-Lickfett, Kara; Empig, Cyril; Schlunegger, Kyle; Barr, John N; Carroll, Miles W; Hewson, Roger; Hiscox, Julian A

2014-01-01

Ebolaviruses causes a severe and often fatal hemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%. Currently the worst Ebola virus outbreak since the disease was discovered is occurring in West Africa. Although thought to be a zoonotic infection, a concern is that with increasing numbers of humans being infected, Ebola virus variants could be selected which are better adapted for human-to-human transmission. To investigate whether genetic changes in Ebola virus become established in response to adaptation in a different host, a guinea pig model of infection was used. In this experimental system, guinea pigs were infected with Ebola virus (EBOV), which initially did not cause disease. To simulate transmission to uninfected individuals, the virus was serially passaged five times in naive animals. As the virus was passaged, virulence increased and clinical effects were observed in the guinea pig. An RNAseq and consensus mapping approach was then used to evaluate potential nucleotide changes in the Ebola virus genome at each passage. Upon passage in the guinea pig model, EBOV become more virulent, RNA editing and also coding changes in key proteins become established. The data suggest that the initial evolutionary trajectory of EBOV in a new host can lead to a gain in virulence. Given the circumstances of the sustained transmission of EBOV in the current outbreak in West Africa, increases in virulence may be associated with prolonged and uncontrolled epidemics of EBOV.

Structural dissection of Ebola virus and its assembly determinants using cryo-electron tomography.

PubMed

Bharat, Tanmay A M; Noda, Takeshi; Riches, James D; Kraehling, Verena; Kolesnikova, Larissa; Becker, Stephan; Kawaoka, Yoshihiro; Briggs, John A G

2012-03-13

Ebola virus is a highly pathogenic filovirus causing severe hemorrhagic fever with high mortality rates. It assembles heterogenous, filamentous, enveloped virus particles containing a negative-sense, single-stranded RNA genome packaged within a helical nucleocapsid (NC). We have used cryo-electron microscopy and tomography to visualize Ebola virus particles, as well as Ebola virus-like particles, in three dimensions in a near-native state. The NC within the virion forms a left-handed helix with an inner nucleoprotein layer decorated with protruding arms composed of VP24 and VP35. A comparison with the closely related Marburg virus shows that the N-terminal region of nucleoprotein defines the inner diameter of the Ebola virus NC, whereas the RNA genome defines its length. Binding of the nucleoprotein to RNA can assemble a loosely coiled NC-like structure; the loose coil can be condensed by binding of the viral matrix protein VP40 to the C terminus of the nucleoprotein, and rigidified by binding of VP24 and VP35 to alternate copies of the nucleoprotein. Four proteins (NP, VP24, VP35, and VP40) are necessary and sufficient to mediate assembly of an NC with structure, symmetry, variability, and flexibility indistinguishable from that in Ebola virus particles released from infected cells. Together these data provide a structural and architectural description of Ebola virus and define the roles of viral proteins in its structure and assembly.

Ebola virus encodes a miR-155 analog to regulate importin-α5 expression.

PubMed

Liu, Yuanwu; Sun, Jing; Zhang, Hongwen; Wang, Mingming; Gao, George Fu; Li, Xiangdong

2016-10-01

The 2014 outbreak of Ebola virus caused more than 10,000 human deaths. Current knowledge of suitable drugs, clinical diagnostic biomarkers and molecular mechanisms of Ebola virus infection is either absent or insufficient. By screening stem-loop structures from the viral genomes of four virulence species, we identified a novel, putative viral microRNA precursor that is specifically expressed by the Ebola virus. The sequence of the microRNA precursor was further confirmed by mining the existing RNA-Seq database. Two putative mature microRNAs were predicted and subsequently validated in human cell lines. Combined with this prediction of the microRNA target, we identified importin-α5, which is a key regulator of interferon signaling following Ebola virus infection, as one putative target. We speculate that this microRNA could facilitate the evasion of the host immune system by the virus. Moreover, this microRNA might be a potential clinical therapeutic target or a diagnostic biomarker for Ebola virus.

Emergence of Vaccine-Derived Polioviruses during Ebola Virus Disease Outbreak, Guinea, 2014–2015

PubMed Central

Majumdar, Manasi; Kebe, Ousmane; Fall, Aichatou D.; Kone, Moussa; Kande, Mouctar; Dabo, Moustapha; Sylla, Mohamed Salif; Sompare, Djenou; Howard, Wayne; Faye, Ousmane; Martin, Javier; Ndiaye, Kader

2018-01-01

During the 2014–2015 outbreak of Ebola virus disease in Guinea, 13 type 2 circulating vaccine-derived polioviruses (cVDPVs) were isolated from 6 polio patients and 7 healthy contacts. To clarify the genetic properties of cVDPVs and their emergence, we combined epidemiologic and virologic data for polio cases in Guinea. Deviation of public health resources to the Ebola outbreak disrupted polio vaccination programs and surveillance activities, which fueled the spread of neurovirulent VDPVs in an area of low vaccination coverage and immunity. Genetic properties of cVDPVs were consistent with their capacity to cause paralytic disease in humans and capacity for sustained person-to-person transmission. Circulation ceased when coverage of oral polio vaccine increased. A polio outbreak in the context of the Ebola virus disease outbreak highlights the need to consider risks for polio emergence and spread during complex emergencies and urges awareness of the challenges in polio surveillance, vaccination, and diagnosis. PMID:29260690

Towards Detection and Diagnosis of Ebola Virus Disease at Point-of-Care

PubMed Central

Kaushik, Ajeet; Tiwari, Sneham; Jayant, Rahul Dev; Marty, Aileen; Nair, Madhavan

2015-01-01

Ebola outbreak-2014 (mainly Zaire strain related Ebola virus) has been declared most widely spread deadly persistent epidemic due to unavailability of rapid diagnostic, detection, and therapeutics. Ebola virus disease (EVD), a severe viral hemorrhagic fever syndrome caused by Ebola virus (EBOV) is transmitted by direct contact with the body fluids of infected person and objects contaminated with virus or infected animals. World Health Organization (WHO) has declared EVD epidemic as public health emergency of international concern with severe global economic burden. At fatal EBOV infection stage, patients usually die before the antibody response. Currently, rapid blood tests to diagnose EBOV infection include the antigen or antibodies capture using ELISA and RNA detection using RT/Q-PCR within 3–10 days after the onset of symptoms. Moreover, few nanotechnology-based colorimetric and paper-based immunoassay methods have been recently reported to detect Ebola virus. Unfortunately, these methods are limited to laboratory only. As state-of-the art (SoA) diagnostics time to confirm Ebola infection, varies from 6 hours to about 3 days, it causes delay in therapeutic approaches. Thus developing a cost-effective, rapid, sensitive, and selective sensor to detect EVD at point-of-care (POC) is certainly worth exploring to establish rapid diagnostics to decide therapeutics. This review highlights SoA of Ebola diagnostics and also a call to develop rapid, selective and sensitive POC detection of EBOV for global health care. We propose that adopting miniaturized electrochemical EBOV immunosensing can detect virus level at pM concentration within ~40 minute compared to 3 days of ELISA test at nM levels. PMID:26319169

Host Cell Plasma Membrane Phosphatidylserine Regulates the Assembly and Budding of Ebola Virus

PubMed Central

Adu-Gyamfi, Emmanuel; Johnson, Kristen A.; Fraser, Mark E.; Scott, Jordan L.; Soni, Smita P.; Jones, Keaton R.; Digman, Michelle A.; Gratton, Enrico; Tessier, Charles R.

2015-01-01

ABSTRACT Lipid-enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Ebola virus, which buds from the plasma membrane of the host cell, causes viral hemorrhagic fever and has a high fatality rate. To date, little has been known about how budding and egress of Ebola virus are mediated at the plasma membrane. We have found that the lipid phosphatidylserine (PS) regulates the assembly of Ebola virus matrix protein VP40. VP40 binds PS-containing membranes with nanomolar affinity, and binding of PS regulates VP40 localization and oligomerization on the plasma membrane inner leaflet. Further, alteration of PS levels in mammalian cells inhibits assembly and egress of VP40. Notably, interactions of VP40 with the plasma membrane induced exposure of PS on the outer leaflet of the plasma membrane at sites of egress, whereas PS is typically found only on the inner leaflet. Taking the data together, we present a model accounting for the role of plasma membrane PS in assembly of Ebola virus-like particles. IMPORTANCE The lipid-enveloped Ebola virus causes severe infection with a high mortality rate and currently lacks FDA-approved therapeutics or vaccines. Ebola virus harbors just seven genes in its genome, and there is a critical requirement for acquisition of its lipid envelope from the plasma membrane of the human cell that it infects during the replication process. There is, however, a dearth of information available on the required contents of this envelope for egress and subsequent attachment and entry. Here we demonstrate that plasma membrane phosphatidylserine is critical for Ebola virus budding from the host cell plasma membrane. This report, to our knowledge, is the first to highlight the role of lipids in human cell membranes in the Ebola virus replication cycle and draws a clear link between selective binding and transport of a lipid across the membrane of the human cell and use of that lipid for subsequent viral entry. PMID

Host Cell Plasma Membrane Phosphatidylserine Regulates the Assembly and Budding of Ebola Virus.

PubMed

Adu-Gyamfi, Emmanuel; Johnson, Kristen A; Fraser, Mark E; Scott, Jordan L; Soni, Smita P; Jones, Keaton R; Digman, Michelle A; Gratton, Enrico; Tessier, Charles R; Stahelin, Robert V

2015-09-01

Lipid-enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Ebola virus, which buds from the plasma membrane of the host cell, causes viral hemorrhagic fever and has a high fatality rate. To date, little has been known about how budding and egress of Ebola virus are mediated at the plasma membrane. We have found that the lipid phosphatidylserine (PS) regulates the assembly of Ebola virus matrix protein VP40. VP40 binds PS-containing membranes with nanomolar affinity, and binding of PS regulates VP40 localization and oligomerization on the plasma membrane inner leaflet. Further, alteration of PS levels in mammalian cells inhibits assembly and egress of VP40. Notably, interactions of VP40 with the plasma membrane induced exposure of PS on the outer leaflet of the plasma membrane at sites of egress, whereas PS is typically found only on the inner leaflet. Taking the data together, we present a model accounting for the role of plasma membrane PS in assembly of Ebola virus-like particles. The lipid-enveloped Ebola virus causes severe infection with a high mortality rate and currently lacks FDA-approved therapeutics or vaccines. Ebola virus harbors just seven genes in its genome, and there is a critical requirement for acquisition of its lipid envelope from the plasma membrane of the human cell that it infects during the replication process. There is, however, a dearth of information available on the required contents of this envelope for egress and subsequent attachment and entry. Here we demonstrate that plasma membrane phosphatidylserine is critical for Ebola virus budding from the host cell plasma membrane. This report, to our knowledge, is the first to highlight the role of lipids in human cell membranes in the Ebola virus replication cycle and draws a clear link between selective binding and transport of a lipid across the membrane of the human cell and use of that lipid for subsequent viral entry. Copyright © 2015, American

Reemerging Sudan Ebola Virus Disease in Uganda, 2011

PubMed Central

Shoemaker, Trevor; Balinandi, Stephen; Campbell, Shelley; Wamala, Joseph Francis; McMullan, Laura K.; Downing, Robert; Lutwama, Julius; Mbidde, Edward; Ströher, Ute; Rollin, Pierre E.; Nichol, Stuart T.

2012-01-01

Two large outbreaks of Ebola hemorrhagic fever occurred in Uganda in 2000 and 2007. In May 2011, we identified a single case of Sudan Ebola virus disease in Luwero District. The establishment of a permanent in-country laboratory and cooperation between international public health entities facilitated rapid outbreak response and control activities. PMID:22931687

ZMappTM Reinforces the Airway Mucosal Barrier Against Ebola Virus.

PubMed

Yang, Bing; Schaefer, Alison; Wang, Ying-Ying; McCallen, Justin; Lee, Phoebe; Newby, Jay M; Arora, Harendra; Kumar, Priya A; Zeitlin, Larry; Whaley, Kevin J; McKinley, Scott A; Fischer, William A; Harit, Dimple; Lai, Samuel K

2018-04-24

Filoviruses, including Ebola, have the potential to be transmitted via virus-laden droplets deposited onto mucus membranes. Protecting against such emerging pathogens will require understanding how they may transmit at mucosal surfaces and developing strategies to reinforce the airway mucus barrier.Here, we prepared Ebola pseudovirus (with Zaire strain glycoproteins) and employed high resolution multiple particle tracking to track the motions of hundreds of individual pseudoviruses in fresh and undiluted human airway mucus isolated from extubated endotracheal tubes.We found that Ebola pseudovirus readily penetrate human airway mucus. Addition of ZMappTM, a cocktail of Ebola-binding IgG antibodies, effectively reduced mobility of Ebola pseudovirus in the same mucus secretions. Topical delivery of ZMappTM to the mouse airways also facilitated rapid elimination of Ebola pseudovirus.Our work demonstrates that antibodies can immobilize virions in airway mucus and reduce access to the airway epithelium, highlighting topical delivery of pathogen-specific antibodies to the lungs as a potential prophylactic or therapeutic approach against emerging viruses or biowarfare agents.

[The Emergence of Ebola virus in humans: a long process not yet fully understood].

PubMed

Leroy, Éric Maurice

2015-01-01

Since 1976 Ebola virus regularly has caused small deadly outbreaks in Central Africa, usually controlled in a few months. For the first time, an Ebola epidemic of exceptional magnitude dramatically engulfed several countries in West Africa since December 2013. Major failures of implementing measures to prevent human-to-human transmissions are the main cause of this large-scale Ebola outbreak. After about one-week incubation period, the Ebola virus disease is characterized by a sudden onset of high fever leading to multiple hemorrhages and to widespread organ failure. Several bat species constitute the main reservoirs of Ebola viruses. Human contamination would occur either directly from bats, widely consumed by the local populations, or through animal species susceptible to Ebola infection, such as chimpanzees and gorillas. Alongside this "natural cycle", an "epidemic cycle" involving domestic animals living in villages such as dogs or pigs, is seriously suggested. Thus, according to the diversity of concerned animals and their clinical infectionform, modalities of human contamination can be multiple and are still largely unknown. In this context, all efforts that could be made to unravel the mystery of the Ebola virus emergence in humans and clarify modalities of the virus transmission, would allow for predicting or for anticipating the future occurrence of epidemics. This review aims to provide an exhaustive inventory of the Ebola ecology to highlight events governing the virus transmission to humans that still remain unsolved.

Ebola: lessons learned and future challenges for Europe.

PubMed

Quaglio, GianLuca; Goerens, Charles; Putoto, Giovanni; Rübig, Paul; Lafaye, Pierre; Karapiperis, Theodoros; Dario, Claudio; Delaunois, Paul; Zachariah, Rony

2016-02-01

The Ebola virus epidemic has topped media and political agendas for months; several countries in west Africa have faced the worst Ebola epidemic in history. At the beginning of the disease outbreak, European Union (EU) policies were notably absent regarding how to respond to the crisis. Although the epidemic is now receding from public view, this crisis has undoubtedly changed the European public perception of Ebola virus disease, which is no longer regarded as a bizarre entity confined in some unknown corner in Africa. Policy makers and researchers in Europe now have an opportunity to consider the lessons learned. In this Personal View, we discuss the EU's response to the Ebola crisis in west Africa. Unfortunately, although ample resources and opportunities for humanitarian and medical action existed, the EU did not use them to promote a rapid and well coordinated response to the Ebola crisis. Lessons learned from this crisis should be used to improve the role of the EU in similar situations in the future, ensuring that European aid can be effectively deployed to set up an improved emergency response system, and supporting the establishment of sustainable health-care services in west Africa. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clinical development of Ebola vaccines

PubMed Central

Sridhar, Saranya

2015-01-01

The ongoing outbreak of Ebola virus disease in West Africa highlighted the lack of a licensed drug or vaccine to combat the disease and has renewed the urgency to develop a pipeline of Ebola vaccines. A number of different vaccine platforms are being developed by assessing preclinical efficacy in animal models and expediting clinical development. Over 15 different vaccines are in preclinical development and 8 vaccines are now in different stages of clinical evaluation. These vaccines include DNA vaccines, virus-like particles and viral vectors such as live replicating vesicular stomatitis virus (rVSV), human and chimpanzee adenovirus, and vaccinia virus. Recently, in preliminary results reported from the first phase III trial of an Ebola vaccine, the rVSV-vectored vaccine showed promising efficacy. This review charts this rapidly advancing area of research focusing on vaccines in clinical development and discusses the future opportunities and challenges faced in the licensure and deployment of Ebola vaccines. PMID:26668751

Acquisition Challenges of a Lethal Virus

DTIC Science & Technology

2014-10-01

March 23, 2014. Since then it has spread to Sierra Leone and Liberia . As of July 3, 2014, WHO reported 779 clini- cal cases of Ebola virus disease...Health Organization team responding to an Ebola virus outbreak. It’s 1995. “The Hot Zone” tops best-seller lists, and millions of people the world...over are fixated on the threat of incurable “hot” hemorrhagic fever viruses like Ebola . Gruesome depictions of melting skin and oozing blood fill

Virtual screening of the inhibitors targeting at the viral protein 40 of Ebola virus.

PubMed

Karthick, V; Nagasundaram, N; Doss, C George Priya; Chakraborty, Chiranjib; Siva, R; Lu, Aiping; Zhang, Ge; Zhu, Hailong

2016-02-17

The Ebola virus is highly pathogenic and destructive to humans and other primates. The Ebola virus encodes viral protein 40 (VP40), which is highly expressed and regulates the assembly and release of viral particles in the host cell. Because VP40 plays a prominent role in the life cycle of the Ebola virus, it is considered as a key target for antiviral treatment. However, there is currently no FDA-approved drug for treating Ebola virus infection, resulting in an urgent need to develop effective antiviral inhibitors that display good safety profiles in a short duration. This study aimed to screen the effective lead candidate against Ebola infection. First, the lead molecules were filtered based on the docking score. Second, Lipinski rule of five and the other drug likeliness properties are predicted to assess the safety profile of the lead candidates. Finally, molecular dynamics simulations was performed to validate the lead compound. Our results revealed that emodin-8-beta-D-glucoside from the Traditional Chinese Medicine Database (TCMD) represents an active lead candidate that targets the Ebola virus by inhibiting the activity of VP40, and displays good pharmacokinetic properties. This report will considerably assist in the development of the competitive and robust antiviral agents against Ebola infection.

Ebola virus disease: preparedness in Japan.

PubMed

Ashino, Yugo; Chagan-Yasutan, Haorile; Egawa, Shinichi; Hattori, Toshio

2015-02-01

The current outbreak of Ebola virus disease (EVD) is due to a lack of resources, untrained medical personnel, and the specific contact-mediated type of infection of this virus. In Japan's history, education and mass vaccination of the native Ainu people successfully eradicated epidemics of smallpox. Even though a zoonotic virus is hard to control, appropriate precautions and personal protection, as well as anti-symptomatic treatment, will control the outbreak of EVD. Ebola virus utilizes the antibody-dependent enhancement of infection to seed the cells of various organs. The pathogenesis of EVD is due to the cytokine storm of pro-inflammatory cytokines and the lack of antiviral interferon-α2. Matricellular proteins of galectin-9 and osteopontin might also be involved in the edema and abnormality of the coagulation system in EVD. Anti-fibrinolytic treatment will be effective. In the era of globalization, interviews of travelers with fever within 3 weeks of departure from the affected areas will be necessary. Not only the hospitals designated for specific biohazards but every hospital should be aware of the biology of biohazards and establish measures to protect both patients and the community.

Euthanasia assessment in ebola virus infected nonhuman primates.

PubMed

Warren, Travis K; Trefry, John C; Marko, Shannon T; Chance, Taylor B; Wells, Jay B; Pratt, William D; Johnson, Joshua C; Mucker, Eric M; Norris, Sarah L; Chappell, Mark; Dye, John M; Honko, Anna N

2014-11-24

Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts.

Euthanasia Assessment in Ebola Virus Infected Nonhuman Primates

PubMed Central

Warren, Travis K.; Trefry, John C.; Marko, Shannon T.; Chance, Taylor B.; Wells, Jay B.; Pratt, William D.; Johnson, Joshua C.; Mucker, Eric M.; Norris, Sarah L.; Chappell, Mark; Dye, John M.; Honko, Anna N.

2014-01-01

Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts. PMID:25421892

Post-exposure treatment of Ebola virus using passive immunotherapy: proposal for a new strategy.

PubMed

Chippaux, Jean-Philippe; Boyer, Leslie V; Alagón, Alejandro

2015-01-01

Better treatments are urgently needed for the management of Ebola virus epidemics in Equatorial Africa. We conducted a systematic review of the literature on the use of passive immunotherapy for the treatment or prevention of Ebola virus disease. We placed findings from this review into the context of passive immunotherapy currently used for venom-induced disease, and recent improvements in manufacturing of polyvalent antivenom products. Passive immunotherapy appears to be one of the most promising specific treatments for Ebola. However, its potential has been incompletely evaluated, considering the overall experience and recent improvement of immunotherapy. Development and use of heterologous serum derivatives could protect people exposed to Ebola viruses with reasonable cost and logistics. Hyperimmune equine IgG fragments and purified polyclonal whole IgG deserve further consideration as treatment for exposure to the Ebola virus.

[Insufficient Preparation of Ambulatory Physicians for Ebola Virus Disease in Germany].

PubMed

Brekle, Verena; Weiß, Christel; Kolobaric, Zvonimir; Schulz-Weidhaas, Claudia; Vogelmann, Roger

2018-05-22

Globalization and climate change increase the likelihood of a global spread of high consequence infectious diseases. We analyzed how outpatient physicians in Germany were prepared to recognize and handle potential Ebola virus-infected patients during the recent Ebola outbreak in West Africa. Outpatient physicians participated in 2 anonymous surveys (n=166 and 129, respectively) and were asked, among others, about their knowledge of Ebola virus disease, their subjective perception of their own knowledge and the practical implementation in their daily routine. This was compared to a minimum standard defined by 14 members of the German "Permanent Working Group of Competence and Treatment Centres for high consequence infectious diseases" (STAKOB). The Ebola virus-specific knowledge of participants was significantly inferior compared to the defined minimum standard. Of 8 factual questions, an average of merely 5 was answered correctly. The physicians' subjective perception of knowledge presented as 'little'. Although 56% of participants indicated that they had received standard operation procedures, 64% had not implemented them into their daily routine. Merely 22% of surveyed medical doctors participated in Ebola virus-specific education programs. Yet participation led to a significantly better subjective knowledge perception. Contrary to the official assessment that Germany is well prepared for high consequence infectious diseases, this study suggests that there are deficits in this area. Despite the abundance of information about Ebola virus disease, preparation of outpatient physicians in Germany was inadequate. Yet nearly half of the participants indicated the potential risk of occurrence as 'likely' or 'very likely'. The presented data show the different consequences to be drawn regarding potential future crises and further research. © Georg Thieme Verlag KG Stuttgart · New York.

Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material.

PubMed

Trefry, John C; Wollen, Suzanne E; Nasar, Farooq; Shamblin, Joshua D; Kern, Steven J; Bearss, Jeremy J; Jefferson, Michelle A; Chance, Taylor B; Kugelman, Jeffery R; Ladner, Jason T; Honko, Anna N; Kobs, Dean J; Wending, Morgan Q S; Sabourin, Carol L; Pratt, William D; Palacios, Gustavo F; Pitt, M Louise M

2015-12-19

Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein's poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.

Low potential for mechanical transmission of Ebola virus via house flies (Musca domestica)

USDA-ARS?s Scientific Manuscript database

Ebola virus emerged in West Africa in March 2014 and has caused more than 28,000 cases and 11,000 deaths. The unusually high number of cases raised the question as to whether muscid flies could mechanically transmit the virus. Mechanical transmission of Ebola virus was attempted using house flies t...

Nurses leading the fight against Ebola virus disease.

PubMed

Sagar, Priscilla L

2015-05-01

The current Ebola crisis has sparked worldwide reaction of panic and disbelief in its wake as it decimated communities in West Africa, particularly in Guinea, Liberia, and Sierra Leone, including its health care workers. This article affirms the crucial role nurses play in maintaining health and preventing diseases, connects the devastating havoc of the Ebola virus disease to another issue of nursing shortage in underdeveloped countries, and asserts the key leadership nurses play in protecting the communities they serve while maintaining their safety and those of other health care workers. Nurses must actively seek a place at the table, as echoed by the American Academy of Nursing and American Nurses Association and the American Nurses Association, when decisions are being made regarding Ebola virus disease: at care settings, in the board room, and at federal, state, and local levels. © The Author(s) 2015.

Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor.

PubMed

Cui, Qinghua; Du, Ruikun; Anantpadma, Manu; Schafer, Adam; Hou, Lin; Tian, Jingzhen; Davey, Robert A; Cheng, Han; Rong, Lijun

2018-03-27

The recent 2014-2016 West African Ebola virus epidemic underscores the need for the development of novel anti-Ebola therapeutics, due to the high mortality rates of Ebola virus infections and the lack of FDA-approved vaccine or therapy that is available for the prevention and treatment. Traditional Chinese medicines (TCMs) represent a huge reservoir of bioactive chemicals and many TCMs have been shown to have antiviral activities. 373 extracts from 128 TCMs were evaluated using a high throughput assay to screen for inhibitors of Ebola virus cell entry. Extract of Rhodiola rosea displayed specific and potent inhibition against cell entry of both Ebola virus and Marburg virus. In addition, twenty commercial compounds that were isolated from Rhodiola rosea were evaluated using the pseudotyped Ebola virus entry assay, and it was found that ellagic acid and gallic acid, which are two structurally related compounds, are the most effective ones. The activity of the extract and the two pure compounds were validated using infectious Ebola virus. The time-of-addition experiments suggest that, mechanistically, the Rhodiola rosea extract and the effective compounds act at an early step in the infection cycle following initial cell attachment, but prior to viral/cell membrane fusion. Our findings provide evidence that Rhodiola rosea has potent anti-filovirus properties that may be developed as a novel anti-Ebola treatment.

Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor

PubMed Central

Cui, Qinghua; Du, Ruikun; Anantpadma, Manu; Schafer, Adam; Hou, Lin; Tian, Jingzhen; Cheng, Han; Rong, Lijun

2018-01-01

The recent 2014–2016 West African Ebola virus epidemic underscores the need for the development of novel anti-Ebola therapeutics, due to the high mortality rates of Ebola virus infections and the lack of FDA-approved vaccine or therapy that is available for the prevention and treatment. Traditional Chinese medicines (TCMs) represent a huge reservoir of bioactive chemicals and many TCMs have been shown to have antiviral activities. 373 extracts from 128 TCMs were evaluated using a high throughput assay to screen for inhibitors of Ebola virus cell entry. Extract of Rhodiola rosea displayed specific and potent inhibition against cell entry of both Ebola virus and Marburg virus. In addition, twenty commercial compounds that were isolated from Rhodiola rosea were evaluated using the pseudotyped Ebola virus entry assay, and it was found that ellagic acid and gallic acid, which are two structurally related compounds, are the most effective ones. The activity of the extract and the two pure compounds were validated using infectious Ebola virus. The time-of-addition experiments suggest that, mechanistically, the Rhodiola rosea extract and the effective compounds act at an early step in the infection cycle following initial cell attachment, but prior to viral/cell membrane fusion. Our findings provide evidence that Rhodiola rosea has potent anti-filovirus properties that may be developed as a novel anti-Ebola treatment. PMID:29584652

Amino acid mutations in Ebola virus glycoprotein of the 2014 epidemic.

PubMed

Giovanetti, Marta; Grifoni, Alba; Lo Presti, Alessandra; Cella, Eleonora; Montesano, Carla; Zehender, Gianguglielmo; Colizzi, Vittorio; Amicosante, Massimo; Ciccozzi, Massimo

2015-06-01

Zaire Ebola virus (EBOV) is an enveloped non-segmented negative strand RNA virus of 19 kb in length belonging to the family Filoviridae. The virus was isolated and identified in 1976 during the epidemic of hemorrhagic fever in Zaire. The most recent outbreak of EBOV among humans, was that occurred in the forested areas of south eastern Guinea, that began in February 2014 and is still ongoing. The recent Ebola outbreak, is affecting other countries in West Africa, in addiction to Guinea: Liberia, Nigeria, and Sierra Leone. In this article, a selective pressure analysis and homology modeling based on the G Glycoprotein (GP) sequences retrieved from public databases were used to investigate the genetic diversity and modification of antibody response in the recent outbreak of Ebola Virus. Structural and the evolutionary analysis underline the 2014 epidemic virus being under negative selective pressure does not change with respect to the old epidemic in terms of genome adaptation. © 2015 Wiley Periodicals, Inc.

Structure and assembly of the Ebola virus nucleocapsid

PubMed Central

Wan, William; Kolesnikova, Larissa; Clarke, Mairi; Koehler, Alexander; Noda, Takeshi; Becker, Stephan; Briggs, John A. G.

2017-01-01

Ebola and Marburg viruses are filoviruses: filamentous, enveloped viruses that cause hemorrhagic fever1. Filoviruses are within the order Mononegavirales2 which also includes rabies virus, measles virus, and respiratory syncytial virus. Mononegaviruses have non-segmented, single-stranded negative-sense RNA genomes that are encapsidated by nucleoprotein (NP) and other viral proteins to form a helical nucleocapsid (NC). NC acts as a scaffold for virus assembly and as a template for genome transcription and replication. Insights into NP-NP interactions have been derived from structural studies of oligomerized, RNA-encapsidating NP3–6 and cryo-electron microscopy (cryo-EM) of NC7–12 or NC-like structures11–13. There have been no high-resolution reconstructions of complete mononegavirus NCs. Here, we have applied cryo-electron tomography and subtomogram averaging to determine the structure of Ebola virus NC within intact viruses and recombinant NC-like assemblies. These structures reveal the identity and arrangement of the NC components, and suggest that the formation of an extended alpha-helix from the disordered C-terminal region of NP-core links NP oligomerization, NC condensation, RNA encapsidation, and accessory protein recruitment. PMID:29144446

Lack of protection against ebola virus from chloroquine in mice and hamsters.

PubMed

Falzarano, Darryl; Safronetz, David; Prescott, Joseph; Marzi, Andrea; Feldmann, Friederike; Feldmann, Heinz

2015-06-01

The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes.

Study of Ebola Virus Disease Survivors in Guinea.

PubMed

Qureshi, Adnan I; Chughtai, Morad; Loua, Tokpagnan Oscar; Pe Kolie, Jean; Camara, Hadja Fatou Sikhe; Ishfaq, Muhammad Fawad; N'Dour, Cheikh Tidane; Beavogui, Kezely

2015-10-01

There is a paucity of data regarding health consequences of Ebola virus disease among survivors. We surveyed 105 Ebola virus disease survivors postdischarge from an Ebola treatment unit in Guinea using a standard data collection form. Patients rated recovery as the percentage of improvement in functional status, where 0% represents "unable to perform" and 100% represents "able to perform at prior level." The mean ± standard deviation time interval between hospital discharge and administration of questionnaire was 103.5 ± 47.9 days in 105 survivors. Anorexia was reported by 103 patients, with varying severity levels: mild (n = 33), moderate (n = 65), or severe (n = 5). Reported pain according to site was chest (30.7%), joint (86.7%), muscle (26.7%), and back (45.7%), among others. Recovery in functional status was graded as mild (10%-30%) (n = 2 [1.9%]), moderate (40%-70%) (n = 52 [50.0%]), and excellent (80%-100%) (n = 50 [48.1%]). Severity of arthralgia (R(2) = 0.09; P = .008) was directly associated with lower recovery in functional status in multivariate analysis. Ebola virus disease survivors frequently reported anorexia and arthralgia. Severity of arthralgia was related to lower functional recovery. There may be a role for focused screening and intervention for symptoms identified in this study of survivors. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Rapid Detection of Ebola Virus with a Reagent-Free, Point-of-Care Biosensor

PubMed Central

Baca, Justin T.; Severns, Virginia; Lovato, Debbie; Branch, Darren W.; Larson, Richard S.

2015-01-01

Surface acoustic wave (SAW) sensors can rapidly detect Ebola antigens at the point-of-care without the need for added reagents, sample processing, or specialized personnel. This preliminary study demonstrates SAW biosensor detection of the Ebola virus in a concentration-dependent manner. The detection limit with this methodology is below the average level of viremia detected on the first day of symptoms by PCR. We observe a log-linear sensor response for highly fragmented Ebola viral particles, with a detection limit corresponding to 1.9 × 104 PFU/mL prior to virus inactivation. We predict greatly improved sensitivity for intact, infectious Ebola virus. This point-of-care methodology has the potential to detect Ebola viremia prior to symptom onset, greatly enabling infection control and rapid treatment. This biosensor platform is powered by disposable AA batteries and can be rapidly adapted to detect other emerging diseases in austere conditions. PMID:25875186

Clinical presentation and management of severe Ebola virus disease.

PubMed

West, T Eoin; von Saint André-von Arnim, Amélie

2014-11-01

Clinicians caring for patients infected with Ebola virus must be familiar not only with screening and infection control measures but also with management of severe disease. By integrating experience from several Ebola epidemics with best practices for managing critical illness, this report focuses on the clinical presentation and management of severely ill infants, children, and adults with Ebola virus disease. Fever, fatigue, vomiting, diarrhea, and anorexia are the most common symptoms of the 2014 West African outbreak. Profound fluid losses from the gastrointestinal tract result in volume depletion, metabolic abnormalities (including hyponatremia, hypokalemia, and hypocalcemia), shock, and organ failure. Overt hemorrhage occurs infrequently. The case fatality rate in West Africa is at least 70%, and individuals with respiratory, neurological, or hemorrhagic symptoms have a higher risk of death. There is no proven antiviral agent to treat Ebola virus disease, although several experimental treatments may be considered. Even in the absence of antiviral therapies, intensive supportive care has the potential to markedly blunt the high case fatality rate reported to date. Optimal treatment requires conscientious correction of fluid and electrolyte losses. Additional management considerations include searching for coinfection or superinfection; treatment of shock (with intravenous fluids and vasoactive agents), acute kidney injury (with renal replacement therapy), and respiratory failure (with invasive mechanical ventilation); provision of nutrition support, pain and anxiety control, and psychosocial support; and the use of strategies to reduce complications of critical illness. Cardiopulmonary resuscitation may be appropriate in certain circumstances, but extracorporeal life support is not advised. Among other ethical issues, patients' medical needs must be carefully weighed against healthcare worker safety and infection control concerns. However, meticulous attention

The Pathogenesis of Ebola Virus Disease.

PubMed

Baseler, Laura; Chertow, Daniel S; Johnson, Karl M; Feldmann, Heinz; Morens, David M

2017-01-24

For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations.

Distinguishing epidemiological features of the 2013–2016 West Africa Ebola virus disease outbreak

PubMed Central

Shultz, James M.; Espinel, Zelde; Espinola, Maria; Rechkemmer, Andreas

2016-01-01

ABSTRACT The 2013–2016 West Africa Ebola virus disease epidemic was notable for its scope, scale, and complexity. This briefing presents a series of distinguishing epidemiological features that set this outbreak apart. Compared to one concurrent and 23 previous outbreaks of the disease over 40 years, this was the only occurrence of Ebola virus disease involving multiple nations and qualifying as a pandemic. Across multiple measures of magnitude, the 2013–2016 outbreak was accurately described using superlatives: largest and deadliest in terms of numbers of cases and fatalities; longest in duration; and most widely dispersed geographically, with outbreak-associated cases occurring in 10 nations. In contrast, the case-fatality rate was much lower for the 2013–2016 outbreak compared to the other 24 outbreaks. A population of particular interest for ongoing monitoring and public health surveillance is comprised of more than 17,000 “survivors,” Ebola patients who successfully recovered from their illness. The daunting challenges posed by this outbreak were met by an intensive international public health response. The near-exponential rate of increase of incident Ebola cases during mid-2014 was successfully slowed, reversed, and finally halted through the application of multiple disease containment and intervention strategies. PMID:28229017

Development of Potential Small Molecule Therapeutics for Treatment of Ebola Virus.

PubMed

Schafer, Adam Michael; Cheng, Han; Lee, Charles; Du, Ruikun; Han, Julianna; Perez, Jasmine; Peet, Norton; Manicassamy, Balaji; Rong, Lijun

2017-10-10

Ebola virus has caused 26 outbreaks in 10 different countries since its identification in 1976, making it one of the deadliest emerging viral pathogens. The most recent outbreak in West Africa from 2014-16 was the deadliest yet and culminated in 11,310 deaths out of 28,616 confirmed cases. Currently there are no FDA-approved therapeutics or vaccines to treat Ebola virus infections. The slow development of effective vaccines combined with the severity of past outbreaks emphasizes the need to accelerate research into understanding the virus lifecycle and the development of therapeutics for post exposure treatment. Here we present a summary of the major findings on the Ebola virus replication cycle and the therapeutic approaches explored to treat this devastating disease. The major focus of this review is on small molecule inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

How Ebola and Marburg viruses battle the immune system.

PubMed

Mohamadzadeh, Mansour; Chen, Lieping; Schmaljohn, Alan L

2007-07-01

The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself.

Ebola Virus Imported from Guinea to Senegal, 2014.

PubMed

Ka, Daye; Fall, Gamou; Diallo, Viviane Cissé; Faye, Ousmane; Fortes, Louise Deguenonvo; Faye, Oumar; Bah, Elhadji Ibrahim; Diallo, Kadia Mbaye; Balique, Fanny; Ndour, Cheikh Tidiane; Seydi, Moussa; Sall, Amadou Alpha

2017-06-01

In March 2014, the World Health Organization declared an outbreak of Ebola virus disease in Guinea. In August 2014, a case caused by virus imported from Guinea occurred in Senegal, most likely resulting from nonsecure funerals and travel. Preparedness and surveillance in Senegal probably prevented secondary cases.

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

PubMed Central

Kash, John C.; Walters, Kathie-Anne; Kindrachuk, Jason; Baxter, David; Scherler, Kelsey; Janosko, Krisztina B.; Adams, Rick D.; Herbert, Andrew S.; James, Rebekah M.; Stonier, Spencer W.; Memoli, Matthew J.; Dye, John M.; Davey, Richard T.; Chertow, Daniel S.; Taubenberger, Jeffery K.

2017-01-01

The 2013–2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration–approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance. PMID:28404864

Rapid detection of Ebola virus with a reagent-free, point-of-care biosensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baca, Justin T.; Severns, Virginia; Lovato, Debbie

Surface acoustic wave (SAW) sensors can rapidly detect Ebola antigens at the point-of-care without the need for added reagents, sample processing, or specialized personnel. This preliminary study demonstrates SAW biosensor detection of the Ebola virus in a concentration-dependent manner. The detection limit with this methodology is below the average level of viremia detected on the first day of symptoms by PCR. We observe a log-linear sensor response for highly fragmented Ebola viral particles, with a detection limit corresponding to 1.9 × 10⁴ PFU/mL prior to virus inactivation. We predict greatly improved sensitivity for intact, infectious Ebola virus. This point-of-care methodologymore » has the potential to detect Ebola viremia prior to symptom onset, greatly enabling infection control and rapid treatment. This biosensor platform is powered by disposable AA batteries and can be rapidly adapted to detect other emerging diseases in austere conditions.« less

Rapid detection of Ebola virus with a reagent-free, point-of-care biosensor

DOE PAGES

Baca, Justin T.; Severns, Virginia; Lovato, Debbie; ...

2015-04-14

Surface acoustic wave (SAW) sensors can rapidly detect Ebola antigens at the point-of-care without the need for added reagents, sample processing, or specialized personnel. This preliminary study demonstrates SAW biosensor detection of the Ebola virus in a concentration-dependent manner. The detection limit with this methodology is below the average level of viremia detected on the first day of symptoms by PCR. We observe a log-linear sensor response for highly fragmented Ebola viral particles, with a detection limit corresponding to 1.9 × 10⁴ PFU/mL prior to virus inactivation. We predict greatly improved sensitivity for intact, infectious Ebola virus. This point-of-care methodologymore » has the potential to detect Ebola viremia prior to symptom onset, greatly enabling infection control and rapid treatment. This biosensor platform is powered by disposable AA batteries and can be rapidly adapted to detect other emerging diseases in austere conditions.« less

On revealing the gene targets of Ebola virus microRNAs involved in the human skin microbiome.

PubMed

Hsu, Pei-Chun; Chiou, Bin-Hao; Huang, Chun-Ming

2018-01-01

Ebola virus, a negative-sense single-stranded RNA virus, causes severe viral hemorrhagic fever and has a high mortality rate. Histopathological and immunopathological analyses of Ebola virus have revealed that histopathological changes in skin tissue are associated with various degrees of endothelial cell swelling and necrosis. The interactions of microbes within or on a host are a crucial for the skin immune shield. The discovery of microRNAs (miRNAs) in Ebola virus implies that immune escape, endothelial cell rupture, and tissue dissolution during Ebola virus infection are a result of the effects of Ebola virus miRNAs. Keratinocytes obtained from normal skin can attach and spread through expression of the thrombospondin family of proteins, playing a role in initiation of cell-mediated immune responses in the skin. Several miRNAs have been shown to bind the 3' untranslated region of thrombospondin mRNA, thereby controlling its stability and translational activity. In this study, we discovered short RNA sequences that may act as miRNAs from Propionibacterium acnes using a practical workflow of bioinformatics methods. Subsequently, we deciphered the common target gene. These RNA sequences tended to bind to the same thrombospondin protein, THSD4, emphasizing the potential importance of the synergistic binding of miRNAs from Ebola virus, Propionibacterium acnes , and humans to the target. These results provide important insights into the molecular mechanisms of thrombospondin proteins and miRNAs in Ebola virus infection.

Persistent infection with ebola virus under conditions of partial immunity.

PubMed

Gupta, Manisha; Mahanty, Siddhartha; Greer, Patricia; Towner, Jonathan S; Shieh, Wun-Ju; Zaki, Sherif R; Ahmed, Rafi; Rollin, Pierre E

2004-01-01

Ebola hemorrhagic fever in humans is associated with high mortality; however, some infected hosts clear the virus and recover. The mechanisms by which this occurs and the correlates of protective immunity are not well defined. Using a mouse model, we determined the role of the immune system in clearance of and protection against Ebola virus. All CD8 T-cell-deficient mice succumbed to subcutaneous infection and had high viral antigen titers in tissues, whereas mice deficient in B cells or CD4 T cells cleared infection and survived, suggesting that CD8 T cells, independent of CD4 T cells and antibodies, are critical to protection against subcutaneous Ebola virus infection. B-cell-deficient mice that survived the primary subcutaneous infection (vaccinated mice) transiently depleted or not depleted of CD4 T cells also survived lethal intraperitoneal rechallenge for >/==" BORDER="0">25 days. However, all vaccinated B-cell-deficient mice depleted of CD8 T cells had high viral antigen titers in tissues following intraperitoneal rechallenge and died within 6 days, suggesting that memory CD8 T cells by themselves can protect mice from early death. Surprisingly, vaccinated B-cell-deficient mice, after initially clearing the infection, were found to have viral antigens in tissues later (day 120 to 150 post-intraperitoneal infection). Furthermore, following intraperitoneal rechallenge, vaccinated B-cell-deficient mice that were transiently depleted of CD4 T cells had high levels of viral antigen in tissues earlier (days 50 to 70) than vaccinated undepleted mice. This demonstrates that under certain immunodeficiency conditions, Ebola virus can persist and that loss of primed CD4 T cells accelerates the course of persistent infections. These data show that CD8 T cells play an important role in protection against acute disease, while both CD4 T cells and antibodies are required for long-term protection, and they provide evidence of persistent infection by Ebola virus suggesting

Epidemiology of the Ebola Virus: Facts and Hypotheses.

PubMed

Portela Câmara F

1998-12-01

Marburg and Ebola viruses are emerging pathogens recognized since 1967, and in 1976, when they were first identified. These viruses are the only members of the Filoviridae family. They cause severe, frequently fatal, hemorrhagic fever. Each genus includes some serotypes with the distinctive characteristics to cause high mortality rate during outbreaks. The Ebola-Zaire subtype is the most lethal variant. The epidemiology of human pathogenic filovirus is reviewed in this paper considering the most relevant facts. Primary human cases arise probably through close contact with infected primates. This point may be the key to preventing the introduction of these viruses in human populations. Once introduced in humans, the infection may spread through close contact with infected individuals or their body fluids, particularly in hospital environments. A main feature of filovirus outbreaks is the occurrence of cycles of secondary infection.

Immune Protection of Nonhuman Primates against Ebola Virus with Single Low-Dose Adenovirus Vectors Encoding Modified GPs

PubMed Central

Geisbert, Joan B; Shedlock, Devon J; Xu, Ling; Lamoreaux, Laurie; Custers, Jerome H. H. V; Popernack, Paul M; Yang, Zhi-Yong; Pau, Maria G; Roederer, Mario; Koup, Richard A; Goudsmit, Jaap; Jahrling, Peter B; Nabel, Gary J

2006-01-01

Background Ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. In the absence of effective therapies for Ebola virus infection, the development of a vaccine becomes an important strategy to contain outbreaks. Immunization with DNA and/or replication-defective adenoviral vectors (rAd) encoding the Ebola glycoprotein (GP) and nucleoprotein (NP) has been previously shown to confer specific protective immunity in nonhuman primates. GP can exert cytopathic effects on transfected cells in vitro, and multiple GP forms have been identified in nature, raising the question of which would be optimal for a human vaccine. Methods and Findings To address this question, we have explored the efficacy of mutant GPs from multiple Ebola virus strains with reduced in vitro cytopathicity and analyzed their protective effects in the primate challenge model, with or without NP. Deletion of the GP transmembrane domain eliminated in vitro cytopathicity but reduced its protective efficacy by at least one order of magnitude. In contrast, a point mutation was identified that abolished this cytopathicity but retained immunogenicity and conferred immune protection in the absence of NP. The minimal effective rAd dose was established at 1010 particles, two logs lower than that used previously. Conclusions Expression of specific GPs alone vectored by rAd are sufficient to confer protection against lethal challenge in a relevant nonhuman primate model. Elimination of NP from the vaccine and dose reductions to 1010 rAd particles do not diminish protection and simplify the vaccine, providing the basis for selection of a human vaccine candidate. PMID:16683867

Ebola Virus Imported from Guinea to Senegal, 2014

PubMed Central

Ka, Daye; Fall, Gamou; Diallo, Viviane Cissé; Fortes, Louise Deguenonvo; Faye, Oumar; Bah, Elhadji Ibrahim; Diallo, Kadia Mbaye; Balique, Fanny; Ndour, Cheikh Tidiane; Seydi, Moussa; Sall, Amadou Alpha

2017-01-01

In March 2014, the World Health Organization declared an outbreak of Ebola virus disease in Guinea. In August 2014, a case caused by virus imported from Guinea occurred in Senegal, most likely resulting from nonsecure funerals and travel. Preparedness and surveillance in Senegal probably prevented secondary cases. PMID:28518019

Operational Research during the Ebola Emergency.

PubMed

Fitzpatrick, Gabriel; Decroo, Tom; Draguez, Bertrand; Crestani, Rosa; Ronsse, Axelle; Van den Bergh, Rafael; Van Herp, Michel

2017-07-01

Operational research aims to identify interventions, strategies, or tools that can enhance the quality, effectiveness, or coverage of programs where the research is taking place. Médecins Sans Frontières admitted ≈5,200 patients with confirmed Ebola virus disease during the Ebola outbreak in West Africa and from the beginning nested operational research within its emergency response. This research covered critical areas, such as understanding how the virus spreads, clinical trials, community perceptions, challenges within Ebola treatment centers, and negative effects on non-Ebola healthcare. Importantly, operational research questions were decided to a large extent by returning volunteers who had first-hand knowledge of the immediate issues facing teams in the field. Such a method is appropriate for an emergency medical organization. Many challenges were also identified while carrying out operational research across 3 different countries, including the basic need for collecting data in standardized format to enable comparison of findings among treatment centers.

Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material

PubMed Central

Trefry, John C.; Wollen, Suzanne E.; Nasar, Farooq; Shamblin, Joshua D.; Kern, Steven J.; Bearss, Jeremy J.; Jefferson, Michelle A.; Chance, Taylor B.; Kugelman, Jeffery R.; Ladner, Jason T.; Honko, Anna N.; Kobs, Dean J.; Wending, Morgan Q.S.; Sabourin, Carol L.; Pratt, William D.; Palacios, Gustavo F.; Pitt, M. Louise M.

2015-01-01

Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein’s poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed; however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations. PMID:26703716

Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

PubMed

Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

2015-01-01

Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD. © 2015 The Author(s) Published by S. Karger AG, Basel.

Recombinant Modified Vaccinia Virus Ankara Generating Ebola Virus-Like Particles.

PubMed

Schweneker, Marc; Laimbacher, Andrea S; Zimmer, Gert; Wagner, Susanne; Schraner, Elisabeth M; Wolferstätter, Michael; Klingenberg, Marieken; Dirmeier, Ulrike; Steigerwald, Robin; Lauterbach, Henning; Hochrein, Hubertus; Chaplin, Paul; Suter, Mark; Hausmann, Jürgen

2017-06-01

There are currently no approved therapeutics or vaccines to treat or protect against the severe hemorrhagic fever and death caused by Ebola virus (EBOV). Ebola virus-like particles (EBOV VLPs) consisting of the matrix protein VP40, the glycoprotein (GP), and the nucleoprotein (NP) are highly immunogenic and protective in nonhuman primates against Ebola virus disease (EVD). We have constructed a modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN) recombinant coexpressing VP40 and GP of EBOV Mayinga and the NP of Taï Forest virus (TAFV) (MVA-BN-EBOV-VLP) to launch noninfectious EBOV VLPs as a second vaccine modality in the MVA-BN-EBOV-VLP-vaccinated organism. Human cells infected with either MVA-BN-EBOV-VLP or MVA-BN-EBOV-GP showed comparable GP expression levels and transport of complex N-glycosylated GP to the cell surface. Human cells infected with MVA-BN-EBOV-VLP produced large amounts of EBOV VLPs that were decorated with GP spikes but excluded the poxviral membrane protein B5, thus resembling authentic EBOV particles. The heterologous TAFV NP enhanced EBOV VP40-driven VLP formation with efficiency similar to that of the homologous EBOV NP in a transient-expression assay, and both NPs were incorporated into EBOV VLPs. EBOV GP-specific CD8 T cell responses were comparable between MVA-BN-EBOV-VLP- and MVA-BN-EBOV-GP-immunized mice. The levels of EBOV GP-specific neutralizing and binding antibodies, as well as GP-specific IgG1/IgG2a ratios induced by the two constructs, in mice were also similar, raising the question whether the quality rather than the quantity of the GP-specific antibody response might be altered by an EBOV VLP-generating MVA recombinant. IMPORTANCE The recent outbreak of Ebola virus (EBOV), claiming more than 11,000 lives, has underscored the need to advance the development of safe and effective filovirus vaccines. Virus-like particles (VLPs), as well as recombinant viral vectors, have proved to be promising vaccine candidates. Modified

Laboratory diagnosis of Ebola virus disease and corresponding biosafety considerations in the China Ebola Treatment Center.

PubMed

Huang, Qing; Fu, Wei-Ling; You, Jian-Ping; Mao, Qing

2016-10-01

Ebola virus disease (EVD), caused by Ebola virus (EBOV), is a potent acute infectious disease with a high case-fatality rate. Etiological and serological EBOV detection methods, including techniques that involve the detection of the viral genome, virus-specific antigens and anti-virus antibodies, are standard laboratory diagnostic tests that facilitate confirmation or exclusion of EBOV infection. In addition, routine blood tests, liver and kidney function tests, electrolytes and coagulation tests and other diagnostic examinations are important for the clinical diagnosis and treatment of EVD. Because of the viral load in body fluids and secretions from EVD patients, all body fluids are highly contagious. As a result, biosafety control measures during the collection, transport and testing of clinical specimens obtained from individuals scheduled to undergo EBOV infection testing (including suspected, probable and confirmed cases) are crucial. This report has been generated following extensive work experience in the China Ebola Treatment Center (ETC) in Liberia and incorporates important information pertaining to relevant diagnostic standards, clinical significance, operational procedures, safety controls and other issues related to laboratory testing of EVD. Relevant opinions and suggestions are presented in this report to provide contextual awareness associated with the development of standards and/or guidelines related to EVD laboratory testing.

Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing.

PubMed

Shrivastava-Ranjan, Punya; Flint, Mike; Bergeron, Éric; McElroy, Anita K; Chatterjee, Payel; Albariño, César G; Nichol, Stuart T; Spiropoulou, Christina F

2018-05-01

Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD. IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune

Immune barriers of Ebola virus infection.

PubMed

McElroy, Anita K; Mühlberger, Elke; Muñoz-Fontela, César

2018-02-01

Since its initial emergence in 1976 in northern Democratic Republic of Congo (DRC), Ebola virus (EBOV) has been a global health concern due to its virulence in humans, the mystery surrounding the identity of its host reservoir and the unpredictable nature of Ebola virus disease (EVD) outbreaks. Early after the first clinical descriptions of a disease resembling a 'septic-shock-like syndrome', with coagulation abnormalities and multi-system organ failure, researchers began to evaluate the role of the host immune response in EVD pathophysiology. In this review, we summarize how data gathered during the last 40 years in the laboratory as well as in the field have provided insight into EBOV immunity. From molecular mechanisms involved in EBOV recognition in infected cells, to antigen processing and adaptive immune responses, we discuss current knowledge on the main immune barriers of infection as well as outstanding research questions. Copyright © 2018 Elsevier B.V. All rights reserved.

Knowledge and attitude towards Ebola and Marburg virus diseases in Uganda using quantitative and participatory epidemiology techniques

PubMed Central

Skjerve, Eystein; Nabadda, Daisy; Sitali, Doreen Chilolo; Mumba, Chisoni; Mwiine, Frank N.; Lutwama, Julius J.; Balinandi, Stephen; Shoemaker, Trevor; Kankya, Clovice

2017-01-01

Background Uganda has reported five (5) Ebola virus disease outbreaks and three (3) Marburg virus disease outbreaks from 2000 to 2016. Peoples’ knowledge and attitude towards Ebola and Marburg virus disease impact on control and prevention measures especially during outbreaks. We describe knowledge and attitude towards Ebola and Marburg virus outbreaks in two affected communities in Uganda to inform future outbreak responses and help in the design of health education and communication messages. Methods The study was a community survey done in Luweero, Ibanda and Kamwenge districts that have experienced outbreaks of Ebola and Marburg virus diseases. Quantitative data were collected using a structured questionnaire and triangulated with qualitative participatory epidemiology techniques to gain a communities’ knowledge and attitude towards Ebola and Marburg virus disease. Results Out of 740 respondents, 48.5% (359/740) were categorized as being knowledgeable about Ebola and Marburg virus diseases, whereas 60.5% (448/740) were having a positive attitude towards control and prevention of Ebola and Marburg virus diseases. The mean knowledge and attitude percentage scores were 54.3 (SD = 23.5, 95%CI = 52.6–56.0) and 69.9 (SD = 16.9, 95%CI = 68.9–71.1) respectively. People educated beyond primary school were more likely to be knowledgeable about Ebola and Marburg virus disease than those who did not attain any formal education (OR = 3.6, 95%CI = 2.1–6.1). Qualitative data revealed that communities describe Ebola and Marburg virus diseases as very severe diseases with no cure and they believe the diseases spread so fast. Respondents reported fear and stigma suffered by survivors, their families and the broader community due to these diseases. Conclusion Communities in Uganda affected by filovirus outbreaks have moderate knowledge about these diseases and have a positive attitude towards practices to prevent and control Ebola and Marburg viral diseases. The public

Knowledge and attitude towards Ebola and Marburg virus diseases in Uganda using quantitative and participatory epidemiology techniques.

PubMed

Nyakarahuka, Luke; Skjerve, Eystein; Nabadda, Daisy; Sitali, Doreen Chilolo; Mumba, Chisoni; Mwiine, Frank N; Lutwama, Julius J; Balinandi, Stephen; Shoemaker, Trevor; Kankya, Clovice

2017-09-01

Uganda has reported five (5) Ebola virus disease outbreaks and three (3) Marburg virus disease outbreaks from 2000 to 2016. Peoples' knowledge and attitude towards Ebola and Marburg virus disease impact on control and prevention measures especially during outbreaks. We describe knowledge and attitude towards Ebola and Marburg virus outbreaks in two affected communities in Uganda to inform future outbreak responses and help in the design of health education and communication messages. The study was a community survey done in Luweero, Ibanda and Kamwenge districts that have experienced outbreaks of Ebola and Marburg virus diseases. Quantitative data were collected using a structured questionnaire and triangulated with qualitative participatory epidemiology techniques to gain a communities' knowledge and attitude towards Ebola and Marburg virus disease. Out of 740 respondents, 48.5% (359/740) were categorized as being knowledgeable about Ebola and Marburg virus diseases, whereas 60.5% (448/740) were having a positive attitude towards control and prevention of Ebola and Marburg virus diseases. The mean knowledge and attitude percentage scores were 54.3 (SD = 23.5, 95%CI = 52.6-56.0) and 69.9 (SD = 16.9, 95%CI = 68.9-71.1) respectively. People educated beyond primary school were more likely to be knowledgeable about Ebola and Marburg virus disease than those who did not attain any formal education (OR = 3.6, 95%CI = 2.1-6.1). Qualitative data revealed that communities describe Ebola and Marburg virus diseases as very severe diseases with no cure and they believe the diseases spread so fast. Respondents reported fear and stigma suffered by survivors, their families and the broader community due to these diseases. Communities in Uganda affected by filovirus outbreaks have moderate knowledge about these diseases and have a positive attitude towards practices to prevent and control Ebola and Marburg viral diseases. The public health sector should enhance this community

Cytotoxic T lymphocytes to Ebola Zaire virus are induced in mice by immunization with liposomes containing lipid A.

PubMed

Rao, M; Matyas, G R; Grieder, F; Anderson, K; Jahrling, P B; Alving, C R

1999-08-06

An eight amino acid sequence (TELRTFSI) present in the carboxy terminal end (aa 577-584) of membrane-anchored GP, the major structural protein of Ebola virus, was identified as an H-2k-specific murine cytotoxic T cell epitope. Cytotoxic T lymphocytes (CTLs) to this epitope were induced by immunizing B10.BR mice intravenously with either irradiated Ebola virus or with irradiated Ebola virus encapsulated in liposomes containing lipid A. The CTL response induced by irradiated Ebola virus could not be sustained after the second round of in vitro stimulation of immune splenocytes with the peptide, unless the irradiated virus was encapsulated in liposomes containing lipid A. The identification of an Ebola GP-specific CTL epitope and the requirement of liposomal lipid A for CTL memory recall responses could prove to be a promising approach for developing a vaccine against Ebola virus infection.

Amiodarone affects Ebola virus binding and entry into target cells.

PubMed

Salata, Cristiano; Munegato, Denis; Martelli, Francesco; Parolin, Cristina; Calistri, Arianna; Baritussio, Aldo; Palù, Giorgio

2018-03-02

Ebola Virus Disease is one of the most lethal transmissible infections characterized by a high fatality rate. Several research studies have aimed to identify effective antiviral agents. Amiodarone, a drug used for the treatment of arrhythmias, has been shown to inhibit filovirus infection in vitro by acting at the early step of the viral replication cycle. Here we demonstrate that amiodarone reduces virus binding to target cells and slows down the progression of the viral particles along the endocytic pathway. Overall our data support the notion that amiodarone interferes with Ebola virus infection by affecting cellular pathways/targets involved in the viral entry process.

Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection

PubMed Central

Kroeker, Andrea; He, Shihua; Kozak, Robert; Audet, Jonathan; Mbikay, Majambu

2016-01-01

Ebola outbreaks occur on a frequent basis, with the 2014-2015 outbreak in West Africa being the largest one ever recorded. This outbreak has resulted in over 11,000 deaths in four African countries and has received international attention and intervention. Although there are currently no approved therapies or vaccines, many promising candidates are undergoing clinical trials, and several have had success in promoting recovery from Ebola. However, these prophylactics and therapeutics have been designed and tested only against the same species of Ebola virus as the one causing the current outbreak. Future outbreaks involving other species would require reformulation and possibly redevelopment. Therefore, a broad-spectrum alternative is highly desirable. We have found that a flavonoid derivative called quercetin 3-β-O-d-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection. Furthermore, we have demonstrated that this compound targets the early steps of viral entry. Most promisingly, antiviral activity against two distinct species of Ebola virus was seen. This study serves as a proof of principle that Q3G has potential as a prophylactic against Ebola virus infection. PMID:27297486

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

PubMed Central

Sobarzo, Ariel; Perelman, Eddie; Groseth, Allison; Dolnik, Olga; Becker, Stephan; Lutwama, Julius Julian; Dye, John M.; Yavelsky, Victoria; Marks, Robert S.

2012-01-01

Ebolavirus, a member of the family Filoviridae, causes high lethality in humans and nonhuman primates. Research focused on protection and therapy for Ebola virus infection has investigated the potential role of antibodies. Recent evidence suggests that antibodies can be effective in protection from lethal challenge with Ebola virus in nonhuman primates. However, despite these encouraging results, studies have not yet determined the optimal antibodies and composition of an antibody cocktail, if required, which might serve as a highly effective and efficient prophylactic. To better understand optimal antibodies and their targets, which might be important for protection from Ebola virus infection, we sought to determine the profile of viral protein-specific antibodies generated during a natural cycle of infection in humans. To this end, we characterized the profile of antibodies against individual viral proteins of Sudan Ebola virus (Gulu) in human survivors and nonsurvivors of the outbreak in Gulu, Uganda, in 2000-2001. We developed a unique chemiluminescence enzyme-linked immunosorbent assay (ELISA) for this purpose based on the full-length recombinant viral proteins NP, VP30, and VP40 and two recombinant forms of the viral glycoprotein (GP1-294 and GP1-649) of Sudan Ebola virus (Gulu). Screening results revealed that the greatest immunoreactivity was directed to the viral proteins NP and GP1-649, followed by VP40. Comparison of positive immunoreactivity between the viral proteins NP, GP1-649, and VP40 demonstrated a high correlation of immunoreactivity between these viral proteins, which is also linked with survival. Overall, our studies of the profile of immunorecognition of antibodies against four viral proteins of Sudan Ebola virus in human survivors may facilitate development of effective monoclonal antibody cocktails in the future. PMID:22993411

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease.

PubMed

Kash, John C; Walters, Kathie-Anne; Kindrachuk, Jason; Baxter, David; Scherler, Kelsey; Janosko, Krisztina B; Adams, Rick D; Herbert, Andrew S; James, Rebekah M; Stonier, Spencer W; Memoli, Matthew J; Dye, John M; Davey, Richard T; Chertow, Daniel S; Taubenberger, Jeffery K

2017-04-12

The 2013-2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration-approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance. Copyright © 2017, American Association for the Advancement of Science.

[Research progress on ebola virus glycoprotein].

PubMed

Ding, Guo-Yong; Wang, Zhi-Yu; Gao, Lu; Jiang, Bao-Fa

2013-03-01

Ebola virus (EBOV) causes outbreaks of a highly lethal hemorrhagic fever in humans and there are no effective therapeutic or prophylactic treatments available. The glycoprotein (GP) of EBOV is a transmembrane envelope protein known to play multiple functions including virus attachment and entry, cell rounding and cytotoxicity, down-regulation of host surface proteins, and enhancement of virus assembly and budding. GP is the primary target of protective immunity and the key target for developing neutralizing antibodies. In this paper, the research progress on genetic structure, pathogenesis and immunogenicity of EBOV GP in the last 5 years is reviewed.

Development of Lentivirus-Based Reference Materials for Ebola Virus Nucleic Acid Amplification Technology-Based Assays.

PubMed

Mattiuzzo, Giada; Ashall, James; Doris, Kathryn S; MacLellan-Gibson, Kirsty; Nicolson, Carolyn; Wilkinson, Dianna E; Harvey, Ruth; Almond, Neil; Anderson, Robert; Efstathiou, Stacey; Minor, Philip D; Page, Mark

2015-01-01

The 2013-present Ebola virus outbreak in Western Africa has prompted the production of many diagnostic assays, mostly based on nucleic acid amplification technologies (NAT). The calibration and performance assessment of established assays and those under evaluation requires reference materials that can be used in parallel with the clinical sample to standardise or control for every step of the procedure, from extraction to the final qualitative/quantitative result. We have developed safe and stable Ebola virus RNA reference materials by encapsidating anti sense viral RNA into HIV-1-like particles. The lentiviral particles are replication-deficient and non-infectious due to the lack of HIV-1 genes and Envelope protein. Ebola virus genes were subcloned for encapsidation into two lentiviral preparations, one containing NP-VP35-GP and the other VP40 and L RNA. Each reference material was formulated as a high-titre standard for use as a calibrator for secondary or internal standards, and a 10,000-fold lower titre preparation to serve as an in-run control. The preparations have been freeze-dried to maximise stability. These HIV-Ebola virus RNA reference materials were suitable for use with in-house and commercial quantitative RT-PCR assays and with digital RT-PCR. The HIV-Ebola virus RNA reference materials are stable at up to 37°C for two weeks, allowing the shipment of the material worldwide at ambient temperature. These results support further evaluation of the HIV-Ebola virus RNA reference materials as part of an International collaborative study for the establishment of the 1st International Standard for Ebola virus RNA.

Prospects for immunisation against Marburg and Ebola viruses.

PubMed

Geisbert, Thomas W; Bausch, Daniel G; Feldmann, Heinz

2010-11-01

For more than 30 years the filoviruses, Marburg virus and Ebola virus, have been associated with periodic outbreaks of hemorrhagic fever that produce severe and often fatal disease. The filoviruses are endemic primarily in resource-poor regions in Central Africa and are also potential agents of bioterrorism. Although no vaccines or antiviral drugs for Marburg or Ebola are currently available, remarkable progress has been made over the last decade in developing candidate preventive vaccines against filoviruses in nonhuman primate models. Due to the generally remote locations of filovirus outbreaks, a single-injection vaccine is desirable. Among the prospective vaccines that have shown efficacy in nonhuman primate models of filoviral hemorrhagic fever, two candidates, one based on a replication-defective adenovirus serotype 5 and the other on a recombinant VSV (rVSV), were shown to provide complete protection to nonhuman primates when administered as a single injection. The rVSV-based vaccine has also shown utility when administered for postexposure prophylaxis against filovirus infections. A VSV-based Ebola vaccine was recently used to manage a potential laboratory exposure. 2010 John Wiley & Sons, Ltd.

High-Dose Mannose-Binding Lectin Therapy for Ebola Virus Infection

DTIC Science & Technology

2010-06-01

viruses . N-glycosylation of viral envelopes is an important such target shared between in- fluenza, HIV, HCV, West Nile virus , SARS-CoV, Hendra virus ...host cells. Therefore, MBL preferentially recognizes glycosylated viruses including influenza virus , human immunodeficiency virus , severe acute...respiratory syndrome coronovirus (SARS-CoV), Ebola virus , and Marburg virus . It also recognizes many glycosylated gram- positive and gram-negative bacteria [1

A Comparison of Personal Protective Standards: Caring for Patients With Ebola Virus.

PubMed

Franklin, Sativa Michelle

2016-01-01

The purpose of this article is to discuss the variance in requirements for personal protective equipment (PPE) used among healthcare workers to treat patients actively infected with the Ebola virus in West Africa. The Ebola virus is a highly contagious disease, which has killed 11020 people within the past year. In order to combat the disease and treat those with active infections, healthcare workers are required to use PPE. The guidelines for the PPE, in addition to the requirements of what should be worn, are varied between the World Health Organization (WHO) and the Centers for Disease Control and Prevention. A military unit was composed of sister services (Army, Navy, and Air Force) deployed to Monrovia, Liberia, to assist in mitigating the devastating effects of the Ebola virus. Each service member was taught PPE standards according to the WHO and were assigned to teach healthcare workers from around the world on how to manage the care of patients infected with the Ebola virus, while simultaneously taking diligent precautions to protect themselves against the deadly disease. More than 1500 healthcare workers were instructed on the latest PPE standards before they entered into the Ebola treatment units (ETUs) that were being constructed in Liberia. Cumulative death rates from the Ebola virus in Liberia increased from 2413 in October 2014 to 3686 by January 2015. The rapid decline in Ebola mortality is multifactorial. The efforts of US military medical personnel likely were a contributing factor in this rapid decline as those international health workers were afforded the latest in PPE training with strict attention to detail. US military medical personnel, in concert with other governmental agencies, created a potent force multiplier in the efforts to curb this deadly infection. The educational initiative was essential to the slowdown in the spread of the Ebola virus in Liberia. Recommendations for a detailed review of the PPE standards and variances in

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease.

PubMed

Kozak, Robert; He, Shihua; Kroeker, Andrea; de La Vega, Marc-Antoine; Audet, Jonathan; Wong, Gary; Urfano, Chantel; Antonation, Kym; Embury-Hyatt, Carissa; Kobinger, Gary P; Qiu, Xiangguo

2016-10-15

Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

PubMed Central

Kozak, Robert; He, Shihua; Kroeker, Andrea; de La Vega, Marc-Antoine; Audet, Jonathan; Wong, Gary; Urfano, Chantel; Antonation, Kym; Embury-Hyatt, Carissa; Kobinger, Gary P.

2016-01-01

ABSTRACT Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCE The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such

Support services for survivors of ebola virus disease - Sierra Leone, 2014.

PubMed

Lee-Kwan, Seung Hee; DeLuca, Nickolas; Adams, Monica; Dalling, Matthew; Drevlow, Elizabeth; Gassama, Gladys; Davies, Tina

2014-12-19

As of December 6, 2014, Sierra Leone reported 6,317 laboratory-confirmed cases of Ebola virus disease (Ebola), the highest number of reported cases in the current West Africa epidemic. The Sierra Leone Ministry of Health and Sanitation reported that as of December 6, 2014, there were 1,181 persons who had survived and were discharged. Survivors from previous Ebola outbreaks have reported major barriers to resuming normal lives after release from treatment, such as emotional distress, health issues, loss of possessions, and difficulty regaining their livelihoods. In August 2014, a knowledge, attitude, and practice survey regarding the Ebola outbreak in Sierra Leone, administered by a consortium of partners that included the Ministry of Health and Sanitation, UNICEF, CDC, and a local nongovernmental organization, Focus 1000, found that 96% of the general population respondents reported some discriminatory attitude towards persons with suspected or known Ebola. Access to increased psychosocial support, provision of goods, and family and community reunification programs might reduce these barriers. Survivors also have unique potential to contribute to the Ebola response, particularly because survivors might have some immunity to the same virus strain. In previous outbreaks, survivors served as burial team members, contact tracers, and community educators promoting messages that seeking treatment improves the chances for survival and that persons who survived Ebola can help their communities. As caregivers in Ebola treatment units, survivors have encouraged patients to stay hydrated and eat and inspired them to believe that they, too, can survive. Survivors regaining livelihood through participation in the response might offset the stigma associated with Ebola.

[Ebola and Marburg hemorrhagic fever viruses: update on filoviruses].

PubMed

Leroy, E; Baize, S; Gonzalez, J P

2011-04-01

The Ebola and Marburg viruses are the sole members of the Filoviridae family of viruses. They are characterized by a long filamentous form that is unique in the viral world. Filoviruses are among the most virulent pathogens currently known to infect humans. They cause fulminating disease characterized by acute fever followed by generalized hemorrhagic syndrome that is associated with 90% mortality in the most severe forms. Epidemic outbreaks of Marburg and Ebola viruses have taken a heavy toll on human life in Central Africa and devastated large ape populations in Gabon and Republic of Congo. Since their discovery in 1967 (Marburg) and 1976 (Ebola), more than 2,300 cases and 1,670 deaths have been reported. These numbers pale in comparison with the burden caused by malnutrition or other infectious disease scourges in Africa such as malaria, cholera, AIDS, dengue or tuberculosis. However, due to their extremely high lethality, association with multifocal hemorrhaging and specificity to the African continent, these hemorrhagic fever viruses have given rise to great interest on the part not only of the international scientific community but also of the general public because of their perceived potential as biological weapons. Much research has been performed on these viruses and major progress has been made in knowledge of their ecology, epidemiology and physiopathology and in development of vaccine candidates and therapeutic schemes. The purpose of this review is to present the main developments in these particular fields in the last decade.

Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: a case-series of health-care workers.

PubMed

Jacobs, Michael; Aarons, Emma; Bhagani, Sanjay; Buchanan, Ruaridh; Cropley, Ian; Hopkins, Susan; Lester, Rebecca; Martin, Daniel; Marshall, Neal; Mepham, Stephen; Warren, Simon; Rodger, Alison

2015-11-01

Although a few international health-care workers who have assisted in the current Ebola outbreak in west Africa have been medically evacuated for treatment of Ebola virus disease, more commonly they were evacuated after potential accidental exposure to Ebola virus. An urgent need exists for a consensus about the risk assessment of Ebola virus transmission after accidental exposure, and to investigate the use of post-exposure prophylaxis (PEP). Experimental vaccines have occasionally been used for Ebola PEP, but newly developed experimental antiviral agents have potential advantages. Here, we describe a new method for risk assessment and management of health-care workers potentially exposed to Ebola virus and report the use of experimental antiviral therapies for Ebola PEP in people. We devised a risk assessment and management algorithm for health-care workers potentially exposed to Ebola virus and applied this to eight consecutive individuals who were medically evacuated to the UK from west Africa between January, and March, 2015. PEP with antiviral agents was given to health-care workers assessed to have had substantial risk exposures to Ebola virus. Participants were followed up for 42 days after potential exposure. Four of eight health-care workers were classified as having had low risk exposures and managed by watchful waiting in the community. None of these health-care workers developed Ebola virus disease. The other four health-care workers had intermediate or maximum risk exposures and were given PEP with antiviral agents. PEP was well tolerated with no serious adverse effects. None of these four health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, developed Ebola virus disease. Standardised risk assessment should be adopted and consensus guidelines developed to systematically study the efficacy and safety of PEP with experimental agents. New experimental antiviral treatments are a

Secondary Infections with Ebola Virus in Rural Communities, Liberia and Guinea, 2014-2015.

PubMed

Lindblade, Kim A; Nyenswah, Tolbert; Keita, Sakoba; Diallo, Boubakar; Kateh, Francis; Amoah, Aurora; Nagbe, Thomas K; Raghunathan, Pratima; Neatherlin, John C; Kinzer, Mike; Pillai, Satish K; Attfield, Kathleen R; Hajjeh, Rana; Dweh, Emmanuel; Painter, John; Barradas, Danielle T; Williams, Seymour G; Blackley, David J; Kirking, Hannah L; Patel, Monita R; Dea, Monica; Massoudi, Mehran S; Barskey, Albert E; Zarecki, Shauna L Mettee; Fomba, Moses; Grube, Steven; Belcher, Lisa; Broyles, Laura N; Maxwell, T Nikki; Hagan, Jose E; Yeoman, Kristin; Westercamp, Matthew; Mott, Joshua; Mahoney, Frank; Slutsker, Laurence; DeCock, Kevin M; Marston, Barbara; Dahl, Benjamin

2016-09-01

Persons who died of Ebola virus disease at home in rural communities in Liberia and Guinea resulted in more secondary infections than persons admitted to Ebola treatment units. Intensified monitoring of contacts of persons who died of this disease in the community is an evidence-based approach to reduce virus transmission in rural communities.

Infection and Activation of Monocytes by Marburg and Ebola Viruses

PubMed Central

Ströher, Ute; West, Elmar; Bugany, Harald; Klenk, Hans-Dieter; Schnittler, Hans-Joachim; Feldmann, Heinz

2001-01-01

In this study we investigated the effects of Marburg virus and Ebola virus (species Zaire and Reston) infections on freshly isolated suspended monocytes in comparison to adherent macrophages under culture conditions. Our data showed that monocytes are permissive for both filoviruses. As is the case in macrophages, infection resulted in the activation of monocytes which was largely independent of virus replication. The activation was triggered similarly by Marburg and Ebola viruses, species Zaire and Reston, as indicated by the release of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6 as well as the chemokines IL-8 and gro-α. Our data suggest that infected monocytes may play an important role in the spread of filoviruses and in the pathogenesis of filoviral hemorrhagic disease. PMID:11602743

Positive evolution of the glycoprotein (GP) gene is related to transmission of the Ebola virus.

PubMed

Jing, Y X; Wang, L N; Wu, X M; Song, C X

2016-03-28

Ebola hemorrhagic fever is a fatal disease caused by the negative-strand RNA of the Ebola virus. A high-intensity outbreak of this fever was reported in West Africa last year; however, there is currently no definitive treatment strategy available for this disease. In this study, we analyzed the molecular evolutionary history and attempted to determine the positive selection sites in the Ebola genes using multiple-genomic sequences of the various Ebola virus subtypes, in order to gain greater clarity into the evolution of the virus and its various subtypes. Only the glycoprotein (GP) gene was positively selected among the 8 Ebola genes, with the other genes remaining in the purification stage. The positive selection sites in the GP gene were identified by a random-site model; these sites were found to be located in the mucin-like region, which is associated with transmembrane protein binding. Additionally, different branches of the phylogenetic tree displayed different positive sites, which in turn was responsible for differences in the cell adhesion ability of the virus. In conclusion, the pattern of positive sites in the GP gene is associated with the epidemiology and prevalence of Ebola in different areas.

Factors Underlying Ebola Virus Infection Among Health Workers, Kenema, Sierra Leone, 2014-2015.

PubMed

Senga, Mikiko; Pringle, Kimberly; Ramsay, Andrew; Brett-Major, David M; Fowler, Robert A; French, Issa; Vandi, Mohamed; Sellu, Josephine; Pratt, Christian; Saidu, Josephine; Shindo, Nahoko; Bausch, Daniel G

2016-08-15

Ebola virus disease (EVD) in health workers (HWs) has been a major challenge during the 2014-2015 outbreak. We examined factors associated with Ebola virus exposure and mortality in HWs in Kenema District, Sierra Leone. We analyzed data from the Sierra Leone National Viral Hemorrhagic Fever Database, contact tracing records, Kenema Government Hospital (KGH) staff and Ebola Treatment Unit (ETU) rosters, and burial logs. From May 2014 through January 2015, 600 cases of EVD originated in Kenema District, including 92 (15%) HWs, 66 (72%) of whom worked at KGH. Among KGH medical staff and international volunteers, 18 of 62 (29%) who worked in the ETU developed EVD, compared with 48 of 83 (58%) who worked elsewhere in the hospital. Thirteen percent of HWs with EVD reported contact with EVD patients, while 27% reported contact with other infected HWs. The number of HW EVD cases at KGH declined roughly 1 month after implementation of a new triage system at KGH and the opening of a second ETU within the district. The case fatality ratio for HWs and non-HWs with EVD was 69% and 74%, respectively. The cluster of HW EVD cases in Kenema District is one of the largest ever reported. Most HWs with EVD had potential virus exposure both inside and outside of hospitals. Prevention measures for HWs must address a spectrum of infection risks in both formal and informal care settings as well as in the community. © 2016 World Health Organization; licensee Oxford Journals.

Ebola virus outbreak, updates on current therapeutic strategies.

PubMed

Elshabrawy, Hatem A; Erickson, Timothy B; Prabhakar, Bellur S

2015-07-01

Filoviruses are enveloped negative-sense single-stranded RNA viruses, which include Ebola and Marburg viruses, known to cause hemorrhagic fever in humans with a case fatality of up to 90%. There have been several Ebola virus outbreaks since the first outbreak in the Democratic Republic of Congo in 1976 of which, the recent 2013-2015 epidemic in Guinea, Liberia, and Sierra Leone is the largest in recorded history. Within a few months of the start of the outbreak in December 2013, thousands of infected cases were reported with a significant number of deaths. As of March 2015, according to the Centers for Disease Control and Prevention, there have been nearly 25,000 suspected cases, with 15,000 confirmed by laboratory testing, and over 10,000 deaths. The large number of cases and the high mortality rate, combined with the lack of effective Food and Drug Administration-approved treatments, necessitate the development of potent and safe therapeutic measures to combat the current and future outbreaks. Since the beginning of the outbreak, there have been considerable efforts to develop and characterize protective measures including vaccines and antiviral small molecules, and some have proven effective in vitro and in animal models. Most recently, a cocktail of monoclonal antibodies has been shown to be highly effective in protecting non-human primates from Ebola virus infection. In this review, we will discuss what is known about the nature of the virus, phylogenetic classification, genomic organization and replication, disease transmission, and viral entry and highlight the current approaches and efforts, in the development of therapeutics, to control the outbreak. Copyright © 2015 John Wiley & Sons, Ltd.

Prevention of sexual transmission of Ebola in Liberia through a national semen testing and counselling programme for survivors: an analysis of Ebola virus RNA results and behavioural data.

PubMed

Soka, Moses J; Choi, Mary J; Baller, April; White, Stephen; Rogers, Emerson; Purpura, Lawrence J; Mahmoud, Nuha; Wasunna, Christine; Massaquoi, Moses; Abad, Neetu; Kollie, Jomah; Dweh, Straker; Bemah, Philip K; Christie, Athalia; Ladele, Victor; Subah, Oneykachi C; Pillai, Satish; Mugisha, Margaret; Kpaka, Jonathan; Kowalewski, Stephen; German, Emilio; Stenger, Mark; Nichol, Stuart; Ströher, Ute; Vanderende, Kristin E; Zarecki, Shauna Mettee; Green, Hugh Henry W; Bailey, Jeffrey A; Rollin, Pierre; Marston, Barbara; Nyenswah, Tolbert G; Gasasira, Alex; Knust, Barbara; Williams, Desmond

2016-10-01

Ebola virus has been detected in semen of Ebola virus disease survivors after recovery. Liberia's Men's Health Screening Program (MHSP) offers Ebola virus disease survivors semen testing for Ebola virus. We present preliminary results and behavioural outcomes from the first national semen testing programme for Ebola virus. The MHSP operates out of three locations in Liberia: Redemption Hospital in Montserrado County, Phebe Hospital in Bong County, and Tellewoyan Hospital in Lofa County. Men aged 15 years and older who had an Ebola treatment unit discharge certificate are eligible for inclusion. Participants' semen samples were tested for Ebola virus RNA by real-time RT-PCR and participants received counselling on safe sexual practices. Participants graduated after receiving two consecutive negative semen tests. Counsellors collected information on sociodemographics and sexual behaviours using questionnaires administered at enrolment, follow up, and graduation visits. Because the programme is ongoing, data analysis was restricted to data obtained from July 7, 2015, to May 6, 2016. As of May 6, 2016, 466 Ebola virus disease survivors had enrolled in the programme; real-time RT-PCR results were available from 429 participants. 38 participants (9%) produced at least one semen specimen that tested positive for Ebola virus RNA. Of these, 24 (63%) provided semen specimens that tested positive 12 months or longer after Ebola virus disease recovery. The longest interval between discharge from an Ebola treatment unit and collection of a positive semen sample was 565 days. Among participants who enrolled and provided specimens more than 90 days since their Ebola treatment unit discharge, men older than 40 years were more likely to have a semen sample test positive than were men aged 40 years or younger (p=0·0004). 84 (74%) of 113 participants who reported not using a condom at enrolment reported using condoms at their first follow-up visit (p<0·0001). 176 (46%) of 385

Effective Chemical Inactivation of Ebola Virus

PubMed Central

Haddock, Elaine; Feldmann, Friederike

2016-01-01

Reliable inactivation of specimens before removal from high-level biocontainment is crucial for safe operation. To evaluate efficacy of methods of chemical inactivation, we compared in vitro and in vivo approaches using Ebola virus as a surrogate pathogen. Consequently, we have established parameters and protocols leading to reliable and effective inactivation. PMID:27070504

Ebola Virus Disease, Democratic Republic of the Congo, 2014.

PubMed

Nanclares, Carolina; Kapetshi, Jimmy; Lionetto, Fanshen; de la Rosa, Olimpia; Tamfun, Jean-Jacques Muyembe; Alia, Miriam; Kobinger, Gary; Bernasconi, Andrea

2016-09-01

During July-November 2014, the Democratic Republic of the Congo underwent its seventh Ebola virus disease (EVD) outbreak. The etiologic agent was Zaire Ebola virus; 66 cases were reported (overall case-fatality rate 74.2%). Through a retrospective observational study of confirmed EVD in 25 patients admitted to either of 2 Ebola treatment centers, we described clinical features and investigated correlates associated with death. Clinical features were mainly generic. At admission, 76% of patients had >1 gastrointestinal symptom and 28% >1 hemorrhagic symptom. The case-fatality rate in this group was 48% and was higher for female patients (67%). Cox regression analysis correlated death with initial low cycle threshold, indicating high viral load. Cycle threshold was a robust predictor of death, as were fever, hiccups, diarrhea, dyspnea, dehydration, disorientation, hematemesis, bloody feces during hospitalization, and anorexia in recent medical history. Differences from other outbreaks could suggest guidance for optimizing clinical management and disease control.

Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine.

PubMed

Zhou, Yan; Sullivan, Nancy J

2015-08-01

The 2014 Ebola virus outbreak caused an order of magnitude more deaths in a single outbreak than all previous known outbreaks combined, affecting both local and international public health, and threatening the security and economic stability of the countries in West Africa directly confronting the outbreak. The severity of the epidemic lead to a global response to assist with patient care, outbreak control, and deployment of vaccines. The latter was possible due to the long history of basic and clinical research aimed at identifying a safe and effective vaccine to protect against Ebola virus infection. This review highlights the immunology, development, and progress of vaccines based on replication-defective adenovirus vectors, culminating in the successful launch of the first Phase III trial of an Ebola virus vaccine. Published by Elsevier Ltd.

Determining the effect of different environmental conditions on Ebola virus viability in clinically relevant specimens.

PubMed

Palyi, Bernadett; Magyar, Nora; Henczko, Judit; Szalai, Balint; Farkas, Agnes; Strecker, Thomas; Takacs, Maria; Kis, Zoltan

2018-03-29

In 2013-2016, West Africa experienced the largest and longest Ebola virus disease outbreak ever documented. The wide geographic spread and magnitude of the outbreak often limited the timely and rapid testing of diagnostic samples from patients with suspected Ebola virus disease, raising questions regarding the optimal storage and shipping conditions of clinically relevant specimens, including EDTA-whole blood, plasma, capillary blood, urine and seminal fluid (associated with sexual transmission of the Ebola virus after recovery from the disease). Therefore, the aim of our study was to identify the extent to which storage temperature and clinical specimen type influence Ebola virus viability. Virus infectivity was determined using a fluorescent focus-forming assay. In our study, we show that Ebola virus was the most stable in EDTA-whole blood and plasma samples, whereas rapid decay of infectivity was observed in simulated capillary blood, urine and semen samples, especially when these samples were stored at higher temperatures. The analysis of variance results demonstrated that both temperature and clinical specimen type have significant effects on virus viability, whereas donor differences were not observed. Repeated freeze and thaw cycles of the samples also had a notable impact on virus viability in EDTA-whole blood and urine. Due to the rapid temperature- and specimen-dependent degradation of the virus observed here, our study highlights the importance of proper clinical sample storage at low temperatures during transportation and laboratory analysis.

Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection.

PubMed

Qiu, Xiangguo; Kroeker, Andrea; He, Shihua; Kozak, Robert; Audet, Jonathan; Mbikay, Majambu; Chrétien, Michel

2016-09-01

Ebola outbreaks occur on a frequent basis, with the 2014-2015 outbreak in West Africa being the largest one ever recorded. This outbreak has resulted in over 11,000 deaths in four African countries and has received international attention and intervention. Although there are currently no approved therapies or vaccines, many promising candidates are undergoing clinical trials, and several have had success in promoting recovery from Ebola. However, these prophylactics and therapeutics have been designed and tested only against the same species of Ebola virus as the one causing the current outbreak. Future outbreaks involving other species would require reformulation and possibly redevelopment. Therefore, a broad-spectrum alternative is highly desirable. We have found that a flavonoid derivative called quercetin 3-β-O-d-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection. Furthermore, we have demonstrated that this compound targets the early steps of viral entry. Most promisingly, antiviral activity against two distinct species of Ebola virus was seen. This study serves as a proof of principle that Q3G has potential as a prophylactic against Ebola virus infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Spatial localization of the Ebola virus glycoprotein mucin-like domain determined by cryo-electron tomography.

PubMed

Tran, Erin E H; Simmons, James A; Bartesaghi, Alberto; Shoemaker, Charles J; Nelson, Elizabeth; White, Judith M; Subramaniam, Sriram

2014-09-01

The Ebola virus glycoprotein mucin-like domain (MLD) is implicated in Ebola virus cell entry and immune evasion. Using cryo-electron tomography of Ebola virus-like particles, we determined a three-dimensional structure for the full-length glycoprotein in a near-native state and compared it to that of a glycoprotein lacking the MLD. Our results, which show that the MLD is located at the apex and the sides of each glycoprotein monomer, provide a structural template for analysis of MLD function. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Dynamic Phosphorylation of VP30 Is Essential for Ebola Virus Life Cycle.

PubMed

Biedenkopf, Nadine; Lier, Clemens; Becker, Stephan

2016-05-15

Ebola virus is the causative agent of a severe fever with high fatality rates in humans and nonhuman primates. The regulation of Ebola virus transcription and replication currently is not well understood. An important factor regulating viral transcription is VP30, an Ebola virus-specific transcription factor associated with the viral nucleocapsid. Previous studies revealed that the phosphorylation status of VP30 impacts viral transcription. Together with NP, L, and the polymerase cofactor VP35, nonphosphorylated VP30 supports viral transcription. Upon VP30 phosphorylation, viral transcription ceases. Phosphorylation weakens the interaction between VP30 and the polymerase cofactor VP35 and/or the viral RNA. VP30 thereby is excluded from the viral transcription complex, simultaneously leading to increased viral replication which is supported by NP, L, and VP35 alone. Here, we use an infectious virus-like particle assay and recombinant viruses to show that the dynamic phosphorylation of VP30 is critical for the cotransport of VP30 with nucleocapsids to the sites of viral RNA synthesis, where VP30 is required to initiate primary viral transcription. We further demonstrate that a single serine residue at amino acid position 29 was sufficient to render VP30 active in primary transcription and to generate a recombinant virus with characteristics comparable to those of wild-type virus. In contrast, the rescue of a recombinant virus with a single serine at position 30 in VP30 was unsuccessful. Our results indicate critical roles for phosphorylated and dephosphorylated VP30 during the viral life cycle. The current Ebola virus outbreak in West Africa has caused more than 28,000 cases and 11,000 fatalities. Very little is known regarding the molecular mechanisms of how the Ebola virus transcribes and replicates its genome. Previous investigations showed that the transcriptional support activity of VP30 is activated upon VP30 dephosphorylation. The current study reveals that

Virus genomes reveal factors that spread and sustained the Ebola epidemic.

PubMed

Dudas, Gytis; Carvalho, Luiz Max; Bedford, Trevor; Tatem, Andrew J; Baele, Guy; Faria, Nuno R; Park, Daniel J; Ladner, Jason T; Arias, Armando; Asogun, Danny; Bielejec, Filip; Caddy, Sarah L; Cotten, Matthew; D'Ambrozio, Jonathan; Dellicour, Simon; Di Caro, Antonino; Diclaro, Joseph W; Duraffour, Sophie; Elmore, Michael J; Fakoli, Lawrence S; Faye, Ousmane; Gilbert, Merle L; Gevao, Sahr M; Gire, Stephen; Gladden-Young, Adrianne; Gnirke, Andreas; Goba, Augustine; Grant, Donald S; Haagmans, Bart L; Hiscox, Julian A; Jah, Umaru; Kugelman, Jeffrey R; Liu, Di; Lu, Jia; Malboeuf, Christine M; Mate, Suzanne; Matthews, David A; Matranga, Christian B; Meredith, Luke W; Qu, James; Quick, Joshua; Pas, Suzan D; Phan, My V T; Pollakis, Georgios; Reusken, Chantal B; Sanchez-Lockhart, Mariano; Schaffner, Stephen F; Schieffelin, John S; Sealfon, Rachel S; Simon-Loriere, Etienne; Smits, Saskia L; Stoecker, Kilian; Thorne, Lucy; Tobin, Ekaete Alice; Vandi, Mohamed A; Watson, Simon J; West, Kendra; Whitmer, Shannon; Wiley, Michael R; Winnicki, Sarah M; Wohl, Shirlee; Wölfel, Roman; Yozwiak, Nathan L; Andersen, Kristian G; Blyden, Sylvia O; Bolay, Fatorma; Carroll, Miles W; Dahn, Bernice; Diallo, Boubacar; Formenty, Pierre; Fraser, Christophe; Gao, George F; Garry, Robert F; Goodfellow, Ian; Günther, Stephan; Happi, Christian T; Holmes, Edward C; Kargbo, Brima; Keïta, Sakoba; Kellam, Paul; Koopmans, Marion P G; Kuhn, Jens H; Loman, Nicholas J; Magassouba, N'Faly; Naidoo, Dhamari; Nichol, Stuart T; Nyenswah, Tolbert; Palacios, Gustavo; Pybus, Oliver G; Sabeti, Pardis C; Sall, Amadou; Ströher, Ute; Wurie, Isatta; Suchard, Marc A; Lemey, Philippe; Rambaut, Andrew

2017-04-20

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.

Virus genomes reveal factors that spread and sustained the Ebola epidemic

PubMed Central

Dudas, Gytis; Carvalho, Luiz Max; Bedford, Trevor; Tatem, Andrew J.; Baele, Guy; Faria, Nuno R.; Park, Daniel J.; Ladner, Jason T.; Arias, Armando; Asogun, Danny; Bielejec, Filip; Caddy, Sarah L.; Cotten, Matthew; D’Ambrozio, Jonathan; Dellicour, Simon; Di Caro, Antonino; Diclaro, JosephW.; Duraffour, Sophie; Elmore, Michael J.; Fakoli, Lawrence S.; Faye, Ousmane; Gilbert, Merle L.; Gevao, Sahr M.; Gire, Stephen; Gladden-Young, Adrianne; Gnirke, Andreas; Goba, Augustine; Grant, Donald S.; Haagmans, Bart L.; Hiscox, Julian A.; Jah, Umaru; Kargbo, Brima; Kugelman, Jeffrey R.; Liu, Di; Lu, Jia; Malboeuf, Christine M.; Mate, Suzanne; Matthews, David A.; Matranga, Christian B.; Meredith, Luke W.; Qu, James; Quick, Joshua; Pas, Suzan D.; Phan, My VT; Pollakis, Georgios; Reusken, Chantal B.; Sanchez-Lockhart, Mariano; Schaffner, Stephen F.; Schieffelin, John S.; Sealfon, Rachel S.; Simon-Loriere, Etienne; Smits, Saskia L.; Stoecker, Kilian; Thorne, Lucy; Tobin, Ekaete Alice; Vandi, Mohamed A.; Watson, Simon J.; West, Kendra; Whitmer, Shannon; Wiley, Michael R.; Winnicki, Sarah M.; Wohl, Shirlee; Wölfel, Roman; Yozwiak, Nathan L.; Andersen, Kristian G.; Blyden, Sylvia O.; Bolay, Fatorma; Carroll, MilesW.; Dahn, Bernice; Diallo, Boubacar; Formenty, Pierre; Fraser, Christophe; Gao, George F.; Garry, Robert F.; Goodfellow, Ian; Günther, Stephan; Happi, Christian T.; Holmes, Edward C.; Kargbo, Brima; Keïta, Sakoba; Kellam, Paul; Koopmans, Marion P. G.; Kuhn, Jens H.; Loman, Nicholas J.; Magassouba, N’Faly; Naidoo, Dhamari; Nichol, Stuart T.; Nyenswah, Tolbert; Palacios, Gustavo; Pybus, Oliver G.; Sabeti, Pardis C.; Sall, Amadou; Ströher, Ute; Wurie, Isatta; Suchard, Marc A.; Lemey, Philippe; Rambaut, Andrew

2017-01-01

The 2013–2016 epidemic of Ebola virus disease was of unprecedented magnitude, duration and impact. Analysing 1610 Ebola virus genomes, representing over 5% of known cases, we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic ‘gravity’ model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already set the seeds for an international epidemic, rendering these measures ineffective in curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing they were susceptible to significant outbreaks but at lower risk of introductions. Finally, we reveal this large epidemic to be a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help inform interventions in future epidemics. PMID:28405027

Preventive malaria treatment for contacts of patients with Ebola virus disease in the context of the west Africa 2014-15 Ebola virus disease response: an economic analysis.

PubMed

Carias, Cristina; Greening, Bradford; Campbell, Caresse G; Meltzer, Martin I; Hamel, Mary J

2016-04-01

After the detection of an Ebola virus disease outbreak in west Africa in 2014, one of the elements of the response was to contact trace and isolate patients in specialised Ebola treatment units (ETUs) at onset of fever. We aimed to assess the economic feasibility of administering preventive malaria treatment to all contacts of patients with Ebola virus disease, to prevent the onset of febrile malaria and subsequent admission to ETUs. We used a decision tree model to analyse the costs of preventive malaria treatment (artemisinin-based combination treatment [ACT]) for all contacts of patients with Ebola virus disease (in terms of administration and averted ETU-stay costs) and benefits (in terms of averted ETU admissions) in west Africa, from a health-care provider perspective. The period of analyses was 1 year, which is roughly similar to the duration of the 2014-15 west Africa Ebola outbreak response. We calculated the intervention's cost per ETU admission averted (average cost-effectiveness ratio) by season (wet and dry), country (Liberia, Sierra Leone, and Guinea), and age of contact (<5 years, 5-14 years, and ≥15 years). We did sensitivity analyses to assess how results varied with malaria parasite prevalence (in children aged 2-10 years), daily cost of ETU stay (for Liberian malaria incidence levels), and compliance and effectiveness of preventive malaria treatment. Administration of ACTs to contacts of patients with Ebola virus disease was cost saving for contacts of all ages in Liberia, Sierra Leone, and Guinea, in both seasons, from a health-care provider perspective. In the wet season, preventive malaria treatment was estimated to reduce the probability of a contact being admitted to an ETU by a maximum of 36% (in Guinea, for contacts aged <5 years), and a minimum of 10% (in Guinea and Sierra Leone, for those aged ≥15 years). Assuming 85% compliance and taking into account the African population pyramid, the intervention is expected to be cost saving in

Ebola haemorrhagic fever

PubMed Central

Feldmann, Heinz; Geisbert, Thomas W

2012-01-01

Ebola viruses are the causative agents of a severe form of viral haemorrhagic fever in man, designated Ebola haemorrhagic fever, and are endemic in regions of central Africa. The exception is the species Reston Ebola virus, which has not been associated with human disease and is found in the Philippines. Ebola virus constitutes an important local public health threat in Africa, with a worldwide effect through imported infections and through the fear of misuse for biological terrorism. Ebola virus is thought to also have a detrimental effect on the great ape population in Africa. Case-fatality rates of the African species in man are as high as 90%, with no prophylaxis or treatment available. Ebola virus infections are characterised by immune suppression and a systemic inflammatory response that causes impairment of the vascular, coagulation, and immune systems, leading to multiorgan failure and shock, and thus, in some ways, resembling septic shock. PMID:21084112

Molecular Evidence of Sexual Transmission of Ebola Virus

PubMed Central

Mate, S.E.; Kugelman, J.R.; Nyenswah, T.G.; Ladner, J.T.; Wiley, M.R.; Cordier-Lassalle, T.; Christie, A; Schroth, G.P.; Gross, S.M.; Davies-Wayne, G.J.; Shinde, S.A.; Murugan, R.; Sieh, S.B.; Badio, M.; Fakoli, L.; Taweh, F.; de Wit, E.; van Doremalen, N.; Munster, V.J.; Pettitt, J.; Prieto, K.; Humrighouse, B.W.; Ströher, U.; DiClaro, J.W.; Hensley, L.E.; Schoepp, R.J.; Safronetz, D.; Fair, J.; Kuhn, J.H.; Blackley, D.J.; Laney, A.S.; Williams, D.E.; Lo, T.; Gasasira, A.; Nichol, S.T.; Formenty, P.; Kateh, F.N.; De Cock, K.M.; Bolay, F.; Sanchez-Lockhart, M.; Palacios, G.

2016-01-01

Summary A suspected case of sexual transmission from a male survivor of Ebola virus disease (EVD) to his female partner (the patient in this report) occurred in Liberia in March 2015. Ebola virus (EBOV) genomes assembled from blood samples from the patient and a semen sample from the survivor were consistent with direct transmission. The genomes shared three substitutions that were absent from all other Western African EBOV sequences and that were distinct from the last documented transmission chain in Liberia before this case. Combined with epidemiologic data, the genomic analysis provides evidence of sexual transmission of EBOV and evidence of the persistence of infective EBOV in semen for 179 days or more after the onset of EVD. (Funded by the Defense Threat Reduction Agency and others.) PMID:26465384

Ebola virus disease and pregnancy - A review of the current knowledge of Ebola virus pathogenesis, maternal and neonatal outcomes

PubMed Central

Bebell, Lisa M.; Oduyebo, Titilope; Riley, Laura E.

2016-01-01

The 2014-2016 Ebola virus disease (EVD) outbreak in West Africa devastated local health systems and caused thousands of deaths. Historical reports from Zaire ebolavirus outbreaks suggested pregnancy was associated with an increased risk of severe illness and death, with mortality rates from 74-100%. In total, 111 cases of pregnant patients with EVD are reported in the literature, with an aggregate maternal mortality of 86%. Pregnancy-specific data published from the recent outbreak include four small descriptive cohort studies and five case reports. Despite limitations including reporting bias and small sample size, these studies suggest mortality in pregnant women may be lower than previously reported, with five of 13(39%) infected women dying. Optimal treatments for pregnant women, and differences in EVD course between pregnant women and non-pregnant individuals are major scientific gaps that have not yet been systematically addressed. Ebola virus may be transmitted from mother to baby in utero, during delivery, or through contact with maternal body fluids after birth including breast milk. EVD is almost universally fatal to the developing fetus, and limited fetal autopsy data prevent inferences on risk of birth defects. Decisions about delivery mode and other obstetric interventions should be individualized. WHO recommends close monitoring of survivors who later become pregnant, but does not recommend enhanced precautions at subsequent delivery. Though sexual transmission of Ebola virus has been documented, birth outcomes among survivors have not been published and will be important to appropriately counsel women on pregnancy outcomes and inform delivery precautions for healthcare providers. PMID:28398679

The Evolution of Ebola virus: Insights from the 2013–2016 Epidemic

PubMed Central

Holmes, Edward C.; Dudas, Gytis; Rambaut, Andrew; Andersen, Kristian G.

2017-01-01

Preface The 2013–2016 epidemic of Ebola virus disease in West Africa was of unprecedented magnitude and changed our perspective on this lethal but sporadically emerging virus. This outbreak also marked the beginning of large-scale real-time molecular epidemiology. Herein, we show how evolutionary analyses of Ebola virus genome sequences provided key insights into virus origins, evolution, and spread during the epidemic. We provide basic scientists, epidemiologists, medical practitioners, and other outbreak responders with an enhanced understanding of the utility and limitations of pathogen genomic sequencing. This will be crucially important in our attempts to track and control future infectious disease outbreaks. PMID:27734858

Unique human immune signature of Ebola virus disease in Guinea

PubMed Central

Ruibal, Paula; Oestereich, Lisa; Lüdtke, Anja; Becker-Ziaja, Beate; Wozniak, David M.; Kerber, Romy; Korva, Miša; Cabeza-Cabrerizo, Mar; Bore, Joseph A.; Koundouno, Fara Raymond; Duraffour, Sophie; Weller, Romy; Thorenz, Anja; Cimini, Eleonora; Viola, Domenico; Agrati, Chiara; Repits, Johanna; Afrough, Babak; Cowley, Lauren A; Ngabo, Didier; Hinzmann, Julia; Mertens, Marc; Vitoriano, Inês; Logue, Christopher H.; Boettcher, Jan Peter; Pallasch, Elisa; Sachse, Andreas; Bah, Amadou; Nitzsche, Katja; Kuisma, Eeva; Michel, Janine; Holm, Tobias; Zekeng, Elsa-Gayle; García-Dorival, Isabel; Wölfel, Roman; Stoecker, Kilian; Fleischmann, Erna; Strecker, Thomas; Di Caro, Antonino; Avšič-Županc, Tatjana; Kurth, Andreas; Meschi, Silvia; Mély, Stephane; Newman, Edmund; Bocquin, Anne; Kis, Zoltan; Kelterbaum, Anne; Molkenthin, Peter; Carletti, Fabrizio; Portmann, Jasmine; Wolff, Svenja; Castilletti, Concetta; Schudt, Gordian; Fizet, Alexandra; Ottowell, Lisa J.; Herker, Eva; Jacobs, Thomas; Kretschmer, Birte; Severi, Ettore; Ouedraogo, Nobila; Lago, Mar; Negredo, Anabel; Franco, Leticia; Anda, Pedro; Schmiedel, Stefan; Kreuels, Benno; Wichmann, Dominic; Addo, Marylyn M.; Lohse, Ansgar W.; De Clerck, Hilde; Nanclares, Carolina; Jonckheere, Sylvie; Van Herp, Michel; Sprecher, Armand; Xiaojiang, Gao; Carrington, Mary; Miranda, Osvaldo; Castro, Carlos M.; Gabriel, Martin; Drury, Patrick; Formenty, Pierre; Diallo, Boubacar; Koivogui, Lamine; Magassouba, N’Faly; Carroll, Miles W.; Günther, Stephan; Muñoz-Fontela, César

2016-01-01

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD1. In particular, very little is known about human immune responses to Ebola virus (EBOV)2,3. Here, we have for the first time evaluated the physiology of the human T cell immune response in EVD patients at the time of admission at the Ebola Treatment Center (ETC) in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we have identified an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by high percentage of CD4 and CD8 T cells expressing the inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1), which was correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation despite comparable overall T cell activation. Concommittant with virus clearance, survivors mounted a robust EBOV-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology. PMID:27147028

Identifying spatio-temporal dynamics of Ebola in Sierra Leone using virus genomes

PubMed Central

Proctor, Joshua L.

2017-01-01

Containing the recent West African outbreak of Ebola virus (EBOV) required the deployment of substantial global resources. Despite recent progress in analysing and modelling EBOV epidemiological data, a complete characterization of the spatio-temporal spread of Ebola cases remains a challenge. In this work, we offer a novel perspective on the EBOV epidemic in Sierra Leone that uses individual virus genome sequences to inform population-level, spatial models. Calibrated to phylogenetic linkages of virus genomes, these spatial models provide unique insight into the disease mobility of EBOV in Sierra Leone without the need for human mobility data. Consistent with other investigations, our results show that the spread of EBOV during the beginning and middle portions of the epidemic strongly depended on the size of and distance between populations. Our phylodynamic analysis also revealed a change in model preference towards a spatial model with power-law characteristics in the latter portion of the epidemic, correlated with the timing of major intervention campaigns. More generally, we believe this framework, pairing molecular diagnostics with a dynamic model selection procedure, has the potential to be a powerful forecasting tool along with offering operationally relevant guidance for surveillance and sampling strategies during an epidemic. PMID:29187639

Ebola virus disease cluster in the United States--Dallas County, Texas, 2014.

PubMed

Chevalier, Michelle S; Chung, Wendy; Smith, Jessica; Weil, Lauren M; Hughes, Sonya M; Joyner, Sibeso N; Hall, Emily; Srinath, Divya; Ritch, Julia; Thathiah, Prea; Threadgill, Heidi; Cervantes, Diana; Lakey, David L

2014-11-21

Since March 10, 2014, Guinea, Liberia, and Sierra Leone have experienced the largest known Ebola virus disease (Ebola) epidemic with approximately 13,000 persons infected as of October 28, 2014. Before September 25, 2014, only four patients with Ebola had been treated in the United States; all of these patients had been diagnosed in West Africa and medically evacuated to the United States for care.

Ebola vaccine and treatment.

PubMed

Takada, Ayato

2015-01-01

Filoviruses (Ebola and Marburg viruses) cause severe hemorrhagic fever in humans and nonhuman primates. No effective prophylaxis or treatment for filovirus diseases is yet commercially available. The recent outbreak of Ebola virus disease in West Africa has accelerated efforts to develop anti-Ebola virus prophylaxis and treatment, and unapproved drugs were indeed used for the treatment of patients during the outbreak. This article reviews previous researches and the latest topics on vaccine and therapy for Ebola virus disease.

Perspectives on West Africa Ebola Virus Disease Outbreak, 2013-2016

DOE PAGES

Spengler, Jessica R.; Ervin, Elizabeth D.; Towner, Jonathan S.; ...

2016-06-01

The variety of factors that contributed to the initial undetected spread of Ebola virus disease in West Africa during 2013-2016 and the difficulty controlling the outbreak once the etiology was identified highlight priorities for disease prevention, detection, and response. These factors include occurrence in a region recovering from civil instability and lacking experience with Ebola response; inadequate surveillance, recognition of suspected cases, and Ebola diagnosis; mobile populations and extensive urban transmission; and the community's insufficient general understanding about the disease. The magnitude of the outbreak was not attributable to a substantial change of the virus. Finally, continued efforts during themore » outbreak and in preparation for future outbreak response should involve identifying the reservoir, improving in-country detection and response capacity, conducting survivor studies and supporting survivors, engaging in culturally appropriate public education and risk communication, building productive interagency relationships, and continuing support for basic research.« less

Perspectives on West Africa Ebola Virus Disease Outbreak, 2013-2016

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spengler, Jessica R.; Ervin, Elizabeth D.; Towner, Jonathan S.

The variety of factors that contributed to the initial undetected spread of Ebola virus disease in West Africa during 2013-2016 and the difficulty controlling the outbreak once the etiology was identified highlight priorities for disease prevention, detection, and response. These factors include occurrence in a region recovering from civil instability and lacking experience with Ebola response; inadequate surveillance, recognition of suspected cases, and Ebola diagnosis; mobile populations and extensive urban transmission; and the community's insufficient general understanding about the disease. The magnitude of the outbreak was not attributable to a substantial change of the virus. Finally, continued efforts during themore » outbreak and in preparation for future outbreak response should involve identifying the reservoir, improving in-country detection and response capacity, conducting survivor studies and supporting survivors, engaging in culturally appropriate public education and risk communication, building productive interagency relationships, and continuing support for basic research.« less

Perspectives on West Africa Ebola Virus Disease Outbreak, 2013-2016.

PubMed

Spengler, Jessica R; Ervin, Elizabeth D; Towner, Jonathan S; Rollin, Pierre E; Nichol, Stuart T

2016-06-01

The variety of factors that contributed to the initial undetected spread of Ebola virus disease in West Africa during 2013-2016 and the difficulty controlling the outbreak once the etiology was identified highlight priorities for disease prevention, detection, and response. These factors include occurrence in a region recovering from civil instability and lacking experience with Ebola response; inadequate surveillance, recognition of suspected cases, and Ebola diagnosis; mobile populations and extensive urban transmission; and the community's insufficient general understanding about the disease. The magnitude of the outbreak was not attributable to a substantial change of the virus. Continued efforts during the outbreak and in preparation for future outbreak response should involve identifying the reservoir, improving in-country detection and response capacity, conducting survivor studies and supporting survivors, engaging in culturally appropriate public education and risk communication, building productive interagency relationships, and continuing support for basic research.

Modelling Ebola virus dynamics: Implications for therapy.

PubMed

Martyushev, Alexey; Nakaoka, Shinji; Sato, Kei; Noda, Takeshi; Iwami, Shingo

2016-11-01

Ebola virus (EBOV) causes a severe, often fatal Ebola virus disease (EVD), for which no approved antivirals exist. Recently, some promising anti-EBOV drugs, which are experimentally potent in animal models, have been developed. However, because the quantitative dynamics of EBOV replication in humans is uncertain, it remains unclear how much antiviral suppression of viral replication affects EVD outcome in patients. Here, we developed a novel mathematical model to quantitatively analyse human viral load data obtained during the 2000/01 Uganda EBOV outbreak and evaluated the effects of different antivirals. We found that nucleoside analogue- and siRNA-based therapies are effective if a therapy with a >50% inhibition rate is initiated within a few days post-symptom-onset. In contrast, antibody-based therapy requires not only a higher inhibition rate but also an earlier administration, especially for otherwise fatal cases. Our results demonstrate that an appropriate choice of EBOV-specific drugs is required for effective EVD treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Modeling the effect of comprehensive interventions on Ebola virus transmission

NASA Astrophysics Data System (ADS)

Shen, Mingwang; Xiao, Yanni; Rong, Libin

2015-10-01

Since the re-emergence of Ebola in West Africa in 2014, comprehensive and stringent interventions have been implemented to decelerate the spread of the disease. The effectiveness of interventions still remains unclear. In this paper, we develop an epidemiological model that includes various controlling measures to systematically evaluate their effects on the disease transmission dynamics. By fitting the model to reported cumulative cases and deaths in Guinea, Sierra Leone and Liberia until March 22, 2015, we estimate the basic reproduction number in these countries as 1.2552, 1.6093 and 1.7994, respectively. Model analysis shows that there exists a threshold of the effectiveness of isolation, below which increasing the fraction of latent individuals diagnosed prior to symptoms onset or shortening the duration between symptoms onset and isolation may lead to more Ebola infection. This challenges an existing view. Media coverage plays a substantial role in reducing the final epidemic size. The response to reported cumulative infected cases and deaths may have a different effect on the epidemic spread in different countries. Among all the interventions, we find that shortening the duration between death and burial and improving the effectiveness of isolation are two effective interventions for controlling the outbreak of Ebola virus infection.

Modeling the effect of comprehensive interventions on Ebola virus transmission.

PubMed

Shen, Mingwang; Xiao, Yanni; Rong, Libin

2015-10-30

Since the re-emergence of Ebola in West Africa in 2014, comprehensive and stringent interventions have been implemented to decelerate the spread of the disease. The effectiveness of interventions still remains unclear. In this paper, we develop an epidemiological model that includes various controlling measures to systematically evaluate their effects on the disease transmission dynamics. By fitting the model to reported cumulative cases and deaths in Guinea, Sierra Leone and Liberia until March 22, 2015, we estimate the basic reproduction number in these countries as 1.2552, 1.6093 and 1.7994, respectively. Model analysis shows that there exists a threshold of the effectiveness of isolation, below which increasing the fraction of latent individuals diagnosed prior to symptoms onset or shortening the duration between symptoms onset and isolation may lead to more Ebola infection. This challenges an existing view. Media coverage plays a substantial role in reducing the final epidemic size. The response to reported cumulative infected cases and deaths may have a different effect on the epidemic spread in different countries. Among all the interventions, we find that shortening the duration between death and burial and improving the effectiveness of isolation are two effective interventions for controlling the outbreak of Ebola virus infection.

Single-Injection Vaccine Protects Nonhuman Primates against Infection with Marburg Virus and Three Species of Ebola Virus▿

PubMed Central

Geisbert, Thomas W.; Geisbert, Joan B.; Leung, Anders; Daddario-DiCaprio, Kathleen M.; Hensley, Lisa E.; Grolla, Allen; Feldmann, Heinz

2009-01-01

The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (VSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman primates against Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Marburgvirus (MARV). In this study, 11 cynomolgus monkeys were vaccinated with a blended vaccine consisting of equal parts of the vaccine vectors VSVΔG/SEBOVGP, VSVΔG/ZEBOVGP, and VSVΔG/MARVGP. Four weeks later, three of these animals were challenged with MARV, three with CIEBOV, three with ZEBOV, and two with SEBOV. Three control animals were vaccinated with VSV vectors encoding a nonfilovirus GP and challenged with SEBOV, ZEBOV, and MARV, respectively, and five unvaccinated control animals were challenged with CIEBOV. Importantly, none of the macaques vaccinated with the blended vaccine succumbed to a filovirus challenge. As expected, an experimental control animal vaccinated with VSVΔG/ZEBOVGP and challenged with SEBOV succumbed, as did the positive controls challenged with SEBOV, ZEBOV, and MARV, respectively. All five control animals challenged with CIEBOV became severely ill, and three of the animals succumbed on days 12, 12, and 14, respectively. The two animals that survived CIEBOV infection were protected from subsequent challenge with either SEBOV or ZEBOV, suggesting that immunity to CIEBOV may be protective against other species of Ebola virus. In conclusion, we developed an immunization scheme based on a single-injection vaccine that protects nonhuman primates against lethal challenge with representative strains of all human pathogenic filovirus species

Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses.

PubMed

Holtsberg, Frederick W; Shulenin, Sergey; Vu, Hong; Howell, Katie A; Patel, Sonal J; Gunn, Bronwyn; Karim, Marcus; Lai, Jonathan R; Frei, Julia C; Nyakatura, Elisabeth K; Zeitlin, Larry; Douglas, Robin; Fusco, Marnie L; Froude, Jeffrey W; Saphire, Erica Ollmann; Herbert, Andrew S; Wirchnianski, Ariel S; Lear-Rooney, Calli M; Alter, Galit; Dye, John M; Glass, Pamela J; Warfield, Kelly L; Aman, M Javad

2016-01-01

The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species. Filoviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross

Control of Ebola hemorrhagic fever: vaccine development and our Ebola project in Sierra Leone.

PubMed

Watanabe, Tokiko; Kawaoka, Yoshihiro

2016-01-01

Since December 2013, West Africa has experienced the worst Ebola virus outbreak in recorded history. Of the 28,639 cases reported to the World Health Organization as of March 2016, nearly half (14,124) occurred in Sierra Leone. With a case fatality rate of approximately 40%, this outbreak has claimed the lives of 11,316 individuals. No FDA-approved vaccines or drugs are available to prevent or treat Ebola virus infection. Experimental vaccines and therapies are being developed; however, their safety and efficacy are still being evaluated. Therefore, there is an urgent need to develop control measures to prevent or limit future Ebola virus outbreaks.Previously, we developed a replication-defective Ebola virus that lacks the coding region for the essential viral transcription activator VP30 (Ebola ΔVP30 virus). Here, we evaluated the vaccine efficacy of Ebola ΔVP30 virus in a non-human primate model and describe our collaborative Ebola project in Sierra Leone.

Evaluation of the Activity of Lamivudine and Zidovudine against Ebola Virus.

PubMed

Cong, Yu; Dyall, Julie; Hart, Brit J; DeWald, Lisa Evans; Johnson, Joshua C; Postnikova, Elena; Zhou, Huanying; Gross, Robin; Rojas, Oscar; Alexander, Isis; Josleyn, Nicole; Zhang, Tengfei; Michelotti, Julia; Janosko, Krisztina; Glass, Pamela J; Flint, Mike; McMullan, Laura K; Spiropoulou, Christina F; Mierzwa, Tim; Guha, Rajarshi; Shinn, Paul; Michael, Sam; Klumpp-Thomas, Carleen; McKnight, Crystal; Thomas, Craig; Eakin, Ann E; O'Loughlin, Kathleen G; Green, Carol E; Catz, Paul; Mirsalis, Jon C; Honko, Anna N; Olinger, Gene G; Bennett, Richard S; Holbrook, Michael R; Hensley, Lisa E; Jahrling, Peter B

2016-01-01

In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD.

Inactivation of Lassa, Marburg, and Ebola viruses by gamma irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elliott, L.H.; McCormick, J.B.; Johnson, K.M.

1982-10-01

Because of the cumbersome conditions experienced in a maximum containment laboratory, methods for inactivating highly pathogenic viruses were investigated. The infectivity of Lassa, Marburg, and Ebola viruses was inactivated without altering the immunological activity after radiation with /sup 60/Co gamma rays. At 4 degrees C, Lassa virus was the most difficult to inactivate with a rate of 5.3 X 10(-6) log 50% tissue culture infective dose per rad of /sup 60/Co radiation, as compared with 6.8 X 10(-6) log 50% tissue culture infective dose per rad for Ebola virus and 8.4 X 10(-6) log 50% tissue culture infective dose permore » rad for Marburg virus. Experimental inactivation curves, as well as curves giving the total radiation needed to inactivate a given concentration of any of the three viruses, are presented. We found this method of inactivation to be superior to UV light or beta-propiolactone inactivation and now routinely use it for preparation of material for protein-chemistry studies or for preparation of immunological reagents.« less

Inactivation of Lassa, Marburg, and Ebola viruses by gamma irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elliott, L.H.; McCormick, J.B.; Johnson, K.M.

1982-10-01

Because of the cumbersome conditions experienced in a maximum containment laboratory, methods for inactivating highly pathogenic viruses were investigated. The infectivity of Lassa, Marburg, and Ebola viruses was inactivated without altering the immunological activity after radiation with /sup 60/CO gamma rays. At 4 degrees C, Lassa virus was the most difficult to inactivate with a rate of 5.3 X 10(-6) log 50% tissue culture infective dose per rad of /sup 60/CO radiation, as compared with 6.8 X 10(-6) log 50% tissue culture infective dose per rad for Ebola virus and 8.4 X 10(-6) log 50% tissue culture infective dose permore » rad for Marburg virus. Experimental inactivation curves, as well as curves giving the total radiation needed to inactivate a given concentration of any of the three viruses, are presented. The authors found this method of inactivation to be superior to UV light or beta-propiolactone inactivation and now routinely use it for preparation of material for protein-chemistry studies or for preparation of immunological reagents.« less

Secondary Infections with Ebola Virus in Rural Communities, Liberia and Guinea, 2014–2015

PubMed Central

Nyenswah, Tolbert; Keita, Sakoba; Diallo, Boubakar; Kateh, Francis; Amoah, Aurora; Nagbe, Thomas K.; Raghunathan, Pratima; Neatherlin, John C.; Kinzer, Mike; Pillai, Satish K.; Attfield, Kathleen R.; Hajjeh, Rana; Dweh, Emmanuel; Painter, John; Barradas, Danielle T.; Williams, Seymour G.; Blackley, David J.; Kirking, Hannah L.; Patel, Monita R.; Dea, Monica; Massoudi, Mehran S.; Barskey, Albert E.; Zarecki, Shauna L. Mettee; Fomba, Moses; Grube, Steven; Belcher, Lisa; Broyles, Laura N.; Maxwell, T. Nikki; Hagan, Jose E.; Yeoman, Kristin; Westercamp, Matthew; Mott, Joshua; Mahoney, Frank; Slutsker, Laurence; DeCock, Kevin M.; Marston, Barbara; Dahl, Benjamin

2016-01-01

Persons who died of Ebola virus disease at home in rural communities in Liberia and Guinea resulted in more secondary infections than persons admitted to Ebola treatment units. Intensified monitoring of contacts of persons who died of this disease in the community is an evidence-based approach to reduce virus transmission in rural communities. PMID:27268508

Ebola virus-like particles produced in insect cells exhibit dendritic cell stimulating activity and induce neutralizing antibodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye Ling; Lin Jianguo; Sun Yuliang

2006-08-01

Recombinant baculoviruses (rBV) expressing Ebola virus VP40 (rBV-VP40) or GP (rBV-GP) proteins were generated. Infection of Sf9 insect cells by rBV-VP40 led to assembly and budding of filamentous particles from the cell surface as shown by electron microscopy. Ebola virus-like particles (VLPs) were produced by coinfection of Sf9 cells with rBV-VP40 and rBV-GP, and incorporation of Ebola GP into VLPs was demonstrated by SDS-PAGE and Western blot analysis. Recombinant baculovirus infection of insect cells yielded high levels of VLPs, which were shown to stimulate cytokine secretion from human dendritic cells similar to VLPs produced in mammalian cells. The immunogenicity ofmore » Ebola VLPs produced in insect cells was evaluated by immunization of mice. Analysis of antibody responses showed that most of the GP-specific antibodies were of the IgG2a subtype, while no significant level of IgG1 subtype antibodies specific for GP was induced, indicating the induction of a Th1-biased immune response. Furthermore, sera from Ebola VLP immunized mice were able to block infection by Ebola GP pseudotyped HIV virus in a single round infection assay, indicating that a neutralizing antibody against the Ebola GP protein was induced. These results show that production of Ebola VLPs in insect cells using recombinant baculoviruses represents a promising approach for vaccine development against Ebola virus infection.« less

Extracorporeal virus elimination for the treatment of severe Ebola virus disease--first experience with lectin affinity plasmapheresis.

PubMed

Büttner, Stefan; Koch, Benjamin; Dolnik, Olga; Eickmann, Markus; Freiwald, Tilo; Rudolf, Sarah; Engel, Jürgen; Becker, Stephan; Ronco, Claudio; Geiger, Helmut

2014-01-01

Therapeutic options for Ebola virus disease (EVD) are currently limited to (1) best supportive care, and (2) evolving virus-specific therapies, resulting from decades of analyzing one of the world's deadliest diseases. Supportive care ranges from oral or intravenous rehydration therapy and anti-emetics in developing countries to much more extensive life-support interventions in resource-rich countries. Current EVD-specific therapies attempt to either interfere with the earliest steps of viral replication or to elicit a strong immune response against the virus. An entirely new approach is the extracorporeal elimination of viruses and viral glycoproteins by lectin affinity plasmapheresis. Herein, we report for the first time the successful and safe use of lectin affinity plasmapheresis in a patient with severe Ebola virus disease. © 2015 S. Karger AG, Basel.

Ultrasensitive Detection of Ebola Virus Oligonucleotide Based on Upconversion Nanoprobe/Nanoporous Membrane System.

PubMed

Tsang, Ming-Kiu; Ye, WeiWei; Wang, Guojing; Li, Jingming; Yang, Mo; Hao, Jianhua

2016-01-26

Ebola outbreaks are currently of great concern, and therefore, development of effective diagnosis methods is urgently needed. The key for lethal virus detection is high sensitivity, since early-stage detection of virus may increase the probability of survival. Here, we propose a luminescence scheme of assay consisting of BaGdF5:Yb/Er upconversion nanoparticles (UCNPs) conjugated with oligonucleotide probe and gold nanoparticles (AuNPs) linked with target Ebola virus oligonucleotide. As a proof of concept, a homogeneous assay was fabricated and tested, yielding a detection limit at picomolar level. The luminescence resonance energy transfer is ascribed to the spectral overlapping of upconversion luminescence and the absorption characteristics of AuNPs. Moreover, we anchored the UCNPs and AuNPs on a nanoporous alumina (NAAO) membrane to form a heterogeneous assay. Importantly, the detection limit was greatly improved, exhibiting a remarkable value at the femtomolar level. The enhancement is attributed to the increased light-matter interaction throughout the nanopore walls of the NAAO membrane. The specificity test suggested that the nanoprobes were specific to Ebola virus oligonucleotides. The strategy combining UCNPs, AuNPs, and NAAO membrane provides new insight into low-cost, rapid, and ultrasensitive detection of different diseases. Furthermore, we explored the feasibility of clinical application by using inactivated Ebola virus samples. The detection results showed great potential of our heterogeneous design for practical application.

Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study.

PubMed

Geisbert, Thomas W; Lee, Amy C H; Robbins, Marjorie; Geisbert, Joan B; Honko, Anna N; Sood, Vandana; Johnson, Joshua C; de Jong, Susan; Tavakoli, Iran; Judge, Adam; Hensley, Lisa E; Maclachlan, Ian

2010-05-29

We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. Defense Threat Reduction Agency. Copyright 2010 Elsevier Ltd. All rights reserved.

Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

PubMed

Kumar, Anoop

2016-01-01

Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complement-mediated virus neutralization.

PubMed

Ji, Xin; Olinger, Gene G; Aris, Sheena; Chen, Ying; Gewurz, Henry; Spear, Gregory T

2005-09-01

Mannose-binding lectin (MBL), a serum lectin that mediates innate immune functions including activation of the lectin complement pathway, binds to carbohydrates expressed on some viral glycoproteins. In this study, the ability of MBL to bind to virus particles pseudotyped with Ebola and Marburg envelope glycoproteins was evaluated. Virus particles bearing either Ebola (Zaire strain) or Marburg (Musoke strain) envelope glycoproteins bound at significantly higher levels to immobilized MBL compared with virus particles pseudotyped with vesicular stomatitis virus glycoprotein or with no virus glycoprotein. As observed in previous studies, Ebola-pseudotyped virus bound to cells expressing the lectin DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin). However, pre-incubation of virus with MBL blocked DC-SIGN-mediated binding to cells, suggesting that the two lectins bind at the same or overlapping sites on the Ebola glycoprotein. Neutralization experiments showed that virus pseudotyped with Ebola or Marburg (Musoke) glycoprotein was neutralized by complement, while the Marburg (Ravn strain) glycoprotein-pseudotyped virus was less sensitive to neutralization. Neutralization was partially mediated through the lectin complement pathway, since a complement source deficient in MBL was significantly less effective at neutralizing viruses pseudotyped with filovirus glycoproteins and addition of purified MBL to the MBL-deficient complement increased neutralization. These experiments demonstrated that MBL binds to filovirus envelope glycoproteins resulting in important biological effects and suggest that MBL can interact with filoviruses during infection in humans.

Misconceptions about Ebola virus disease among lay people in Guinea: Lessons for community education.

PubMed

Kpanake, Lonzozou; Gossou, Komlantsè; Sorum, Paul Clay; Mullet, Etienne

2016-05-01

To characterize the perception of Ebola virus disease (EVD) in Guinea, we administered, from November 2014 to February 2015, a questionnaire to a convenience sample of 200 lay people in Conakry and a group of 8 physicians. We found widespread misconceptions among lay people, including that praying to God can protect against EVD, that traditional healers are more competent than physicians in treating EVD, that people get infected through physical proximity without contact, that the Ebola epidemic is the result of Western bioterrorism experiments, that Western medical staff disseminated the virus, and that the purpose of quarantine measures is to hasten the death of Ebola patients. Major educational interventions, sensitive to local cultural beliefs, are needed to overcome the misconceptions about Ebola in Guinea.

Control of Ebola virus disease - firestone district, liberia, 2014.

PubMed

Reaves, Erik J; Mabande, Lyndon G; Thoroughman, Douglas A; Arwady, M Allison; Montgomery, Joel M

2014-10-24

On March 30, 2014, the Ministry of Health and Social Welfare (MOHSW) of Liberia alerted health officials at Firestone Liberia, Inc. (Firestone) of the first known case of Ebola virus disease (Ebola) inside the Firestone rubber tree plantation of Liberia. The patient, who was the wife of a Firestone employee, had cared for a family member with confirmed Ebola in Lofa County, the epicenter of the Ebola outbreak in Liberia during March-April 2014. To prevent a large outbreak among Firestone's 8,500 employees, their dependents, and the surrounding population, the company responded by 1) establishing an incident management system, 2) instituting procedures for the early recognition and isolation of Ebola patients, 3) enforcing adherence to standard Ebola infection control guidelines, and 4) providing differing levels of management for contacts depending on their exposure, including options for voluntary quarantine in the home or in dedicated facilities. In addition, Firestone created multidisciplinary teams to oversee the outbreak response, address case detection, manage cases in a dedicated unit, and reintegrate convalescent patients into the community. The company also created a robust risk communication, prevention, and social mobilization campaign to boost community awareness of Ebola and how to prevent transmission. During August 1-September 23, a period of intense Ebola transmission in the surrounding areas, 71 cases of Ebola were diagnosed among the approximately 80,000 Liberians for whom Firestone provides health care (cumulative incidence = 0.09%). Fifty-seven (80%) of the cases were laboratory confirmed; 39 (68%) of these cases were fatal. Aspects of Firestone's response appear to have minimized the spread of Ebola in the local population and might be successfully implemented elsewhere to limit the spread of Ebola and prevent transmission to health care workers (HCWs).

Multi-platform 'Omics Analysis of Human Ebola Virus Disease Pathogenesis.

PubMed

Eisfeld, Amie J; Halfmann, Peter J; Wendler, Jason P; Kyle, Jennifer E; Burnum-Johnson, Kristin E; Peralta, Zuleyma; Maemura, Tadashi; Walters, Kevin B; Watanabe, Tokiko; Fukuyama, Satoshi; Yamashita, Makoto; Jacobs, Jon M; Kim, Young-Mo; Casey, Cameron P; Stratton, Kelly G; Webb-Robertson, Bobbie-Jo M; Gritsenko, Marina A; Monroe, Matthew E; Weitz, Karl K; Shukla, Anil K; Tian, Mingyuan; Neumann, Gabriele; Reed, Jennifer L; van Bakel, Harm; Metz, Thomas O; Smith, Richard D; Waters, Katrina M; N'jai, Alhaji; Sahr, Foday; Kawaoka, Yoshihiro

2017-12-13

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity. Copyright © 2017 Elsevier Inc. All rights reserved.

Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection.

PubMed

Geisbert, Thomas W; Strong, James E; Feldmann, Heinz

2015-10-01

The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

The Ebola Virus VP30-NP Interaction Is a Regulator of Viral RNA Synthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirchdoerfer, Robert N.; Moyer, Crystal L.; Abelson, Dafna M.

Filoviruses are capable of causing deadly hemorrhagic fevers. All nonsegmented negative-sense RNA-virus nucleocapsids are composed of a nucleoprotein (NP), a phosphoprotein (VP35) and a polymerase (L). However, the VP30 RNA-synthesis co-factor is unique to the filoviruses. The assembly, structure, and function of the filovirus RNA replication complex remain unclear. Here, we have characterized the interactions of Ebola, Sudan and Marburg virus VP30 with NP using in vitro biochemistry, structural biology and cell-based mini-replicon assays. We have found that the VP30 C-terminal domain interacts with a short peptide in the C-terminal region of NP. Further, we have solved crystal structures ofmore » the VP30-NP complex for both Ebola and Marburg viruses. These structures reveal that a conserved, proline-rich NP peptide binds a shallow hydrophobic cleft on the VP30 C-terminal domain. Structure-guided Ebola virus VP30 mutants have altered affinities for the NP peptide. Correlation of these VP30-NP affinities with the activity for each of these mutants in a cell-based mini-replicon assay suggests that the VP30-NP interaction plays both essential and inhibitory roles in Ebola virus RNA synthesis.« less

[Ocular symptoms and treatment of Ebola virus disease].

PubMed

Végh, Mihály; Roth, Hans-Walter; Hári-Kovács, András; Facskó, Andrea

2015-03-01

Ocular signs and symptoms of Ebola infection initially suggest banal conjunctivitis, but in advanced cases severe haemorrhagic conjunctivitis appears and, in the final stage of the disease, retinal and chorioidal haemorrhages may occur which can cause even blindness. Although the viral infection accompanied by ocular symptoms of a non-specific conjunctivitis, the high fever present from the onset of the disease should raise the suspicion of Ebola infection. There is no causal therapy know so far, and the only adjunctive treatment may be delivered by an ophthalmologist. Because the virus can be detected in the tear, it can theoretically be the mediator of the infection and, therefore, ophthalmological examinations should be carried out with the highest caution. In case of suspected Ebola infection the nearest competent healthcare authority should be immediately alerted in order to take further actions.

Validating the Inactivation Effectiveness of Chemicals on Ebola Virus.

PubMed

Haddock, Elaine; Feldmann, Friederike

2017-01-01

While viruses such as Ebola virus must be handled in high-containment laboratories, there remains the need to process virus-infected samples for downstream research testing. This processing often includes removal to lower containment areas and therefore requires assurance of complete viral inactivation within the sample before removal from high-containment. Here we describe methods for the removal of chemical reagents used in inactivation procedures, allowing for validation of the effectiveness of various inactivation protocols.

Neutralizing Antibody Fails to Impact the Course of Ebola Virus Infection in Monkeys

DTIC Science & Technology

2007-01-19

endothelial cells. Am J Pathol 163: 2371–2382. 16. Geisbert TW, Hensley LE , Jahrling PB, Larsen T, Geisbert JB, et al. (2003) Treatment of Ebola virus...Hernandez HJ, Thomas WD Jr, et al. (2005) Development and characterization of a severe acute respiratory syndrome-associated coronavirus -neutralizing human...Citation: Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, et al. (2007) Neutralizing antibody fails to impact the course of Ebola virus

Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain.

PubMed

Mora-Rillo, Marta; Arsuaga, Marta; Ramírez-Olivencia, Germán; de la Calle, Fernando; Borobia, Alberto M; Sánchez-Seco, Paz; Lago, Mar; Figueira, Juan C; Fernández-Puntero, Belén; Viejo, Aurora; Negredo, Anabel; Nuñez, Concepción; Flores, Eva; Carcas, Antonio J; Jiménez-Yuste, Victor; Lasala, Fátima; García-de-Lorenzo, Abelardo; Arnalich, Francisco; Arribas, Jose R

2015-07-01

In the current epidemic of Ebola virus disease, health-care workers have been transferred to Europe and the USA for optimised supportive care and experimental treatments. We describe the clinical course of the first case of Ebola virus disease contracted outside of Africa, in Madrid, Spain. Herein we report clinical, laboratory, and virological findings of the treatment of a female nurse assistant aged 44 years who was infected with Ebola virus around Sept 25-26, 2014, while caring for a Spanish missionary with confirmed Ebola virus disease who had been medically evacuated from Sierra Leone to La Paz-Carlos III University Hospital, Madrid. We also describe the use of experimental treatments for Ebola virus disease in this patient. The patient was symptomatic for 1 week before first hospital admission on Oct 6, 2014. We used supportive treatment with intravenous fluids, broad-spectrum antibiotics, and experimental treatments with convalescent plasma from two survivors of Ebola virus disease and high-dose favipiravir. On day 10 of illness, she had acute respiratory distress syndrome, possibly caused by transfusion-related acute lung injury, which was managed without mechanical ventilation. Discharge was delayed because of the detection of viral RNA in several bodily fluids despite clearance of viraemia. The patient was discharged on day 34 of illness. At the time of discharge, the patient had possible subacute post-viral thyroiditis. None of the people who had contact with the patient before and after admission became infected with Ebola virus. This report emphasises the uncertainties about the efficacy of experimental treatments for Ebola virus disease. Clinicians should be aware of the possibility of transfusion-related acute lung injury when using convalescent plasma for the treatment of Ebola virus disease. La Paz-Carlos III University Hospital. Copyright © 2015 Elsevier Ltd. All rights reserved.

Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days.

PubMed

Diallo, Boubacar; Sissoko, Daouda; Loman, Nicholas J; Bah, Hadja Aïssatou; Bah, Hawa; Worrell, Mary Claire; Conde, Lya Saidou; Sacko, Ramata; Mesfin, Samuel; Loua, Angelo; Kalonda, Jacques Katomba; Erondu, Ngozi A; Dahl, Benjamin A; Handrick, Susann; Goodfellow, Ian; Meredith, Luke W; Cotten, Matthew; Jah, Umaru; Guetiya Wadoum, Raoul Emeric; Rollin, Pierre; Magassouba, N'Faly; Malvy, Denis; Anglaret, Xavier; Carroll, Miles W; Aylward, Raymond Bruce; Djingarey, Mamoudou Harouna; Diarra, Abdoulaye; Formenty, Pierre; Keïta, Sakoba; Günther, Stephan; Rambaut, Andrew; Duraffour, Sophie

2016-11-15

We report on an Ebola virus disease (EVD) survivor who showed Ebola virus in seminal fluid 531 days after onset of disease. The persisting virus was sexually transmitted in February 2016, about 470 days after onset of symptoms, and caused a new cluster of EVD in Guinea and Liberia. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Apoptosis in fatal Ebola infection. Does the virus toll the bell for immune system?

PubMed

Baize, S; Leroy, E M; Mavoungou, E; Fisher-Hoch, S P

2000-02-01

In fatal Ebola virus hemorrhagic fever massive intravascular apoptosis develops rapidly following infection and progressing relentlessly until death. While data suggest that T lymphocytes are mainly deleted by apoptosis in PBMC of human fatal cases, experimental Ebola infection in animal models have shown some evidence of destruction of lymphocytes in spleen and lymph nodes probably involving both T and B cells. Nevertheless, we are able to conclude from the accumulated evidence that early interactions between Ebola virus and the immune system, probably via macrophages, main targets for viral replication, lead to massive destruction of immune cells in fatal cases.

A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.

PubMed

Regules, Jason A; Beigel, John H; Paolino, Kristopher M; Voell, Jocelyn; Castellano, Amy R; Hu, Zonghui; Muñoz, Paula; Moon, James E; Ruck, Richard C; Bennett, Jason W; Twomey, Patrick S; Gutiérrez, Ramiro L; Remich, Shon A; Hack, Holly R; Wisniewski, Meagan L; Josleyn, Matthew D; Kwilas, Steven A; Van Deusen, Nicole; Mbaya, Olivier Tshiani; Zhou, Yan; Stanley, Daphne A; Jing, Wang; Smith, Kirsten S; Shi, Meng; Ledgerwood, Julie E; Graham, Barney S; Sullivan, Nancy J; Jagodzinski, Linda L; Peel, Sheila A; Alimonti, Judie B; Hooper, Jay W; Silvera, Peter M; Martin, Brian K; Monath, Thomas P; Ramsey, W Jay; Link, Charles J; Lane, H Clifford; Michael, Nelson L; Davey, Richard T; Thomas, Stephen J

2017-01-26

The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses

New Perspectives on Ebola Virus Evolution.

PubMed

Brown, Celeste J; Quates, Caleb J; Mirabzadeh, Christopher A; Miller, Craig R; Wichman, Holly A; Miura, Tanya A; Ytreberg, F Marty

2016-01-01

Since the recent devastating outbreak of Ebola virus disease in western Africa, there has been significant effort to understand the evolution of the deadly virus that caused the outbreak. There has been a considerable investment in sequencing Ebola virus (EBOV) isolates, and the results paint an important picture of how the virus has spread in western Africa. EBOV evolution cannot be understood outside the context of previous outbreaks, however. We have focused this study on the evolution of the EBOV glycoprotein gene (GP) because one of its products, the spike glycoprotein (GP1,2), is central to the host immune response and because it contains a large amount of the phylogenetic signal for this virus. We inferred the maximum likelihood phylogeny of 96 nonredundant GP gene sequences representing each of the outbreaks since 1976 up to the end of 2014. We tested for positive selection and considered the placement of adaptive amino acid substitutions along the phylogeny and within the protein structure of GP1,2. We conclude that: 1) the common practice of rooting the phylogeny of EBOV between the first known outbreak in 1976 and the next outbreak in 1995 provides a misleading view of EBOV evolution that ignores the fact that there is a non-human EBOV host between outbreaks; 2) the N-terminus of GP1 may be constrained from evolving in response to the host immune system by the highly expressed, secreted glycoprotein, which is encoded by the same region of the GP gene; 3) although the mucin-like domain of GP1 is essential for EBOV in vivo, it evolves rapidly without losing its twin functions: providing O-linked glycosylation sites and a flexible surface.

Studies of Ebola Virus Glycoprotein-Mediated Entry and Fusion by Using Pseudotyped Human Immunodeficiency Virus Type 1 Virions: Involvement of Cytoskeletal Proteins and Enhancement by Tumor Necrosis Factor Alpha

PubMed Central

Yonezawa, Akihito; Cavrois, Marielle; Greene, Warner C.

2005-01-01

The Ebola filoviruses are aggressive pathogens that cause severe and often lethal hemorrhagic fever syndromes in humans and nonhuman primates. To date, no effective therapies have been identified. To analyze the entry and fusion properties of Ebola virus, we adapted a human immunodeficiency virus type 1 (HIV-1) virion-based fusion assay by substituting Ebola virus glycoprotein (GP) for the HIV-1 envelope. Fusion was detected by cleavage of the fluorogenic substrate CCF2 by β-lactamase-Vpr incorporated into virions and released as a result of virion fusion. Entry and fusion induced by the Ebola virus GP occurred with much slower kinetics than with vesicular stomatitis virus G protein (VSV-G) and were blocked by depletion of membrane cholesterol and by inhibition of vesicular acidification with bafilomycin A1. These properties confirmed earlier studies and validated the assay for exploring other properties of Ebola virus GP-mediated entry and fusion. Entry and fusion of Ebola virus GP pseudotypes, but not VSV-G or HIV-1 Env pseudotypes, were impaired in the presence of the microtubule-disrupting agent nocodazole but were enhanced in the presence of the microtubule-stabilizing agent paclitaxel (Taxol). Agents that impaired microfilament function, including cytochalasin B, cytochalasin D, latrunculin A, and jasplakinolide, also inhibited Ebola virus GP-mediated entry and fusion. Together, these findings suggest that both microtubules and microfilaments may play a role in the effective trafficking of vesicles containing Ebola virions from the cell surface to the appropriate acidified vesicular compartment where fusion occurs. In terms of Ebola virus GP-mediated entry and fusion to various target cells, primary macrophages proved highly sensitive, while monocytes from the same donors displayed greatly reduced levels of entry and fusion. We further observed that tumor necrosis factor alpha, which is released by Ebola virus-infected monocytes/macrophages, enhanced Ebola

Outbreaks-of Ebola virus disease in the West African sub-region.

PubMed

Osungbade, K O; Oni, A A

2014-06-01

Five West African countries, including Nigeria are currently experiencing the largest, most severe, most complex outbreak of Ebola virus disease in history. This paper provided a chronology of outbreaks of Ebola virus disease in the West African sub-region and provided an update on efforts at containing the present outbreak. Literature from Pubmed (MEDLINE), AJOL, Google Scholar and Cochrane database were reviewed. Outbreaks of Ebola, virus disease had frequently occurred mainly in Central and East African countries. Occasional outbreaks reported from outside of Africa were due to laboratory contamination and imported monkeys in quarantine facilities. The ongoing outbreak in West Africa is the largest and first in the sub-region; the number of suspected cases and deaths from this single current outbreak is already about three times the total of all cases and deaths from previous known outbreaks in 40 years. Prevention and control efforts are hindered not only by lack of a known vaccine and virus-specific treatment, but also by weak health systems, poor sanitation, poor personal hygiene and cultural beliefs and practices, including myths and misconceptions about Ebola virus disease--all of which are prevalent in affected countries. Constrained by this situation, the World Health Organisation departed from the global standard and recommended the use of not yet proven treatments to treat or prevent the disease in humans on ethical and evidential grounds. The large number of people affected by the present outbreak in West Africa and the high case-fatality rate calls for accelerated evaluation and development of the investigational medical interventions for life saving and curbing the epidemic. Meanwhile, existing interventions such as early detection and isolation, contact tracing and monitoring, and adherence to rigorous procedures of infection prevention and control should be intensified.

Reduced evolutionary rate in reemerged Ebola virus transmission chains.

PubMed

Blackley, David J; Wiley, Michael R; Ladner, Jason T; Fallah, Mosoka; Lo, Terrence; Gilbert, Merle L; Gregory, Christopher; D'ambrozio, Jonathan; Coulter, Stewart; Mate, Suzanne; Balogun, Zephaniah; Kugelman, Jeffrey; Nwachukwu, William; Prieto, Karla; Yeiah, Adolphus; Amegashie, Fred; Kearney, Brian; Wisniewski, Meagan; Saindon, John; Schroth, Gary; Fakoli, Lawrence; Diclaro, Joseph W; Kuhn, Jens H; Hensley, Lisa E; Jahrling, Peter B; Ströher, Ute; Nichol, Stuart T; Massaquoi, Moses; Kateh, Francis; Clement, Peter; Gasasira, Alex; Bolay, Fatorma; Monroe, Stephan S; Rambaut, Andrew; Sanchez-Lockhart, Mariano; Scott Laney, A; Nyenswah, Tolbert; Christie, Athalia; Palacios, Gustavo

2016-04-01

On 29 June 2015, Liberia's respite from Ebola virus disease (EVD) was interrupted for the second time by a renewed outbreak ("flare-up") of seven confirmed cases. We demonstrate that, similar to the March 2015 flare-up associated with sexual transmission, this new flare-up was a reemergence of a Liberian transmission chain originating from a persistently infected source rather than a reintroduction from a reservoir or a neighboring country with active transmission. Although distinct, Ebola virus (EBOV) genomes from both flare-ups exhibit significantly low genetic divergence, indicating a reduced rate of EBOV evolution during persistent infection. Using this rate of change as a signature, we identified two additional EVD clusters that possibly arose from persistently infected sources. These findings highlight the risk of EVD flare-ups even after an outbreak is declared over.

Recent advances in the development of vaccines for Ebola virus disease.

PubMed

Ohimain, Elijah Ige

2016-01-04

Ebola virus is one of the most dangerous microorganisms in the world causing hemorrhagic fevers in humans and non-human primates. Ebola virus (EBOV) is a zoonotic infection, which emerges and re-emerges in human populations. The 2014 outbreak was caused by the Zaire strain, which has a kill rate of up to 90%, though 40% was recorded in the current outbreak. The 2014 outbreak is larger than all 20 outbreaks that have occurred since 1976, when the virus was first discovered. It is the first time that the virus was sustained in urban centers and spread beyond Africa into Europe and USA. Thus far, over 22,000 cases have been reported with about 50% mortality in one year. There are currently no approved therapeutics and preventive vaccines against Ebola virus disease (EVD). Responding to the devastating effe1cts of the 2014 outbreak and the potential risk of global spread, has spurred research for the development of therapeutics and vaccines. This review is therefore aimed at presenting the progress of vaccine development. Results showed that conventional inactivated vaccines produced from EBOV by heat, formalin or gamma irradiation appear to be ineffective. However, novel vaccines production techniques have emerged leading to the production of candidate vaccines that have been demonstrated to be effective in preclinical trials using small animal and non-human primates (NHP) models. Some of the promising vaccines have undergone phase 1 clinical trials, which demonstrated their safety and immunogenicity. Many of the candidate vaccines are vector based such as Vesicular Stomatitis Virus (VSV), Rabies Virus (RABV), Adenovirus (Ad), Modified Vaccinia Ankara (MVA), Cytomegalovirus (CMV), human parainfluenza virus type 3 (HPIV3) and Venezuelan Equine Encephalitis Virus (VEEV). Other platforms include virus like particle (VLP), DNA and subunit vaccines. Copyright © 2015 Elsevier B.V. All rights reserved.

Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.

PubMed

Mahanty, Siddhartha; Hutchinson, Karen; Agarwal, Sudhanshu; McRae, Michael; Rollin, Pierre E; Pulendran, Bali

2003-03-15

Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-alpha, IL-1 beta, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

Analysis of patient data from laboratories during the Ebola virus disease outbreak in Liberia, April 2014 to March 2015

PubMed Central

Fallah, Mosoka; Oshitani, Hitoshi; Kituyi, Ling; Mahmoud, Nuha; Musa, Emmanuel; Gasasira, Alex; Nyenswah, Tolbert; Dahn, Bernice; Bawo, Luke

2017-01-01

An outbreak of Ebola virus disease (EVD) in Liberia began in March 2014 and ended in January 2016. Epidemiological information on the EVD cases was collected and managed nationally; however, collection and management of the data were challenging at the time because surveillance and reporting systems malfunctioned during the outbreak. EVD diagnostic laboratories, however, were able to register basic demographic and clinical information of patients more systematically. Here we present data on 16,370 laboratory samples that were tested between April 4, 2014 and March 29, 2015. A total of 10,536 traceable individuals were identified, of whom 3,897 were confirmed cases (positive for Ebola virus RNA). There were significant differences in sex, age, and place of residence between confirmed and suspected cases that tested negative for Ebola virus RNA. Age (young children and the elderly) and place of residence (rural areas) were the risk factors for death due to the disease. The case fatality rate of confirmed cases decreased from 80% to 63% during the study period. These findings may help support future investigations and lead to a fuller understanding of the outbreak in Liberia. PMID:28732038

Analysis of patient data from laboratories during the Ebola virus disease outbreak in Liberia, April 2014 to March 2015.

PubMed

Furuse, Yuki; Fallah, Mosoka; Oshitani, Hitoshi; Kituyi, Ling; Mahmoud, Nuha; Musa, Emmanuel; Gasasira, Alex; Nyenswah, Tolbert; Dahn, Bernice; Bawo, Luke

2017-07-01

An outbreak of Ebola virus disease (EVD) in Liberia began in March 2014 and ended in January 2016. Epidemiological information on the EVD cases was collected and managed nationally; however, collection and management of the data were challenging at the time because surveillance and reporting systems malfunctioned during the outbreak. EVD diagnostic laboratories, however, were able to register basic demographic and clinical information of patients more systematically. Here we present data on 16,370 laboratory samples that were tested between April 4, 2014 and March 29, 2015. A total of 10,536 traceable individuals were identified, of whom 3,897 were confirmed cases (positive for Ebola virus RNA). There were significant differences in sex, age, and place of residence between confirmed and suspected cases that tested negative for Ebola virus RNA. Age (young children and the elderly) and place of residence (rural areas) were the risk factors for death due to the disease. The case fatality rate of confirmed cases decreased from 80% to 63% during the study period. These findings may help support future investigations and lead to a fuller understanding of the outbreak in Liberia.

Media Messages and Perception of Risk for Ebola Virus Infection, United States.

PubMed

Sell, Tara Kirk; Boddie, Crystal; McGinty, Emma E; Pollack, Keshia; Smith, Katherine Clegg; Burke, Thomas A; Rutkow, Lainie

2017-01-01

News media have been blamed for sensationalizing Ebola in the United States, causing unnecessary alarm. To investigate this issue, we analyzed US-focused news stories about Ebola virus disease during July 1-November 30, 2014. We found frequent use of risk-elevating messages, which may have contributed to increased public concern.

Acute rhabdomyolysis and delayed pericardial effusion in an Italian patient with Ebola virus disease: a case report.

PubMed

Nicastri, Emanuele; Brucato, Antonio; Petrosillo, Nicola; Biava, Gianluigi; Uyeki, Timothy M; Ippolito, Giuseppe

2017-08-30

During the 2013-2016 West Africa Ebola virus disease (EVD) epidemic, some EVD patients, mostly health care workers, were evacuated to Europe and the USA. In May 2015, a 37-year old male nurse contracted Ebola virus disease in Sierra Leone. After Ebola virus detection in plasma, he was medically-evacuated to Italy. At admission, rhabdomyolysis was clinically and laboratory-diagnosed and was treated with aggressive hydration, oral favipiravir and intravenous investigational monoclonal antibodies against Ebola virus. The recovery clinical phase was complicated by a febrile thrombocytopenic syndrome with pericardial effusion treated with corticosteroids for 10 days and indomethacin for 2 months. No evidence of recurrence is reported. A febrile thrombocytopenic syndrome with pericardial effusion during the recovery phase of EVD appears to be uncommon. Clinical improvement with corticosteroid treatment suggests that an immune-mediated mechanism contributed to the pericardial effusion.

Perspectives on West Africa Ebola Virus Disease Outbreak, 2013–2016

PubMed Central

Spengler, Jessica R.; Ervin, Elizabeth D.; Towner, Jonathan S.; Rollin, Pierre E.

2016-01-01

The variety of factors that contributed to the initial undetected spread of Ebola virus disease in West Africa during 2013–2016 and the difficulty controlling the outbreak once the etiology was identified highlight priorities for disease prevention, detection, and response. These factors include occurrence in a region recovering from civil instability and lacking experience with Ebola response; inadequate surveillance, recognition of suspected cases, and Ebola diagnosis; mobile populations and extensive urban transmission; and the community’s insufficient general understanding about the disease. The magnitude of the outbreak was not attributable to a substantial change of the virus. Continued efforts during the outbreak and in preparation for future outbreak response should involve identifying the reservoir, improving in-country detection and response capacity, conducting survivor studies and supporting survivors, engaging in culturally appropriate public education and risk communication, building productive interagency relationships, and continuing support for basic research. PMID:27070842

Factors Underlying Ebola Virus Infection Among Health Workers, Kenema, Sierra Leone, 2014–2015

PubMed Central

Senga, Mikiko; Pringle, Kimberly; Ramsay, Andrew; Brett-Major, David M.; Fowler, Robert A.; French, Issa; Vandi, Mohamed; Sellu, Josephine; Pratt, Christian; Saidu, Josephine; Shindo, Nahoko; Bausch, Daniel G.

2016-01-01

Background. Ebola virus disease (EVD) in health workers (HWs) has been a major challenge during the 2014–2015 outbreak. We examined factors associated with Ebola virus exposure and mortality in HWs in Kenema District, Sierra Leone. Methods. We analyzed data from the Sierra Leone National Viral Hemorrhagic Fever Database, contact tracing records, Kenema Government Hospital (KGH) staff and Ebola Treatment Unit (ETU) rosters, and burial logs. Results. From May 2014 through January 2015, 600 cases of EVD originated in Kenema District, including 92 (15%) HWs, 66 (72%) of whom worked at KGH. Among KGH medical staff and international volunteers, 18 of 62 (29%) who worked in the ETU developed EVD, compared with 48 of 83 (58%) who worked elsewhere in the hospital. Thirteen percent of HWs with EVD reported contact with EVD patients, while 27% reported contact with other infected HWs. The number of HW EVD cases at KGH declined roughly 1 month after implementation of a new triage system at KGH and the opening of a second ETU within the district. The case fatality ratio for HWs and non-HWs with EVD was 69% and 74%, respectively. Conclusions. The cluster of HW EVD cases in Kenema District is one of the largest ever reported. Most HWs with EVD had potential virus exposure both inside and outside of hospitals. Prevention measures for HWs must address a spectrum of infection risks in both formal and informal care settings as well as in the community. PMID:27193749

Assessment of Ebola virus disease preparedness in the WHO South-East Asia Region.

PubMed

Vong, Sirenda; Samuel, Reuben; Gould, Philip; El Sakka, Hammam; Rana, Bardan J; Pinyowiwat, Vason; Bezbaruah, Supriya; Ofrin, Roderico

2016-12-01

To conduct assessments of Ebola virus disease preparedness in countries of the World Health Organization (WHO) South-East Asia Region. Nine of 11 countries in the region agreed to be assessed. During February to November 2015 a joint team from WHO and ministries of health conducted 4-5 day missions to Bangladesh, Bhutan, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. We collected information through guided discussions with senior technical leaders and visits to hospitals, laboratories and airports. We assessed each country's Ebola virus disease preparedness on 41 tasks under nine key components adapted from the WHO Ebola preparedness checklist of January 2015. Political commitment to Ebola preparedness was high in all countries. Planning was most advanced for components that had been previously planned or tested for influenza pandemics: multilevel and multisectoral coordination; multidisciplinary rapid response teams; public communication and social mobilization; drills in international airports; and training on personal protective equipment. Major vulnerabilities included inadequate risk assessment and risk communication; gaps in data management and analysis for event surveillance; and limited capacity in molecular diagnostic techniques. Many countries had limited planning for a surge of Ebola cases. Other tasks needing improvement included: advice to inbound travellers; adequate isolation rooms; appropriate infection control practices; triage systems in hospitals; laboratory diagnostic capacity; contact tracing; and danger pay to staff to ensure continuity of care. Joint assessment and feedback about the functionality of Ebola virus preparedness systems help countries strengthen their core capacities to meet the International Health Regulations.

Assessment of Ebola virus disease preparedness in the WHO South-East Asia Region

PubMed Central

Samuel, Reuben; Gould, Philip; El Sakka, Hammam; Rana, Bardan J; Pinyowiwat, Vason; Bezbaruah, Supriya; Ofrin, Roderico

2016-01-01

Abstract Objective To conduct assessments of Ebola virus disease preparedness in countries of the World Health Organization (WHO) South-East Asia Region. Methods Nine of 11 countries in the region agreed to be assessed. During February to November 2015 a joint team from WHO and ministries of health conducted 4–5 day missions to Bangladesh, Bhutan, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. We collected information through guided discussions with senior technical leaders and visits to hospitals, laboratories and airports. We assessed each country’s Ebola virus disease preparedness on 41 tasks under nine key components adapted from the WHO Ebola preparedness checklist of January 2015. Findings Political commitment to Ebola preparedness was high in all countries. Planning was most advanced for components that had been previously planned or tested for influenza pandemics: multilevel and multisectoral coordination; multidisciplinary rapid response teams; public communication and social mobilization; drills in international airports; and training on personal protective equipment. Major vulnerabilities included inadequate risk assessment and risk communication; gaps in data management and analysis for event surveillance; and limited capacity in molecular diagnostic techniques. Many countries had limited planning for a surge of Ebola cases. Other tasks needing improvement included: advice to inbound travellers; adequate isolation rooms; appropriate infection control practices; triage systems in hospitals; laboratory diagnostic capacity; contact tracing; and danger pay to staff to ensure continuity of care. Conclusion Joint assessment and feedback about the functionality of Ebola virus preparedness systems help countries strengthen their core capacities to meet the International Health Regulations. PMID:27994284

A review on the antagonist Ebola: A prophylactic approach.

PubMed

Khan, Fatima Nazish; Qazi, Sahar; Tanveer, Khushnuma; Raza, Khalid

2017-12-01

Ebola virus (EBOV), a member of Filoviridae virus family under the genus Ebolavirus, has emerged as a dangerous and potential threat to human health globally. It causes a severe and deadly hemorrhagic fever in humans and other mammals, called Ebola Virus Disease (EVD). In recent outbreaks of EVD, there has been loss of large numbers of individual's life. Therefore, EBOV has attracted researchers and increased interests in developing new models for virus evolution, and therapies. The EBOV interacts with the immune system of the host which led to understand how the virus functions and effects immune system behaviour. This article presents an exhaustive review on Ebola research which includes EVD illness, symptoms, transmission patterns, patho-physiology conditions, development of antiviral agents and vaccines, resilient health system, dynamics and mathematical model of EBOV, challenges and prospects for future studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

PubMed Central

Choi, Jin Huk; Croyle, Maria A.

2013-01-01

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant-virus based vectors have been identified as potent vaccine candidates with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the United States (U.S.) Food and Drug Administration (FDA) and Phase I clinical trials initiated for two small molecule therapeutics, 1) anti-sense phosphorodiamidate morphino oligomers (PMOs: AVI-6002, AVI-6003), and 2) lipid-nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms will also be discussed. PMID:23813435

In vivo Ebola virus infection leads to a strong innate response in circulating immune cells.

PubMed

Caballero, Ignacio S; Honko, Anna N; Gire, Stephen K; Winnicki, Sarah M; Melé, Marta; Gerhardinger, Chiara; Lin, Aaron E; Rinn, John L; Sabeti, Pardis C; Hensley, Lisa E; Connor, John H

2016-09-05

Ebola virus is the causative agent of a severe syndrome in humans with a fatality rate that can approach 90 %. During infection, the host immune response is thought to become dysregulated, but the mechanisms through which this happens are not entirely understood. In this study, we analyze RNA sequencing data to determine the host response to Ebola virus infection in circulating immune cells. Approximately half of the 100 genes with the strongest early increases in expression were interferon-stimulated genes, such as ISG15, OAS1, IFIT2, HERC5, MX1 and DHX58. Other highly upregulated genes included cytokines CXCL11, CCL7, IL2RA, IL2R1, IL15RA, and CSF2RB, which have not been previously reported to change during Ebola virus infection. Comparing this response in two different models of exposure (intramuscular and aerosol) revealed a similar signature of infection. The strong innate response in the aerosol model was seen not only in circulating cells, but also in primary and secondary target tissues. Conversely, the innate immune response of vaccinated macaques was almost non-existent. This suggests that the innate response is a major aspect of the cellular response to Ebola virus infection in multiple tissues. Ebola virus causes a severe infection in humans that is associated with high mortality. The host immune response to virus infection is thought to be an important aspect leading to severe pathology, but the components of this overactive response are not well characterized. Here, we analyzed how circulating immune cells respond to the virus and found that there is a strong innate response dependent on active virus replication. This finding is in stark contrast to in vitro evidence showing a suppression of innate immune signaling, and it suggests that the strong innate response we observe in infected animals may be an important contributor to pathogenesis.

FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection

PubMed Central

Johansen, Lisa M.; Brannan, Jennifer M.; Delos, Sue E.; Shoemaker, Charles J.; Stossel, Andrea; Lear, Calli; Hoffstrom, Benjamin G.; DeWald, Lisa Evans; Schornberg, Kathryn L.; Scully, Corinne; Lehár, Joseph; Hensley, Lisa E.; White, Judith M.; Olinger, Gene G.

2014-01-01

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections. PMID:23785035

A No-Notice Drill of Hospital Preparedness in Responding to Ebola Virus Disease in Taiwan.

PubMed

Hsu, Shih-Min; Chien, Li-Jung; Tseng, Shu-Hui; Kuo, Steve H S

2015-01-01

The Ebola virus was first discovered in 1976, but the outbreak of Ebola virus disease that began in Guinea, West Africa, in December 2013 shocked the world. It is the largest and most severe epidemic of Ebola virus disease to date. The US Centers for Disease Control and Prevention confirmed that inadequate implementation of the policy of acquiring travel history led to a delay in identifying the first imported Ebola virus disease case. The Taiwan Centers for Disease Control developed a no-notice drill that used a simulated patient to assess hospitals' emergency preparedness capacity in responding to Ebola virus disease. Despite the fact that regular inspection shows that more than 90% of regional hospitals and medical centers inquired about patients' travel history, occupation, contact history, and cluster information, the no-notice drill revealed that more than 40% of regional hospitals and medical centers failed to ask emergency room patients about these factors. Therefore, to assist in inquiries about travel history, occupation, contact history, and cluster information in emergency triage and outpatient settings, the Taiwan CDC revised the criteria for hospital infection control inspection. It requested that hospitals issue appropriate reminders and implement process control mechanisms to block diagnostic processes in instances in which healthcare workers do not inquire about travel history, occupation, contact history, and cluster information. Furthermore, the Taiwan CDC will continue no-notice inspections in order to strengthen hospitals' infection control measures and reduce the risk of infectious disease transmission in the healthcare system.

[The wanderings of the communication on the Ebola virus disease].

PubMed

Seytre, B

2016-10-01

For two reasons, communication is one of the major tools in the fight against any Ebola epidemics. Firstly, because Ebola is one of the most easily preventable of all infectious diseases and the thorough application of health-protection measures by the community of the sick persons is the best tool to fight any Ebola epidemic. Secondly, because during the two dozens of known Ebola epidemics health care workers have often met with people's skepticism, or even hostility. However, our review of Ebola communication, as defined by WHO since 2013, shows that it has been marked by a series of errors, as well from a strategic perspective as in its concrete deployment. The same communication messages and tools have been used in non-epidemic and epidemic countries. A general ban on hunting has been promoted, while only 2% of sub-Saharan Africans live in areas inhabited by the bats that are the reservoir of the Ebola virus and while it is not proven that hunting is a major risk of infection. Erroneous or inappropriate messages have contributed to doubts and created anxiety. To be effective, Ebola communication should be based on education about the disease, meaning explanation of its cause, its transmission and its prevention.

Transmission of Ebola Viruses: What We Know and What We Do Not Know

PubMed Central

Moore, Kristine A.; Kelley, Nicholas S.; Brosseau, Lisa M.; Wong, Gary; Murphy, Frederick A.; Peters, Clarence J.; LeDuc, James W.; Russell, Phillip K.; Van Herp, Michel; Kapetshi, Jimmy; Muyembe, Jean-Jacques T.; Ilunga, Benoit Kebela; Strong, James E.; Grolla, Allen; Wolz, Anja; Kargbo, Brima; Kargbo, David K.; Formenty, Pierre; Sanders, David Avram; Kobinger, Gary P.

2015-01-01

ABSTRACT Available evidence demonstrates that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, but this is based on a limited number of studies. Key areas requiring further study include (i) the role of aerosol transmission (either via large droplets or small particles in the vicinity of source patients), (ii) the role of environmental contamination and fomite transmission, (iii) the degree to which minimally or mildly ill persons transmit infection, (iv) how long clinically relevant infectiousness persists, (v) the role that “superspreading events” may play in driving transmission dynamics, (vi) whether strain differences or repeated serial passage in outbreak settings can impact virus transmission, and (vii) what role sylvatic or domestic animals could play in outbreak propagation, particularly during major epidemics such as the 2013–2015 West Africa situation. In this review, we address what we know and what we do not know about Ebola virus transmission. We also hypothesize that Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread. PMID:25698835

Epidemiological features and trends of Ebola virus disease in West Africa.

PubMed

Wang, Ligui; Yang, Guang; Jia, Leili; Li, Zhenjun; Xie, Jing; Li, Peng; Qiu, Shaofu; Hao, Rongzhang; Wu, Zhihao; Ma, Hui; Song, Hongbin

2015-09-01

According to a World Health Organization report, the epidemiological features of Ebola virus disease (EVD) have changed significantly in West Africa. In this study, the new epidemiological features and prevalence trends for EVD in Guinea, Liberia, and Sierra Leone are described. It was predicted that the Ebola outbreak would end in June 2015. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Media Messages and Perception of Risk for Ebola Virus Infection, United States

PubMed Central

Boddie, Crystal; McGinty, Emma E.; Pollack, Keshia; Smith, Katherine Clegg; Burke, Thomas A.; Rutkow, Lainie

2017-01-01

News media have been blamed for sensationalizing Ebola in the United States, causing unnecessary alarm. To investigate this issue, we analyzed US-focused news stories about Ebola virus disease during July 1–November 30, 2014. We found frequent use of risk-elevating messages, which may have contributed to increased public concern. PMID:27983495

An update on ocular complications of Ebola virus disease

PubMed Central

Shantha, Jessica G.; Crozier, Ian; Yeh, Steven

2018-01-01

Purpose of review This review provides a summary of our current understanding of the ophthalmic manifestations of Ebola virus disease (EVD), pathogenesis, treatment options and directions for future study. The individual, public health and global health implications of eye disease in EVD survivors are discussed. Recent findings The West Africa EVD outbreak was of unprecedented magnitude, leading to the largest survivor cohort since the first documented EVD outbreak in 1976. Because of the magnitude of the recent outbreak, thousands of survivors are at-risk of systemic and ophthalmic sequelae termed the ‘post Ebola virus disease syndrome’. Uveitis is the most common finding during EVD convalescence and may lead to severe vision impairment or blindness in 40% of affected individuals. Ocular complications leading to vision loss include cataract, retinal scarring, optic neuropathy, hypotony and phthisis bulbi. The pathogenesis of eye disease in EVD survivors likely involves Ebola virus persistence, severe inflammation and tissue edema, which present as acute, rapidly progressive disease or chronic, smoldering disease. Further studies into disease pathogenesis including mechanisms of viral persistence may provide guidance into therapies for uveitis secondary to EVD. Summary Uveitis is the most common ophthalmic finding in EVD survivors and can lead to vision loss. Further studies into the clinical manifestations and mechanisms of disease are needed to improve therapies for EVD survivors who often have limited access to ophthalmic medical and surgical care. PMID:28872492

Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference.

PubMed

Geisbert, Thomas W; Hensley, Lisa E; Kagan, Elliott; Yu, Erik Zhaoying; Geisbert, Joan B; Daddario-DiCaprio, Kathleen; Fritz, Elizabeth A; Jahrling, Peter B; McClintock, Kevin; Phelps, Janet R; Lee, Amy C H; Judge, Adam; Jeffs, Lloyd B; MacLachlan, Ian

2006-06-15

Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

Chains of transmission and control of Ebola virus disease in Conakry, Guinea, in 2014: an observational study.

PubMed

Faye, Ousmane; Boëlle, Pierre-Yves; Heleze, Emmanuel; Faye, Oumar; Loucoubar, Cheikh; Magassouba, N'Faly; Soropogui, Barré; Keita, Sakoba; Gakou, Tata; Bah, El Hadji Ibrahima; Koivogui, Lamine; Sall, Amadou Alpha; Cauchemez, Simon

2015-03-01

hospital admissions could have reduced the length of chains by 26% (95% CI 4-45). In Conakry, interventions had the potential to stop the epidemic, but reintroductions of the disease and poor cooperation of a few families led to prolonged low-level spread, showing the challenges of Ebola virus disease control in large urban centres. Monitoring of chains of transmission is crucial to assess and optimise local control strategies for Ebola virus disease. Labex IBEID, Reacting, PREDEMICS, NIGMS MIDAS initiative, Institut Pasteur de Dakar. Copyright © 2015 Elsevier Ltd. All rights reserved.

Treatment of Ebola Virus Infection With a Recombinant Inhibitor of Factor Vlla/Tissue Factor: A Study in Rhesus Monkeys

DTIC Science & Technology

2003-12-13

ameliorate the effects of Ebola haemorrhagic fever . Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with...Ebola virus. Methods We used a rhesus macaque model of Ebola haemorrhagic fever , which produces near 100% mortality. We administered recombinant...severe haemorrhagic fever in primates.1,2 Acute mortality caused by the Zaire species of Ebola virus has been about 80% in outbreaks in human beings1

Ebola virus disease cases among health care workers not working in Ebola treatment units--Liberia, June-August, 2014.

PubMed

Matanock, Almea; Arwady, M Allison; Ayscue, Patrick; Forrester, Joseph D; Gaddis, Bethany; Hunter, Jennifer C; Monroe, Benjamin; Pillai, Satish K; Reed, Christie; Schafer, Ilana J; Massaquoi, Moses; Dahn, Bernice; De Cock, Kevin M

2014-11-21

West Africa is experiencing the largest Ebola virus disease (Ebola) epidemic in recorded history. Health care workers (HCWs) are at increased risk for Ebola. In Liberia, as of August 14, 2014, a total of 810 cases of Ebola had been reported, including 10 clusters of Ebola cases among HCWs working in facilities that were not Ebola treatment units (non-ETUs). The Liberian Ministry of Health and Social Welfare and CDC investigated these clusters by reviewing surveillance data, interviewing county health officials, HCWs, and contact tracers, and visiting health care facilities. Ninety-seven cases of Ebola (12% of the estimated total) were identified among HCWs; 62 HCW cases (64%) were part of 10 distinct clusters in non-ETU health care facilities, primarily hospitals. Early recognition and diagnosis of Ebola in patients who were the likely source of introduction to the HCWs (i.e., source patients) was missed in four clusters. Inconsistent recognition and triage of cases of Ebola, overcrowding, limitations in layout of physical spaces, lack of training in the use of and adequate supply of personal protective equipment (PPE), and limited supervision to ensure consistent adherence to infection control practices all were observed. Improving infection control infrastructure in non-ETUs is essential for protecting HCWs. Since August, the Liberian Ministry of Health and Social Welfare with a consortium of partners have undertaken collaborative efforts to strengthen infection control infrastructure in non-ETU health facilities.

Evidence for a decrease in transmission of Ebola virus--Lofa County, Liberia, June 8-November 1, 2014.

PubMed

Sharma, Aditya; Heijenberg, Nico; Peter, Clement; Bolongei, Josephus; Reeder, Bruce; Alpha, Tamba; Sterk, Esther; Robert, Hugues; Kurth, Andreas; Cannas, Angela; Bocquin, Anne; Strecker, Thomas; Logue, Christopher; Di Caro, Antonino; Pottage, Thomas; Yue, Constanze; Stoecker, Kilian; Wölfel, Roman; Gabriel, Martin; Günther, Stephan; Damon, Inger

2014-11-21

Lofa County has one of the highest cumulative incidences of Ebola virus disease (Ebola) in Liberia. Recent situation reports from the Liberian Ministry of Health and Social Welfare (MoHSW) have indicated a decrease in new cases of Ebola in Lofa County. In October 2014, the Liberian MoHSW requested the assistance of CDC to further characterize recent trends in Ebola in Lofa County. Data collected during June 8-November 1, 2014 from three sources were analyzed: 1) aggregate data for newly reported cases, 2) case-based data for persons admitted to the dedicated Ebola treatment unit (ETU) for the county, and 3) test results for community decedents evaluated for Ebola. Trends from all three sources suggest that transmission of Ebola virus decreased as early as August 17, 2014, following rapid scale-up of response activities in Lofa County after a resurgence of Ebola in early June 2014. The comprehensive response strategy developed with participation from the local population in Lofa County might serve as a model to implement in other affected areas to accelerate control of Ebola.

Reduced evolutionary rate in reemerged Ebola virus transmission chains

PubMed Central

Blackley, David J.; Wiley, Michael R.; Ladner, Jason T.; Fallah, Mosoka; Lo, Terrence; Gilbert, Merle L.; Gregory, Christopher; D’ambrozio, Jonathan; Coulter, Stewart; Mate, Suzanne; Balogun, Zephaniah; Kugelman, Jeffrey; Nwachukwu, William; Prieto, Karla; Yeiah, Adolphus; Amegashie, Fred; Kearney, Brian; Wisniewski, Meagan; Saindon, John; Schroth, Gary; Fakoli, Lawrence; Diclaro, Joseph W.; Kuhn, Jens H.; Hensley, Lisa E.; Jahrling, Peter B.; Ströher, Ute; Nichol, Stuart T.; Massaquoi, Moses; Kateh, Francis; Clement, Peter; Gasasira, Alex; Bolay, Fatorma; Monroe, Stephan S.; Rambaut, Andrew; Sanchez-Lockhart, Mariano; Scott Laney, A.; Nyenswah, Tolbert; Christie, Athalia; Palacios, Gustavo

2016-01-01

On 29 June 2015, Liberia’s respite from Ebola virus disease (EVD) was interrupted for the second time by a renewed outbreak (“flare-up”) of seven confirmed cases. We demonstrate that, similar to the March 2015 flare-up associated with sexual transmission, this new flare-up was a reemergence of a Liberian transmission chain originating from a persistently infected source rather than a reintroduction from a reservoir or a neighboring country with active transmission. Although distinct, Ebola virus (EBOV) genomes from both flare-ups exhibit significantly low genetic divergence, indicating a reduced rate of EBOV evolution during persistent infection. Using this rate of change as a signature, we identified two additional EVD clusters that possibly arose from persistently infected sources. These findings highlight the risk of EVD flare-ups even after an outbreak is declared over. PMID:27386513

Spontaneous Mutation at Amino Acid 544 of the Ebola Virus Glycoprotein Potentiates Virus Entry and Selection in Tissue Culture.

PubMed

Ruedas, John B; Ladner, Jason T; Ettinger, Chelsea R; Gummuluru, Suryaram; Palacios, Gustavo; Connor, John H

2017-08-01

Ebolaviruses have a surface glycoprotein (GP 1,2 ) that is required for virus attachment and entry into cells. Mutations affecting GP 1,2 functions can alter virus growth properties. We generated a recombinant vesicular stomatitis virus encoding Ebola virus Makona variant GP 1,2 (rVSV-MAK-GP) and observed emergence of a T544I mutation in the Makona GP 1,2 gene during tissue culture passage in certain cell lines. The T544I mutation emerged within two passages when VSV-MAK-GP was grown on Vero E6, Vero, and BS-C-1 cells but not when it was passaged on Huh7 and HepG2 cells. The mutation led to a marked increase in virus growth kinetics and conferred a robust growth advantage over wild-type rVSV-MAK-GP on Vero E6 cells. Analysis of complete viral genomes collected from patients in western Africa indicated that this mutation was not found in Ebola virus clinical samples. However, we observed the emergence of T544I during serial passage of various Ebola Makona isolates on Vero E6 cells. Three independent isolates showed emergence of T544I from undetectable levels in nonpassaged virus or virus passaged once to frequencies of greater than 60% within a single passage, consistent with it being a tissue culture adaptation. Intriguingly, T544I is not found in any Sudan, Bundibugyo, or Tai Forest ebolavirus sequences. Furthermore, T544I did not emerge when we serially passaged recombinant VSV encoding GP 1,2 from these ebolaviruses. This report provides experimental evidence that the spontaneous mutation T544I is a tissue culture adaptation in certain cell lines and that it may be unique for the species Zaire ebolavirus IMPORTANCE The Ebola virus (Zaire) species is the most lethal species of all ebolaviruses in terms of mortality rate and number of deaths. Understanding how the Ebola virus surface glycoprotein functions to facilitate entry in cells is an area of intense research. Recently, three groups independently identified a polymorphism in the Ebola glycoprotein (I544

Spontaneous Mutation at Amino Acid 544 of the Ebola Virus Glycoprotein Potentiates Virus Entry and Selection in Tissue Culture

PubMed Central

Ladner, Jason T.; Ettinger, Chelsea R.; Palacios, Gustavo

2017-01-01

ABSTRACT Ebolaviruses have a surface glycoprotein (GP1,2) that is required for virus attachment and entry into cells. Mutations affecting GP1,2 functions can alter virus growth properties. We generated a recombinant vesicular stomatitis virus encoding Ebola virus Makona variant GP1,2 (rVSV-MAK-GP) and observed emergence of a T544I mutation in the Makona GP1,2 gene during tissue culture passage in certain cell lines. The T544I mutation emerged within two passages when VSV-MAK-GP was grown on Vero E6, Vero, and BS-C-1 cells but not when it was passaged on Huh7 and HepG2 cells. The mutation led to a marked increase in virus growth kinetics and conferred a robust growth advantage over wild-type rVSV-MAK-GP on Vero E6 cells. Analysis of complete viral genomes collected from patients in western Africa indicated that this mutation was not found in Ebola virus clinical samples. However, we observed the emergence of T544I during serial passage of various Ebola Makona isolates on Vero E6 cells. Three independent isolates showed emergence of T544I from undetectable levels in nonpassaged virus or virus passaged once to frequencies of greater than 60% within a single passage, consistent with it being a tissue culture adaptation. Intriguingly, T544I is not found in any Sudan, Bundibugyo, or Tai Forest ebolavirus sequences. Furthermore, T544I did not emerge when we serially passaged recombinant VSV encoding GP1,2 from these ebolaviruses. This report provides experimental evidence that the spontaneous mutation T544I is a tissue culture adaptation in certain cell lines and that it may be unique for the species Zaire ebolavirus. IMPORTANCE The Ebola virus (Zaire) species is the most lethal species of all ebolaviruses in terms of mortality rate and number of deaths. Understanding how the Ebola virus surface glycoprotein functions to facilitate entry in cells is an area of intense research. Recently, three groups independently identified a polymorphism in the Ebola glycoprotein (I544

Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak.

PubMed

Bogoch, Isaac I; Creatore, Maria I; Cetron, Martin S; Brownstein, John S; Pesik, Nicki; Miniota, Jennifer; Tam, Theresa; Hu, Wei; Nicolucci, Adriano; Ahmed, Saad; Yoon, James W; Berry, Isha; Hay, Simon I; Anema, Aranka; Tatem, Andrew J; MacFadden, Derek; German, Matthew; Khan, Kamran

2015-01-03

The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports. We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus. Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2.8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91,547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection

Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak

PubMed Central

Bogoch, Isaac I; Creatore, Maria I; Cetron, Martin S; Brownstein, John S; Pesik, Nicki; Miniota, Jennifer; Tam, Theresa; Hu, Wei; Nicolucci, Adriano; Ahmed, Saad; Yoon, James W; Berry, Isha; Hay, Simon I; Anema, Aranka; Tatem, Andrew J; MacFadden, Derek; German, Matthew; Khan, Kamran

2015-01-01

Summary Background The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports. Methods We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus. Findings Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2·8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91 547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk

Active Monitoring of Travelers for Ebola Virus Disease-New York City, October 25, 2014-December 29, 2015.

PubMed

Saffa, Alhaji; Tate, Anna; Ezeoke, Ifeoma; Jacobs-Wingo, Jasmine; Iqbal, Maryam; Baumgartner, Jennifer; Fine, Anne; Perri, Bianca R; McIntosh, Natasha; Levy Stennis, Natalie; Lee, Kristen; Peterson, Eric; Jones, Lucretia; Helburn, Lisa; Heindrichs, Caroline; Guthartz, Seth; Chamany, Shadi; Starr, David; Scaccia, Allison; Raphael, Marisa; Varma, Jay K; Vora, Neil M

The CDC recommended active monitoring of travelers potentially exposed to Ebola virus during the 2014 West African Ebola virus disease outbreak, which involved daily contact between travelers and health authorities to ascertain the presence of fever or symptoms for 21 days after the travelers' last potential Ebola virus exposure. From October 25, 2014, to December 29, 2015, the New York City Department of Health and Mental Hygiene (DOHMH) monitored 5,359 persons for Ebola virus disease, corresponding to 5,793 active monitoring events. Most active monitoring events were in travelers classified as low (but not zero) risk (n = 5,778; 99%). There were no gaps in contact with DOHMH of ≥2 days during 95% of active monitoring events. Instances of not making any contact with travelers decreased after CDC began distributing mobile telephones at the airport. Ebola virus disease-like symptoms or a temperature ≥100.0°F were reported in 122 (2%) active monitoring events. In the final month of active monitoring, an optional health insurance enrollment referral was offered for interested travelers, through which 8 travelers are known to have received coverage. Because it is possible that active monitoring will be used again for an infectious threat, the experience we describe might help to inform future such efforts.

Detection and classification of ebola on microfluidic chips

NASA Astrophysics Data System (ADS)

Lin, Xue; Jin, Xiangyu; Fan, Yunqian; Huang, Qin; Kou, Yue; Zu, Guo; Huang, Shiguang; Liu, Xiaosheng; Huang, Guoliang

2016-10-01

Point-of-care testing (POCT) for an infectious diseases is the prerequisite to control of the disease and limitation of its spread. A microfluidic chip for detection and classification of four strains of Ebola virus was developed and evaluated. This assay was based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) and specific primers for Ebola Zaire virus, Ebola Sudan virus, Ebola Tai Forest virus and Ebola Bundibugyo virus were designed. The sensitivity of the microfluidic chip was under 103 copies per milliliter, as determined by ten repeated tests. This assay is unique in its ability to enable diagnosis of the Ebola infections and simultaneous typing of Ebola virus on a single chip. It offers short reaction time, ease of use and high specificity. These features should enable POCT in remote area during outbreaks of Ebola virus.

Effect of the Ebola-virus-disease epidemic on malaria case management in Guinea, 2014: a cross-sectional survey of health facilities

PubMed Central

Plucinski, Mateusz M; Guilavogui, Timothée; Sidikiba, Sidibe; Diakité, Nouman; Diakité, Souleymane; Dioubaté, Mohamed; Bah, Ibrahima; Hennessee, Ian; Butts, Jessica K; Halsey, Eric S; McElroy, Peter D; Kachur, S Patrick; Aboulhab, Jamila; James, Richard; Keita, Moussa

2015-01-01

Summary Background The ongoing west Africa Ebola-virus-disease epidemic has disrupted the entire health-care system in affected countries. Because of the overlap of symptoms of Ebola virus disease and malaria, the care delivery of malaria is particularly sensitive to the indirect effects of the current Ebola-virus-disease epidemic. We therefore characterise malaria case management in the context of the Ebola-virus-disease epidemic and document the effect of the Ebola-virus-disease epidemic on malaria case management. Methods We did a cross-sectional survey of public health facilities in Guinea in December, 2014. We selected the four prefectures most affected by Ebola virus disease and selected four randomly from prefectures without any reported cases of the disease. 60 health facilities were sampled in Ebola-affected and 60 in Ebola-unaffected prefectures. Study teams abstracted malaria case management indicators from registers for January to November for 2013 and 2014 and interviewed health-care workers. Nationwide weekly surveillance data for suspect malaria cases reported between 2011 and 2014 were analysed independently. Data for malaria indicators in 2014 were compared with previous years. Findings We noted substantial reductions in all-cause outpatient visits (by 23 103 [11%] of 214 899), cases of fever (by 20249 [15%] of 131 330), and patients treated with oral (by 22 655 [24%] of 94 785) and injectable (by 5219 [30%] of 17 684) antimalarial drugs in surveyed health facilities. In Ebola-affected prefectures, 73 of 98 interviewed community health workers were operational (74%, 95% CI 65–83) and 35 of 73 were actively treating malaria cases (48%, 36–60) compared with 106 of 112 (95%, 89–98) and 102 of 106 (96%, 91–99), respectively, in Ebola-unaffected prefectures. Nationwide, the Ebola-virus-disease epidemic was estimated to have resulted in 74 000 (71 000–77 000) fewer malaria cases seen at health facilities in 2014. Interpretation The reduction in

Effect of the Ebola-virus-disease epidemic on malaria case management in Guinea, 2014: a cross-sectional survey of health facilities.

PubMed

Plucinski, Mateusz M; Guilavogui, Timothée; Sidikiba, Sidibe; Diakité, Nouman; Diakité, Souleymane; Dioubaté, Mohamed; Bah, Ibrahima; Hennessee, Ian; Butts, Jessica K; Halsey, Eric S; McElroy, Peter D; Kachur, S Patrick; Aboulhab, Jamila; James, Richard; Keita, Moussa

2015-09-01

The ongoing west Africa Ebola-virus-disease epidemic has disrupted the entire health-care system in affected countries. Because of the overlap of symptoms of Ebola virus disease and malaria, the care delivery of malaria is particularly sensitive to the indirect effects of the current Ebola-virus-disease epidemic. We therefore characterise malaria case management in the context of the Ebola-virus-disease epidemic and document the effect of the Ebola-virus-disease epidemic on malaria case management. We did a cross-sectional survey of public health facilities in Guinea in December, 2014. We selected the four prefectures most affected by Ebola virus disease and selected four randomly from prefectures without any reported cases of the disease. 60 health facilities were sampled in Ebola-affected and 60 in Ebola-unaffected prefectures. Study teams abstracted malaria case management indicators from registers for January to November for 2013 and 2014 and interviewed health-care workers. Nationwide weekly surveillance data for suspect malaria cases reported between 2011 and 2014 were analysed independently. Data for malaria indicators in 2014 were compared with previous years. We noted substantial reductions in all-cause outpatient visits (by 23 103 [11%] of 214 899), cases of fever (by 20249 [15%] of 131 330), and patients treated with oral (by 22 655 [24%] of 94 785) and injectable (by 5219 [30%] of 17 684) antimalarial drugs in surveyed health facilities. In Ebola-affected prefectures, 73 of 98 interviewed community health workers were operational (74%, 95% CI 65-83) and 35 of 73 were actively treating malaria cases (48%, 36-60) compared with 106 of 112 (95%, 89-98) and 102 of 106 (96%, 91-99), respectively, in Ebola-unaffected prefectures. Nationwide, the Ebola-virus-disease epidemic was estimated to have resulted in 74 000 (71 000-77 000) fewer malaria cases seen at health facilities in 2014. The reduction in the delivery of malaria care because of

Emerging sexually transmitted viral infections: 1. Review of Ebola virus disease.

PubMed

Caswell, Rachel J; Manavi, Kaveh

2017-11-01

This is the first in a series of articles reviewing four viral infections, Ebola virus, Zika virus, human T-cell lymphotropic virus, type 1 and hepatitis C virus, with an emphasis on recent advances in our understanding of their sexual transmission. With current day speed and ease of travel it is important for staff in sexual healthcare services to know and understand these infections when patients present to them and also to be able to advise those travelling to endemic regions. Following the recent resurgence in West Africa, this first article looks at Ebola virus disease (EVD). EVD has a high mortality rate and, of note, has been detected in the semen of those who have cleared the virus from their blood and have clinically recovered from the disease. As the result of emerging data, the WHO now recommends safe sex practices for all male survivors of EVD for 12 months after the onset of the disease or after having had two consecutive negative tests of semen specimens for the virus. This review provides an up-to-date summary of what is currently known about EVD and its implications for sexual health practice.

Deaths, late deaths, and role of infecting dose in Ebola virus disease in Sierra Leone: retrospective cohort study.

PubMed

Bower, Hilary; Smout, Elizabeth; Bangura, Mohamed S; Kamara, Osman; Turay, Cecilia; Johnson, Sembia; Oza, Shefali; Checchi, Francesco; Glynn, Judith R

2016-05-17

 To assess the frequency of fatal recrudescence from Ebola virus disease after discharge from treatment centres, and explore the influence of infecting dose on case fatality rates.  Retrospective cohort study.  Western Area, Sierra Leone.  151 survivors treated for Ebola virus disease at the Kerry Town treatment centre and discharged. Survivors were followed up for a vital status check at four to nine months after discharge, and again at six to 13 months after discharge. Verbal autopsies were conducted for four survivors who had died since discharge (that is, late deaths). Survivors still living in Western Area were interviewed together with their household members. Exposure level to Ebola virus disease was ascertained as a proxy of infecting dose, including for those who died.  Risks and causes of late death; case fatality rates; odds ratios of death from Ebola virus disease by age, sex, exposure level, date, occupation, and household risk factors.  Follow-up information was obtained on all 151 survivors of Ebola virus disease, a mean of 10 months after discharge. Four deaths occurred after discharge, all within six weeks: two probably due to late complications, one to prior tuberculosis, and only one after apparent full recovery, giving a maximum estimate of recrudescence leading to death of 0.7%. In these households, 395 people were reported to have had Ebola virus disease, of whom 227 died. A further 53 people fulfilled the case definition for probable disease, of whom 11 died. Therefore, the case fatality rate was 57.5% (227/395) for reported Ebola virus disease, or 53.1% (238/448) including probable disease. Case fatality rates were higher in children aged under 2 years and adults older than 30 years, in larger households, and in infections occurring earlier in the epidemic in Sierra Leone. There was no consistent trend of case fatality rate with exposure level, although increasing exposure increased the risk of Ebola virus disease.  In this study of

Clinical Presentation and Care of Patients with Ebola Virus Disease in the China Ebola Treatment Unit, Liberia.

PubMed

Shao, Xiaoping; Ren, Weizheng; Zhou, Feihu

2017-01-24

In order to evaluate the clinical characteristics of confirmed Ebola Virus Disease (EVD) patients admitted to the China Ebola Treatment Unit (China ETU) between January 2015 and March 2015, we retrospectively analyzed clinical symptoms, treatment, and epidemiologic features of 5 patients with confirmed EVD, and reviewed the relevant medical literature. Of these, 3 patients survived, and 2 died. The time interval from the onset of symptoms to the negative PCR test for Ebola virus in the 3 survivors was 14-18 days. All survivors reported direct contact with confirmed EVD patients up to 21 days prior to admission. All patients developed a fever, fatigue, and anorexia. Fever was generally the first symptom to develop, followed by a gastrointestinal phase characterized by vomiting/nausea (3 cases, 60%), diarrhea (3 cases), and abdominal pain (4 cases, 80%). Three patients (60%) reported joint pain, muscle pain, and conjunctival hemorrhage, respectively, and 2 patients (40%) developed a headache. We concluded that strict isolation and interruption of the route of transmission were required for suspected or confirmed EVD patients. The main treatment strategies were supportive care, maintenance of blood volume and electrolyte balance, and the prevention of complications.

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisfeld, Amie J.; Halfmann, Peter J.; Wendler, Jason P.

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ’omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integratedmore » biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.« less

Ebola Virus Neutralizing Antibodies Detectable in Survivors of theYambuku, Zaire Outbreak 40 Years after Infection.

PubMed

Rimoin, Anne W; Lu, Kai; Bramble, Matthew S; Steffen, Imke; Doshi, Reena H; Hoff, Nicole A; Mukadi, Patrick; Nicholson, Bradly P; Alfonso, Vivian H; Olinger, Gerrard; Sinai, Cyrus; Yamamoto, Lauren K; Ramirez, Christina M; Okitolonda Wemakoy, Emile; Kebela Illunga, Benoit; Pettitt, James; Logue, James; Bennett, Richard S; Jahrling, Peter; Heymann, David L; Piot, Peter; Muyembe-Tamfum, Jean Jacques; Hensley, Lisa E; Simmons, Graham

2018-01-04

The first reported outbreak of Ebola virus disease occurred in 1976 in Yambuku, Democratic Republic of Congo. Antibody responses in survivors 11 years after infection have been documented. However, this report is the first characterization of anti-Ebola virus antibody persistence and neutralization capacity 40 years after infection. Using ELISAs we measured survivor's immunological response to Ebola virus Zaire (EBOV) glycoprotein and nucleoprotein, and assessed VP40 reactivity. Neutralization of EBOV was measured using a pseudovirus approach and plaque reduction neutralization test with live EBOV. Some survivors from the original EBOV outbreak still harbor antibodies against all 3 measures. Interestingly, a subset of these survivors' serum antibodies could still neutralize live virus 40 years postinitial infection. These data provide the longest documentation of both anti-Ebola serological response and neutralization capacity within any survivor cohort, extending the known duration of response from 11 years postinfection to at least 40 years after symptomatic infection. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Immunobiology of Ebola and Lassa virus infections.

PubMed

Prescott, Joseph B; Marzi, Andrea; Safronetz, David; Robertson, Shelly J; Feldmann, Heinz; Best, Sonja M

2017-03-01

Two of the most important contemporary emerging viruses that affect human health in Africa are Ebola virus (EBOV) and Lassa virus (LASV). The 2013-2016 West African outbreak of EBOV was responsible for more than 11,000 deaths, primarily in Guinea, Sierra Leone and Liberia. LASV is constantly emerging in these and surrounding West African countries, with an estimate of more than 500,000 cases of Lassa fever, and approximately 5,000 deaths, annually. Both EBOV and LASV are zoonotic, and human infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes.

Evolution and Spread of Ebola Virus in Liberia, 2014-2015.

PubMed

Ladner, Jason T; Wiley, Michael R; Mate, Suzanne; Dudas, Gytis; Prieto, Karla; Lovett, Sean; Nagle, Elyse R; Beitzel, Brett; Gilbert, Merle L; Fakoli, Lawrence; Diclaro, Joseph W; Schoepp, Randal J; Fair, Joseph; Kuhn, Jens H; Hensley, Lisa E; Park, Daniel J; Sabeti, Pardis C; Rambaut, Andrew; Sanchez-Lockhart, Mariano; Bolay, Fatorma K; Kugelman, Jeffrey R; Palacios, Gustavo

2015-12-09

The 2013-present Western African Ebola virus disease (EVD) outbreak is the largest ever recorded with >28,000 reported cases. Ebola virus (EBOV) genome sequencing has played an important role throughout this outbreak; however, relatively few sequences have been determined from patients in Liberia, the second worst-affected country. Here, we report 140 EBOV genome sequences from the second wave of the Liberian outbreak and analyze them in combination with 782 previously published sequences from throughout the Western African outbreak. While multiple early introductions of EBOV to Liberia are evident, the majority of Liberian EVD cases are consistent with a single introduction, followed by spread and diversification within the country. Movement of the virus within Liberia was widespread, and reintroductions from Liberia served as an important source for the continuation of the already ongoing EVD outbreak in Guinea. Overall, little evidence was found for incremental adaptation of EBOV to the human host. Copyright © 2015 Elsevier Inc. All rights reserved.

Pathogenicity Comparison Between the Kikwit and Makona Ebola Virus Variants in Rhesus Macaques.

PubMed

Wong, Gary; Qiu, Xiangguo; de La Vega, Marc-Antoine; Fernando, Lisa; Wei, Haiyan; Bello, Alexander; Fausther-Bovendo, Hugues; Audet, Jonathan; Kroeker, Andrea; Kozak, Robert; Tran, Kaylie; He, Shihua; Tierney, Kevin; Soule, Geoff; Moffat, Estella; Günther, Stephan; Gao, George F; Strong, Jim; Embury-Hyatt, Carissa; Kobinger, Gary

2016-10-15

Enhanced virulence and/or transmission of West African Ebola virus (EBOV) variants, which are divergent from their Central African counterparts, are suspected to have contributed to the sizable toll of the recent Ebola virus disease (EVD) outbreak. This study evaluated the pathogenicity and shedding in rhesus macaques infected with 1 of 2 West African isolates (EBOV-C05 or EBOV-C07) or a Central African isolate (EBOV-K). All animals infected with EBOV-C05 or EBOV-C07 died of EVD, whereas 2 of 3 EBOV-K-infected animals died. The viremia level was elevated 10-fold in EBOV-C05-infected animals, compared with EBOV-C07- or EBOV-K-infected animals. More-severe lung pathology was observed in 2 of 6 EBOV-C05/C07-infected macaques. This is the first detailed analysis of the recently circulating EBOV-C05/C07 in direct comparison to EBOV-K with 6 animals per group, and it showed that EBOV-C05 but not EBOV-C07 can replicate at higher levels and cause more tissue damage in some animals. Increased virus shedding from individuals who are especially susceptible to EBOV replication is possibly one of the many challenges facing the community of healthcare and policy-making responders since the beginning of the outbreak. © Crown copyright 2016.

Vaccine to Confer to Nonhuman Primates Complete Protection Against Multistrain Ebola and Marburg Virus Infections

DTIC Science & Technology

2008-01-01

current filovirus threats in the event of natural hemorrhagic fever outbreak or biological attack. Ebola virus (EBOV) and Marburg virus (MARV) are mem...lethal, causing severe hemorrhagic fever disease in humans and apes with high mortality rates (up to 90%). The recent description of massive gorilla...threats in the event of natural hemorrhagic fever outbreak or biological attack. 15. SUBJECT TERMS filovirus, Ebola, Marburg, adenovirus-based vaccine

Ebola

MedlinePlus

... virus. It is a severe and often fatal disease. It can affect humans and other primates. Researchers ... of Ebola are similar to other, more common, diseases. This makes it difficult to diagnose Ebola in ...

Macrocyclic peptide inhibitors for the protein-protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5.

PubMed

Song, Xiao; Lu, Lu-Yi; Passioura, Toby; Suga, Hiroaki

2017-06-21

Ebola virus infection leads to severe hemorrhagic fever in human and non-human primates with an average case fatality rate of 50%. To date, numerous potential therapies are in development, but FDA-approved drugs or vaccines are yet unavailable. Ebola viral protein 24 (VP24) is a multifunctional protein that plays critical roles in the pathogenesis of Ebola virus infection, e.g. innate immune suppression by blocking the interaction between KPNA and PY-STAT1. Here we report macrocyclic peptide inhibitors of the VP24-KPNA5 protein-protein interaction (PPI) by means of the RaPID (Random non-standard Peptides Integrated Discovery) system. These macrocyclic peptides showed remarkably high affinity to recombinant Zaire Ebola virus VP24 (eVP24), with a dissociation constant in the single digit nanomolar range, and could also successfully disrupt the eVP24-KPNA interaction. This work provides for the first time a chemical probe capable of modulating this PPI interaction and is the starting point for the development of unique anti-viral drugs against the Ebola virus.

Ebola virus disease

MedlinePlus

... body fluids of infected animals Contact with infected bats Ebola does NOT spread through: Air Water Food ... who has died from Ebola. Avoid contact with bats and nonhuman primates or blood, fluids, and raw ...

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol.

PubMed

Hacke, Moritz; Björkholm, Patrik; Hellwig, Andrea; Himmels, Patricia; Ruiz de Almodóvar, Carmen; Brügger, Britta; Wieland, Felix; Ernst, Andreas M

2015-07-09

The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP1,2 or the subunit GP2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

Ebola virus disease outbreak: what's going on.

PubMed

Giraldi, G; Marsella, L T

2015-01-01

The current West African Ebola Virus Disease (EVD) outbreak was confirmed in March, 2014, and after months of slow, fragmented responses, the EVD has been recognized as a public health emergency of international concern. The early diagnosis of the disease is difficult without laboratory testing, because its symptoms can be seen in many other infections. In the wake of international agencies advices, the Italian Ministry of Health, on October 1, 2014, released to the Healthcare Professional Workers (HPWs) the Protocol about the management of cases and contacts within the national territory. Due to the increasing number of humanitarian groups and HPWs involved in the field, the probability to have new cases of contamination is higher than ever. Proven specific treatments against EVD are not yet available, however, a variety of compounds have been under testing. The most effective are select monoclonal antibodies that have a high neutralizing potential against epitopes of Ebola Virus. For facing the matter, it is important a comprehensive approach according to the recommendations proposed by the international agencies because no single institution or country has all the capacities to respond to a new and emerging infectious disease.

[Establishment of Quality Control System of Nucleic Acid Detection for Ebola Virus in Sierra Leone-China Friendship Biological Safety Laboratory].

PubMed

Wang, Qin; Zhang, Yong; Nie, Kai; Wang, Huanyu; Du, Haijun; Song, Jingdong; Xiao, Kang; Lei, Wenwen; Guo, Jianqiang; Wei, Hejiang; Cai, Kun; Wang, Yanhai; Wu, Jiang; Gerald, Bangura; Kamara, Idrissa Laybohr; Liang, Mifang; Wu, Guizhen; Dong, Xiaoping

2016-03-01

The quality control process throughout the Ebola virus nucleic acid detection in Sierra Leone-China Friendship Biological Safety Laboratory (SLE-CHN Biosafety Lab) was described in detail, in order to comprehensively display the scientific, rigorous, accurate and efficient practice in detection of Ebola virus of first batch detection team in SLE-CHN Biosafety Lab. Firstly, the key points of laboratory quality control system was described, including the managements and organizing, quality control documents and information management, instrument, reagents and supplies, assessment, facilities design and space allocation, laboratory maintenance and biosecurity. Secondly, the application of quality control methods in the whole process of the Ebola virus detection, including before the test, during the test and after the test, was analyzed. The excellent and professional laboratory staffs, the implementation of humanized management are the cornerstone of the success; High-level biological safety protection is the premise for effective quality control and completion of Ebola virus detection tasks. And professional logistics is prerequisite for launching the laboratory diagnosis of Ebola virus. The establishment and running of SLE-CHN Biosafety Lab has landmark significance for the friendship between Sierra Leone and China, and the lab becomes the most important base for Ebola virus laboratory testing in Sierra Leone.

Ebola virus vaccine: benefit and risks of adenovirus-based vectors.

PubMed

Mennechet, Franck J D; Tran, Thi Thu Phuong; Eichholz, Karsten; van de Perre, Philippe; Kremer, Eric J

2015-01-01

In 2014, an outbreak of Ebola virus spread rapidly in West Africa. The epidemic killed more than 10,000 people and resulted in transmissions outside the endemic countries. WHO hopes for effective vaccines by the end of 2015. Numerous vaccine candidates have been proposed, and several are currently being evaluated in humans. Among the vaccine candidates are vectors derived from adenovirus (Ad). Despite previous encouraging preclinical and Phase I/II trials, Ad vectors used in three Phase II trials targeting HIV were prematurely interrupted because of the lack of demonstrated efficacy. The vaccine was not only ineffective but also led to a higher rate of HIV acquisition. In this context, the authors discuss the potential benefits, risks and impact of using Ad-derived vaccines to control Ebola virus disease.

Ebola virus disease and social media: A systematic review.

PubMed

Fung, Isaac Chun-Hai; Duke, Carmen Hope; Finch, Kathryn Cameron; Snook, Kassandra Renee; Tseng, Pei-Ling; Hernandez, Ana Cristina; Gambhir, Manoj; Fu, King-Wa; Tse, Zion Tsz Ho

2016-12-01

We systematically reviewed existing research pertinent to Ebola virus disease and social media, especially to identify the research questions and the methods used to collect and analyze social media. We searched 6 databases for research articles pertinent to Ebola virus disease and social media. We extracted the data using a standardized form. We evaluated the quality of the included articles. Twelve articles were included in the main analysis: 7 from Twitter with 1 also including Weibo, 1 from Facebook, 3 from YouTube, and 1 from Instagram and Flickr. All the studies were cross-sectional. Eleven of the 12 articles studied ≥ 1of these 3 elements of social media and their relationships: themes or topics of social media contents, meta-data of social media posts (such as frequency of original posts and reposts, and impressions) and characteristics of the social media accounts that made these posts (such as whether they are individuals or institutions). One article studied how news videos influenced Twitter traffic. Twitter content analysis methods included text mining (n = 3) and manual coding (n = 1). Two studies involved mathematical modeling. All 3 YouTube studies and the Instagram/Flickr study used manual coding of videos and images, respectively. Published Ebola virus disease-related social media research focused on Twitter and YouTube. The utility of social media research to public health practitioners is warranted. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

On the Regularities of the Polar Profiles of Proteins Related to Ebola Virus Infection and their Functional Domains.

PubMed

Polanco, Carlos; Samaniego Mendoza, José Lino; Buhse, Thomas; Uversky, Vladimir N; Bañuelos Chao, Ingrid Paola; Bañuelos Cedano, Marcela Angola; Tavera, Fernando Michel; Tavera, Daniel Michel; Falconi, Manuel; Ponce de León, Abelardo Vela

2018-03-06

The number of fatalities and economic losses caused by the Ebola virus infection across the planet culminated in the havoc that occurred between August and November 2014. However, little is known about the molecular protein profile of this devastating virus. This work represents a thorough bioinformatics analysis of the regularities of charge distribution (polar profiles) in two groups of proteins and their functional domains associated with Ebola virus disease: Ebola virus proteins and Human proteins interacting with Ebola virus. Our analysis reveals that a fragment exists in each of these proteins-one named the "functional domain"-with the polar profile similar to the polar profile of the protein that contains it. Each protein is formed by a group of short sub-sequences, where each fragment has a different and distinctive polar profile and where the polar profile between adjacent short sub-sequences changes orderly and gradually to coincide with the polar profile of the whole protein. When using the charge distribution as a metric, it was observed that it effectively discriminates the proteins from their functional domains. As a counterexample, the same test was applied to a set of synthetic proteins built for that purpose, revealing that any of the regularities reported here for the Ebola virus proteins and human proteins interacting with Ebola virus were not present in the synthetic proteins. Our results indicate that the polar profile of each protein studied and its corresponding functional domain are similar. Thus, when building each protein from its functional domai-adding one amino acid at a time and plotting each time its polar profile-it was observed that the resulting graphs can be divided into groups with similar polar profiles.

A cellular automata model of Ebola virus dynamics

NASA Astrophysics Data System (ADS)

Burkhead, Emily; Hawkins, Jane

2015-11-01

We construct a stochastic cellular automaton (SCA) model for the spread of the Ebola virus (EBOV). We make substantial modifications to an existing SCA model used for HIV, introduced by others and studied by the authors. We give a rigorous analysis of the similarities between models due to the spread of virus and the typical immune response to it, and the differences which reflect the drastically different timing of the course of EBOV. We demonstrate output from the model and compare it with clinical data.

A novel life cycle modeling system for Ebola virus shows a genome length-dependent role of VP24 in virus infectivity.

PubMed

Watt, Ari; Moukambi, Felicien; Banadyga, Logan; Groseth, Allison; Callison, Julie; Herwig, Astrid; Ebihara, Hideki; Feldmann, Heinz; Hoenen, Thomas

2014-09-01

Work with infectious Ebola viruses is restricted to biosafety level 4 (BSL4) laboratories, presenting a significant barrier for studying these viruses. Life cycle modeling systems, including minigenome systems and transcription- and replication-competent virus-like particle (trVLP) systems, allow modeling of the virus life cycle under BSL2 conditions; however, all current systems model only certain aspects of the virus life cycle, rely on plasmid-based viral protein expression, and have been used to model only single infectious cycles. We have developed a novel life cycle modeling system allowing continuous passaging of infectious trVLPs containing a tetracistronic minigenome that encodes a reporter and the viral proteins VP40, VP24, and GP1,2. This system is ideally suited for studying morphogenesis, budding, and entry, in addition to genome replication and transcription. Importantly, the specific infectivity of trVLPs in this system was ∼ 500-fold higher than that in previous systems. Using this system for functional studies of VP24, we showed that, contrary to previous reports, VP24 only very modestly inhibits genome replication and transcription when expressed in a regulated fashion, which we confirmed using infectious Ebola viruses. Interestingly, we also discovered a genome length-dependent effect of VP24 on particle infectivity, which was previously undetected due to the short length of monocistronic minigenomes and which is due at least partially to a previously unknown function of VP24 in RNA packaging. Based on our findings, we propose a model for the function of VP24 that reconciles all currently available data regarding the role of VP24 in nucleocapsid assembly as well as genome replication and transcription. Ebola viruses cause severe hemorrhagic fevers in humans, with no countermeasures currently being available, and must be studied in maximum-containment laboratories. Only a few of these laboratories exist worldwide, limiting our ability to study

Recurrence and reinfection--a new paradigm for the management of Ebola virus disease.

PubMed

MacIntyre, C Raina; Chughtai, Abrar Ahmad

2016-02-01

Ebola virus disease (EVD) is an understudied infection and many aspects of viral transmission and clinical course remain unclear. With over 17000 EVD survivors in West Africa, the World Health Organization has focused its strategy on managing survivors and the risk of re-emergence of outbreaks posed by persistence of the virus during convalescence. Sexual transmission from survivors has also been documented following the 2014 epidemic and there are documented cases of survivors readmitted to hospital with 'recurrence' of EVD symptoms. In addition to persistence of virus in survivors, there is also some evidence for 'reinfection' with Ebola virus. In this paper, the evidence for recurrence and reinfection of EVD and implications for epidemic control are reviewed. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ebola virus entry requires the cholesterol transporter Niemann-Pick C1.

PubMed

Carette, Jan E; Raaben, Matthijs; Wong, Anthony C; Herbert, Andrew S; Obernosterer, Gregor; Mulherkar, Nirupama; Kuehne, Ana I; Kranzusch, Philip J; Griffin, April M; Ruthel, Gordon; Dal Cin, Paola; Dye, John M; Whelan, Sean P; Chandran, Kartik; Brummelkamp, Thijn R

2011-08-24

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection.

PubMed

Ekins, Sean; Lingerfelt, Mary A; Comer, Jason E; Freiberg, Alexander N; Mirsalis, Jon C; O'Loughlin, Kathleen; Harutyunyan, Anush; McFarlane, Claire; Green, Carol E; Madrid, Peter B

2018-02-01

Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine-learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2- and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ∼2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD. Copyright © 2018 American Society for Microbiology.

Ebola virus disease in a humanitarian aid worker - New York City, October 2014.

PubMed

Yacisin, Kari; Balter, Sharon; Fine, Annie; Weiss, Don; Ackelsberg, Joel; Prezant, David; Wilson, Ross; Starr, David; Rakeman, Jennifer; Raphael, Marisa; Quinn, Celia; Toprani, Amita; Clark, Nancy; Link, Nathan; Daskalakis, Demetre; Maybank, Aletha; Layton, Marcelle; Varma, Jay K

2015-04-03

In late October 2014, Ebola virus disease (Ebola) was diagnosed in a humanitarian aid worker who recently returned from West Africa to New York City (NYC). The NYC Department of Health and Mental Hygiene (DOHMH) actively monitored three close contacts of the patient and 114 health care personnel. No secondary cases of Ebola were detected. In collaboration with local and state partners, DOHMH had developed protocols to respond to such an event beginning in July 2014. These protocols included safely transporting a person at the first report of symptoms to a local hospital prepared to treat a patient with Ebola, laboratory testing for Ebola, and monitoring of contacts. In response to this single case of Ebola, initial health care worker active monitoring protocols needed modification to improve clarity about what types of exposure should be monitored. The response costs were high in both human resources and money: DOHMH alone spent $4.3 million. However, preparedness activities that include planning and practice in effectively monitoring the health of workers involved in Ebola patient care can help prevent transmission of Ebola.

Environmental Contamination and Persistence of Ebola Virus RNA in an Ebola Treatment Center.

PubMed

Poliquin, Philippe Guillaume; Vogt, Florian; Kasztura, Miriam; Leung, Anders; Deschambault, Yvon; Van den Bergh, Rafael; Dorion, Claire; Maes, Peter; Kamara, Abdul; Kobinger, Gary; Sprecher, Armand; Strong, James E

2016-10-15

 Ebola viruses (EBOVs) are primarily transmitted by contact with infected body fluids. Ebola treatment centers (ETCs) contain areas that are exposed to body fluids through the care of patients suspected or confirmed to have EBOV disease. There are limited data documenting which areas/fomites within ETCs pose a risk for potential transmission. This study conducted environmental surveillance in 2 ETCs in Freetown, Sierra Leone, during the 2014-2016 West African Ebola outbreak.  ETCs were surveyed over a 3-week period. Sites to be swabbed were identified with input from field personnel. Swab samples were collected and tested for the presence of EBOV RNA. Ebola-positive body fluid-impregnated cotton pads were serially sampled.  General areas of both ETCs were negative for EBOV RNA. The immediate vicinity of patients was the area most likely to be positive for EBOV RNA. Personal protective equipment became positive during patient care, but chlorine solution washes rendered them negative.  Personal protective equipment and patient environs do become positive for EBOV RNA, but careful attention to decontamination seems to remove it. EBOV RNA was not detected in general ward spaces. Careful attention to decontamination protocols seems to be important in minimizing the presence of EBOV RNA within ETC wards. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Generation of Recombinant Ebola Viruses Using Reverse Genetics.

PubMed

Groseth, Allison

2017-01-01

Reverse genetics systems encompass a wide array of tools aimed at recapitulating some or all of the virus life cycle. In their most complete form, full-length clone systems allow us to use plasmid-encoded versions of the ribonucleoprotein (RNP) components to initiate the transcription and replication of a plasmid-encoded version of the complete viral genome, thereby initiating the complete virus life cycle and resulting in infectious virus. As such this approach is ideal for the generation of tailor-made recombinant filoviruses, which can be used to study virus biology. In addition, the generation of tagged and particularly fluorescent or luminescent viruses can be applied as tools for both diagnostic applications and for screening to identify novel countermeasures. Here we describe the generation and basic characterization of recombinant Ebola viruses rescued from cloned cDNA using a T7-driven system.

Computational Modelling and Optimal Control of Ebola Virus Disease with non-Linear Incidence Rate

NASA Astrophysics Data System (ADS)

Takaidza, I.; Makinde, O. D.; Okosun, O. K.

2017-03-01

The 2014 Ebola outbreak in West Africa has exposed the need to connect modellers and those with relevant data as pivotal to better understanding of how the disease spreads and quantifying the effects of possible interventions. In this paper, we model and analyse the Ebola virus disease with non-linear incidence rate. The epidemic model created is used to describe how the Ebola virus could potentially evolve in a population. We perform an uncertainty analysis of the basic reproductive number R 0 to quantify its sensitivity to other disease-related parameters. We also analyse the sensitivity of the final epidemic size to the time control interventions (education, vaccination, quarantine and safe handling) and provide the cost effective combination of the interventions.

Molecular Docking, Pharmacophore, and 3D-QSAR Approach: Can Adenine Derivatives Exhibit Significant Inhibitor Towards Ebola Virus?

PubMed Central

Rai, Amit; Aboumanei, Mohamed H.; Verma, Suraj P.; Kumar, Sachidanand; Raj, Vinit

2017-01-01

Introduction: Ebola Virus Disease (EVD) is caused by Ebola virus, which is often accompanied by fatal hemorrhagic fever upon infection in humans. This virus has caused the majority of deaths in human. There are no proper vaccinations and medications available for EVD. It is pivoting the attraction of scientist to develop the potent vaccination or novel lead to inhibit Ebola virus. Methods & Materials: In the present study, we developed 3D-QSAR and the pharmacophoric model from the previous reported potent compounds for the Ebola virus. Results & Discussion: Results & Discussion: The pharmacophoric model AAAP.116 was generated with better survival value and selectivity. Moreover, the 3D-QSAR model also showed the best r2 value 0.99 using PLS factor. Thereby, we found the higher F value, which demonstrated the statistical significance of both the models. Furthermore, homological modeling and molecular docking study were performed to analyze the affinity of the potent lead. This showed the best binding energy and bond formation with targeted protein. Conclusion: Finally, all the results of this study concluded that 3D-QSAR and Pharmacophore models may be helpful to search potent lead for EVD treatment in future. PMID:29387271

The Ebola virus matrix protein VP40 selectively induces vesiculation from phosphatidylserine-enriched membranes.

PubMed

Soni, Smita P; Stahelin, Robert V

2014-11-28

Ebola virus is from the Filoviridae family of viruses and is one of the most virulent pathogens known with ∼ 60% clinical fatality. The Ebola virus negative sense RNA genome encodes seven proteins including viral matrix protein 40 (VP40), which is the most abundant protein found in the virions. Within infected cells VP40 localizes at the inner leaflet of the plasma membrane (PM), binds lipids, and regulates formation of new virus particles. Expression of VP40 in mammalian cells is sufficient to form virus-like particles that are nearly indistinguishable from the authentic virions. However, how VP40 interacts with the PM and forms virus-like particles is for the most part unknown. To investigate VP40 lipid specificity in a model of viral egress we employed giant unilamellar vesicles with different lipid compositions. The results demonstrate VP40 selectively induces vesiculation from membranes containing phosphatidylserine (PS) at concentrations of PS that are representative of the PM inner leaflet content. The formation of intraluminal vesicles was not significantly detected in the presence of other important PM lipids including cholesterol and polyvalent phosphoinositides, further demonstrating PS selectivity. Taken together, these studies suggest that PM phosphatidylserine may be an important component of Ebola virus budding and that VP40 may be able to mediate PM scission. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Ebola virus disease: radiology preparedness.

PubMed

Bluemke, David A; Meltzer, Carolyn C

2015-02-01

At present, there is a major emphasis on Ebola virus disease (EVD) preparedness training at medical facilities throughout the United States. Failure to have proper EVD procedures in place was cited as a major reason for infection of medical personnel in the United States. Medical imaging does not provide diagnosis of EVD, but patient assessment in the emergency department and treatment isolation care unit is likely to require imaging services. The purpose of this article is to present an overview of relevant aspects of EVD disease and preparedness relevant to the radiologic community. © RSNA, 2014.

A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults.

PubMed

Ledgerwood, J E; Costner, P; Desai, N; Holman, L; Enama, M E; Yamshchikov, G; Mulangu, S; Hu, Z; Andrews, C A; Sheets, R A; Koup, R A; Roederer, M; Bailer, R; Mascola, J R; Pau, M G; Sullivan, N J; Goudsmit, J; Nabel, G J; Graham, B S

2010-12-16

Ebola virus causes irregular outbreaks of severe hemorrhagic fever in equatorial Africa. Case mortality remains high; there is no effective treatment and outbreaks are sporadic and unpredictable. Studies of Ebola virus vaccine platforms in non-human primates have established that the induction of protective immunity is possible and safety and human immunogenicity has been demonstrated in a previous Phase I clinical trial of a 1st generation Ebola DNA vaccine. We now report the safety and immunogenicity of a recombinant adenovirus serotype 5 (rAd5) vaccine encoding the envelope glycoprotein (GP) from the Zaire and Sudan Ebola virus species, in a randomized, placebo-controlled, double-blinded, dose escalation, Phase I human study. Thirty-one healthy adults received vaccine at 2×10(9) (n=12), or 2×10(10) (n=11) viral particles or placebo (n=8) as an intramuscular injection. Antibody responses were assessed by ELISA and neutralizing assays; and T cell responses were assessed by ELISpot and intracellular cytokine staining assays. This recombinant Ebola virus vaccine was safe and subjects developed antigen specific humoral and cellular immune responses. Published by Elsevier Ltd.

Case definition for Ebola and Marburg haemorrhagic fevers: a complex challenge for epidemiologists and clinicians.

PubMed

Pittalis, Silvia; Fusco, Francesco Maria; Lanini, Simone; Nisii, Carla; Puro, Vincenzo; Lauria, Francesco Nicola; Ippolito, Giuseppe

2009-10-01

Viral haemorrhagic fevers (VHFs) represent a challenge for public health because of their epidemic potential, and their possible use as bioterrorism agents poses particular concern. In 1999 the World Health Organization (WHO) proposed a case definition for VHFs, subsequently adopted by other international institutions with the aim of early detection of initial cases/outbreaks in western countries. We applied this case definition to reports of Ebola and Marburg virus infections to estimate its sensitivity to detect cases of the disease. We analyzed clinical descriptions of 795 reported cases of Ebola haemorrhagic fever: only 58.5% of patients met the proposed case definition. A similar figure was obtained reviewing 169 cases of Marburg diseases, of which only 64.5% were in accordance with the case definition. In conclusion, the WHO case definition for hemorrhagic fevers is too specific and has poor sensitivity both for case finding during Ebola or Marburg outbreaks, and for early detection of suspected cases in western countries. It can lead to a hazardous number of false negatives and its use should be discouraged for early detection of cases.

Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques.

PubMed

Guedj, Jérémie; Piorkowski, Géraldine; Jacquot, Frédéric; Madelain, Vincent; Nguyen, Thi Huyen Tram; Rodallec, Anne; Gunther, Stephan; Carbonnelle, Caroline; Mentré, France; Raoul, Hervé; de Lamballerie, Xavier

2018-03-01

Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs). A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 μg/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 μg/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing

Risk in the "Red Zone": Outcomes for Children Admitted to Ebola Holding Units in Sierra Leone Without Ebola Virus Disease.

PubMed

Fitzgerald, F; Wing, K; Naveed, A; Gbessay, M; Ross, J C G; Checchi, F; Youkee, D; Jalloh, M B; Baion, D; Mustapha, A; Jah, H; Lako, S; Oza, S; Boufkhed, S; Feury, R; Bielicki, J; Williamson, E; Gibb, D M; Klein, N; Sahr, F; Yeung, S

2017-07-01

We collected data on 1054 children admitted to Ebola Holding Units in Sierra Leone and describe outcomes of 697/1054 children testing negative for Ebola virus disease (EVD) and accompanying caregivers. Case-fatality was 9%; 3/630 (0.5%) children discharged testing negative were readmitted EVD-positive. Nosocomial EVD transmission risk may be lower than feared. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Experimental Respiratory Infection of Marmosets (Callithrix jacchus) With Ebola Virus Kikwit.

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Nunez, Alejandro; Salguero, Francisco J; Lever, Mark S

2015-10-01

Ebola virus (EBOV) causes a highly infectious and lethal hemorrhagic fever in primates with high fatality rates during outbreaks and EBOV may be exploited as a potential biothreat pathogen. There is therefore a need to develop and license appropriate medical countermeasures against this virus. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess vaccines or therapies against EBOV disease (EVD), initial susceptibility, lethality and pathogenesis studies were performed. Low doses of EBOV-Kikwit, between 4 and 27 times the 50% tissue culture infectious dose, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to EVD between 6 and 8 days after challenge. Typical signs of EVD were observed. Pathogenesis studies revealed that virus was isolated from the lungs of animals beginning on day 3 after challenge and from the liver, spleen and blood beginning on day 5. The most striking features were observed in animals that succumbed to infection, including high viral titers in all organs, increased levels of liver function enzymes and blood clotting times, decreased levels of platelets, multifocal moderate to severe hepatitis, and perivascular edema. © Crown copyright 2015.

Evolutionary conservation of Ebola virus proteins predicts important functions at residue level.

PubMed

Arslan, Ahmed; van Noort, Vera

2017-01-15

The recent outbreak of Ebola virus disease (EVD) resulted in a large number of human deaths. Due to this devastation, the Ebola virus has attracted renewed interest as model for virus evolution. Recent literature on Ebola virus (EBOV) has contributed substantially to our understanding of the underlying genetics and its scope with reference to the 2014 outbreak. But no study yet, has focused on the conservation patterns of EBOV proteins. We analyzed the evolution of functional regions of EBOV and highlight the function of conserved residues in protein activities. We apply an array of computational tools to dissect the functions of EBOV proteins in detail: (i) protein sequence conservation, (ii) protein-protein interactome analysis, (iii) structural modeling and (iv) kinase prediction. Our results suggest the presence of novel post-translational modifications in EBOV proteins and their role in the modulation of protein functions and protein interactions. Moreover, on the basis of the presence of ATM recognition motifs in all EBOV proteins we postulate a role of DNA damage response pathways and ATM kinase in EVD. The ATM kinase is put forward, for further evaluation, as novel potential therapeutic target. http://www.biw.kuleuven.be/CSB/EBOV-PTMs CONTACT: vera.vannoort@biw.kuleuven.beSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Ebola virus infection kinetics in chimeric mice reveal a key role of T cells as barriers for virus dissemination

PubMed Central