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      Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp

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          Abstract

          Without an approved vaccine or treatment, 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. Here we show that a combination of monoclonal antibodies (ZMapp ), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viremia, and abnormalities in blood count and chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal hemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp currently exceeds all previous descriptions of efficacy with other therapeutics, and results warrant further development of this cocktail for clinical use.

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          Most cited references 34

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          Emergence of Zaire Ebola virus disease in Guinea.

          In March 2014, the World Health Organization was notified of an outbreak of a communicable disease characterized by fever, severe diarrhea, vomiting, and a high fatality rate in Guinea. Virologic investigation identified Zaire ebolavirus (EBOV) as the causative agent. Full-length genome sequencing and phylogenetic analysis showed that EBOV from Guinea forms a separate clade in relationship to the known EBOV strains from the Democratic Republic of Congo and Gabon. Epidemiologic investigation linked the laboratory-confirmed cases with the presumed first fatality of the outbreak in December 2013. This study demonstrates the emergence of a new EBOV strain in Guinea.
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            Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study

            Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding Defense Threat Reduction Agency.
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              Epitopes involved in antibody-mediated protection from Ebola virus.

              To determine the ability of antibodies to provide protection from Ebola viruses, monoclonal antibodies (mAbs) to the Ebola glycoprotein were generated and evaluated for efficacy. We identified several protective mAbs directed toward five unique epitopes on Ebola glycoprotein. One of the epitopes is conserved among all Ebola viruses that are known to be pathogenic for humans. Some protective mAbs were also effective therapeutically when administered to mice 2 days after exposure to lethal Ebola virus. The identification of protective mAbs has important implications for developing vaccines and therapies for Ebola virus.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                25 August 2014
                29 August 2014
                2 October 2014
                02 April 2015
                : 514
                : 7520
                : 47-53
                Affiliations
                [1 ]National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, MB, Canada
                [2 ]Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
                [3 ]Institute of Infectious Disease, Henan Centre for Disease Control, China
                [4 ]Kentucky BioProcessing, Owensboro, KY, USA
                [5 ]Mapp Biopharmaceutical Inc., San Diego, CA, USA
                [6 ]United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, MD, USA
                [7 ]Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
                [8 ]Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
                [9 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
                Author notes
                [* ]Corresponding authors: Gary Kobinger, Ph.D., Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2 Canada, Phone: (204) 784-5923, Fax: (204) 789-2140, gary.kobinger@ 123456phac-aspc.gc.ca . Larry Zeitlin, Ph.D., Mapp Biopharmaceutical Inc., 6160 Lusk Blvd #C105, San Diego, CA 92121 USA, Phone: (443) 629-0104, larry.zeitlin@ 123456mappbio.com
                [+]

                current address: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA

                Article
                NIHMS622923
                10.1038/nature13777
                4214273
                25171469
                Categories
                Article

                Uncategorized

                ebola, nonhuman primates, zmapp™, post-exposure therapy, monoclonal antibodies

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