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      Euthanasia Assessment in Ebola Virus Infected Nonhuman Primates

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          Abstract

          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.

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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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            Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease.

            Antibody therapies to prevent or limit filovirus infections have received modest interest in recent years, in part because of early negative experimental evidence. We have overcome the limitations of this approach, leveraging the use of antibody from nonhuman primates (NHPs) that survived challenge to filoviruses under controlled conditions. By using concentrated, polyclonal IgG antibody from these survivors, we treated filovirus-infected NHPs with multiple doses administered over the clinical phase of disease. In the first study, Marburg virus (MARV)-infected NHPs were treated 15 to 30 min postexposure with virus-specific IgG, with additional treatments on days 4 and 8 postexposure. The postexposure IgG treatment was completely protective, with no signs of disease or detectable viremia. MARV-specific IgM antibody responses were generated, and all macaques survived rechallenge with MARV, suggesting that they generated an immune response to virus replication. In the next set of studies, NHPs were infected with MARV or Ebola virus (EBOV), and treatments were delayed 48 h, with additional treatments on days 4 and 8 postexposure. The delayed treatments protected both MARV- and EBOV-challenged NHPs. In both studies, two of the three IgG-treated NHPs had no clinical signs of illness, with the third NHP developing mild and delayed signs of disease followed by full recovery. These studies clearly demonstrate that postexposure antibody treatments can protect NHPs and open avenues for filovirus therapies for human use using established Food and Drug Administration-approved polyclonal or monoclonal antibody technologies.
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              Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates

              Containment of highly lethal Ebola virus outbreaks poses a serious public health challenge. Although an experimental vaccine has successfully protected non-human primates against disease 1 , more than six months was required to complete the immunizations, making it impractical to limit an acute epidemic. Here, we report the development of accelerated vaccination against Ebola virus in non-human primates. The antibody response to immunization with an adenoviral (ADV) vector encoding the Ebola glycoprotein (GP) was induced more rapidly than with DNA priming and ADV boosting, but it was of lower magnitude. To determine whether this earlier immune response could nonetheless protect against disease, cynomolgus macaques were challenged with Ebola virus after vaccination with ADV–GP and nucleoprotein (NP) vectors. Protection was highly effective and correlated with the generation of Ebola-specific CD8+ T-cell and antibody responses. Even when animals were immunized once with ADV–GP/NP and challenged 28 days later, they remained resistant to challenge with either low or high doses of virus. This accelerated vaccine provides an intervention that may help to limit the epidemic spread of Ebola, and is applicable to other viruses. Supplementary information The online version of this article (doi:10.1038/nature01876) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Role: External Editor
                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                24 November 2014
                November 2014
                : 6
                : 11
                : 4666-4682
                Affiliations
                [1 ]US Army Medical Research Institute for Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702, USA; E-Mails: john.c.trefry.ctr@ 123456mail.mil (J.C.T.); shannon.t.marko.mil@ 123456mail.mil (S.T.M.); taylor.b.chance.mil@ 123456mail.mil (T.B.C.); jay.b.wells.ctr@ 123456mail.mil (J.B.W.); william.d.pratt4.civ@ 123456mail.mil (W.D.P.); joshua.johnson@ 123456nih.gov (J.C.J.); eric.m.mucker.ctr@ 123456mail.mil (E.M.M.); sarah.l.norris2.civ@ 123456mail.mil (S.L.N.); mark.chappell@ 123456usuhs.edu (M.C.); john.m.dye1.civ@ 123456mail.mil (J.M.D.); anna.honko@ 123456nih.gov (A.N.H.)
                [2 ]Madigan Army Medical Center, 9040 Jackson Ave., Tacoma, WA 98431, USA
                [3 ]National Institute of Allergy and Infectious Diseases, Integrated Research Facility, 8200 Research Plaza, Fort Detrick, MD 21702, USA
                [4 ]Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Building 42, Bethesda, MD 20889, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: travis.k.warren.ctr@ 123456mail.mil ; Tel.: +1-301-619-3414; Fax: +1-301-619-0350.
                Article
                viruses-06-04666
                10.3390/v6114666
                4246243
                25421892
                f8eb2e29-13c1-4e1c-aa44-b89e03c9ee4b
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 October 2014
                : 17 November 2014
                : 18 November 2014
                Categories
                Article

                Microbiology & Virology
                filovirus,nonhuman primate,viral hemorrhagic fever,euthanasia,clinical pathology,ebola virus

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