Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.

Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require te...

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Autores principales:	Nancy A Niemuth, Dawn Fallacara, Cheryl A Triplett, Sanjay M Tamrakar, Alisha Rajbhandari, Clint Florence, Lucy Ward, Anthony Griffiths, Ricardo Carrion, Yenny Goez-Gazi, Kendra J Alfson, Hilary M Staples, Trevor Brasel, Jason E Comer, Shane Massey, Jeanon Smith, Andrew Kocsis, Jake Lowry, Sara C Johnston, Aysegul Nalca, Arthur J Goff, Amy C Shurtleff, Margaret L Pitt, John Trefry, Michael P Fay
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/872942b1dcae494498eca02d622ed9e7
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spelling	oai:doaj.org-article:872942b1dcae494498eca02d622ed9e72021-12-02T20:05:13ZNatural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.1932-620310.1371/journal.pone.0252874https://doaj.org/article/872942b1dcae494498eca02d622ed9e72021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252874https://doaj.org/toc/1932-6203Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.Nancy A NiemuthDawn FallacaraCheryl A TriplettSanjay M TamrakarAlisha RajbhandariClint FlorenceLucy WardAnthony GriffithsRicardo CarrionYenny Goez-GaziKendra J AlfsonHilary M StaplesTrevor BraselJason E ComerShane MasseyJeanon SmithAndrew KocsisJake LowrySara C JohnstonAysegul NalcaArthur J GoffAmy C ShurtleffMargaret L PittJohn TrefryMichael P FayPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0252874 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nancy A Niemuth Dawn Fallacara Cheryl A Triplett Sanjay M Tamrakar Alisha Rajbhandari Clint Florence Lucy Ward Anthony Griffiths Ricardo Carrion Yenny Goez-Gazi Kendra J Alfson Hilary M Staples Trevor Brasel Jason E Comer Shane Massey Jeanon Smith Andrew Kocsis Jake Lowry Sara C Johnston Aysegul Nalca Arthur J Goff Amy C Shurtleff Margaret L Pitt John Trefry Michael P Fay Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
description	Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.
format	article
author	Nancy A Niemuth Dawn Fallacara Cheryl A Triplett Sanjay M Tamrakar Alisha Rajbhandari Clint Florence Lucy Ward Anthony Griffiths Ricardo Carrion Yenny Goez-Gazi Kendra J Alfson Hilary M Staples Trevor Brasel Jason E Comer Shane Massey Jeanon Smith Andrew Kocsis Jake Lowry Sara C Johnston Aysegul Nalca Arthur J Goff Amy C Shurtleff Margaret L Pitt John Trefry Michael P Fay
author_facet	Nancy A Niemuth Dawn Fallacara Cheryl A Triplett Sanjay M Tamrakar Alisha Rajbhandari Clint Florence Lucy Ward Anthony Griffiths Ricardo Carrion Yenny Goez-Gazi Kendra J Alfson Hilary M Staples Trevor Brasel Jason E Comer Shane Massey Jeanon Smith Andrew Kocsis Jake Lowry Sara C Johnston Aysegul Nalca Arthur J Goff Amy C Shurtleff Margaret L Pitt John Trefry Michael P Fay
author_sort	Nancy A Niemuth
title	Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
title_short	Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
title_full	Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
title_fullStr	Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
title_full_unstemmed	Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.
title_sort	natural history of disease in cynomolgus monkeys exposed to ebola virus kikwit strain demonstrates the reliability of this non-human primate model for ebola virus disease.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/872942b1dcae494498eca02d622ed9e7
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Natural history of disease in cynomolgus monkeys exposed to Ebola virus Kikwit strain demonstrates the reliability of this non-human primate model for Ebola virus disease.

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