{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T08:39:25Z","timestamp":1775983165141,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,19]],"date-time":"2021-09-19T00:00:00Z","timestamp":1632009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.<\/jats:p>","DOI":"10.3390\/vaccines9091045","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T22:35:20Z","timestamp":1632263720000},"page":"1045","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Selection of Filovirus Isolates for Vaccine Development Programs"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8392-9506","authenticated-orcid":false,"given":"Daniel N.","family":"Wolfe","sequence":"first","affiliation":[{"name":"U.S. Department of Health and Human Services (DHHS), Assistant Secretary for Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), Washington, DC 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol L.","family":"Sabourin","sequence":"additional","affiliation":[{"name":"Tunnell Government Services, Inc., Supporting Biomedical Advanced Research & Development Authority (BARDA), Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services (DHHS), Washington, DC 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Merchlinsky","sequence":"additional","affiliation":[{"name":"U.S. Department of Health and Human Services (DHHS), Assistant Secretary for Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), Washington, DC 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C.","family":"Florence","sequence":"additional","affiliation":[{"name":"U.S. Department of Health and Human Services (DHHS), National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD 20852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry A.","family":"Wolfraim","sequence":"additional","affiliation":[{"name":"U.S. Department of Health and Human Services (DHHS), National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD 20852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly L.","family":"Taylor","sequence":"additional","affiliation":[{"name":"U.S. Department of Health and Human Services (DHHS), National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD 20852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy A.","family":"Ward","sequence":"additional","affiliation":[{"name":"U.S. Department of Defense (DOD), Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), Joint Project Manager for Chemical, Biological, Radiological, and Nuclear Medical (JPM CBRN Medical), Fort Detrick, MD 21702, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41579-019-0187-4","article-title":"New filovirus disease classification and no-menclature","volume":"17","author":"Kuhn","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102375","DOI":"10.1016\/j.jaut.2019.102375","article-title":"Ebola virus disease: An emerging and re-emerging viral threat","volume":"106","author":"Rojas","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(16)32621-6","article-title":"Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: Final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola \u00c7a Suffit!)","volume":"389","author":"Camacho","year":"2017","journal-title":"Lancet"},{"key":"ref_4","unstructured":"World Health Organization (2021, September 15). Preliminary Results on the Efficacy of rVSV-ZEBOV-GP Ebola Vaccine Using the Ring Vaccination Strategy in the Control of an Ebola Outbreak in the Democratic Republic of the Congo: An Example of Integration of Research into Epidemic Response, Available online: https:\/\/www.who.int\/publications\/m\/item\/preliminary-results-on-the-efficacy-of-rvsv-zebov-gp-ebola-vaccine-using-the-strategy-in-the-control-of-an-ebola-outbreak."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1046\/j.1365-3156.2002.00944.x","article-title":"An outbreak of Ebola in Uganda","volume":"7","author":"Okware","year":"2002","journal-title":"Trop. Med. Int. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10370","DOI":"10.1128\/JVI.78.19.10370-10377.2004","article-title":"Analysis of Human Peripheral Blood Samples from Fatal and Nonfatal Cases of Ebola (Sudan) Hemorrhagic Fever: Cellular Responses, Virus Load, and Nitric Oxide Levels","volume":"78","author":"Sanchez","year":"2004","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.3201\/eid1612.100627","article-title":"Proportion of Deaths and Clinical Features in Bundibugyo Ebola Virus Infection, Uganda","volume":"16","author":"MacNeil","year":"2010","journal-title":"Emerg. Infect. Dis."},{"key":"ref_8","unstructured":"Centers for Disease Control and Prevention (2021, May 28). Outbreaks Chronology: Marburg Hemorrhagic Fever, Available online: https:\/\/www.cdc.gov\/vhf\/marburg\/outbreaks\/chronology.html."},{"key":"ref_9","first-page":"241","article-title":"A Comparison of the Pathogenesis of Marburg Virus Disease in Humans and Nonhuman Primates and Evaluation of the Suitability of These Animal Models for Predicting Clinical Efficacy under the \u2018Animal Rule\u2019","volume":"65","author":"Glaze","year":"2015","journal-title":"Comp. Med."},{"key":"ref_10","unstructured":"U.S. Food and Drug Administration (2021, September 15). Product Development under the Animal Rule, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/product-development-under-animal-rule."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wolf, J., Jannat, R., Dubey, S., Troth, S., Onorato, M., Coller, B.-A., Hanson, M., and Simon, J. (2021). Development of Pandemic Vaccines: ERVEBO Case Study. Vaccines, 9.","DOI":"10.3390\/vaccines9030190"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.vaccine.2010.10.037","article-title":"A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults","volume":"29","author":"Ledgerwood","year":"2010","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1128\/CVI.00162-06","article-title":"A DNA Vaccine for Ebola Virus Is Safe and Immunogenic in a Phase I Clinical Trial","volume":"13","author":"Martin","year":"2006","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7178","DOI":"10.1016\/j.vaccine.2017.10.111","article-title":"Progress towards a vaccine against Ebola to meet emergency medical countermeasure needs","volume":"37","author":"Wolfe","year":"2019","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.vaccine.2020.11.042","article-title":"Systematic review of Marburg virus vaccine nonhuman primate studies and human clinical trials","volume":"39","author":"Dulin","year":"2020","journal-title":"Vaccine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1080\/21645515.2020.1741313","article-title":"Lessons learned from Zaire ebolavirus to help address urgent needs for vaccines against Sudan ebolavirus and Marburg virus","volume":"16","author":"Wolfe","year":"2020","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41541-020-00261-9","article-title":"Nonhuman primate to human immunobridging to infer the protective effect of an Ebola virus vaccine candidate","volume":"5","author":"Roozendaal","year":"2020","journal-title":"NPJ Vaccines"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1126\/science.aab3920","article-title":"VSV-EBOV rapidly protects macaques against infection with the 2014\/15 Ebola virus outbreak strain","volume":"349","author":"Marzi","year":"2015","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.cell.2015.06.007","article-title":"Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone","volume":"161","author":"Park","year":"2015","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00820-18","DOI":"10.1128\/JVI.00820-18","article-title":"Growth-Adaptive Mutations in the Ebola Virus Makona Glycoprotein Alter Different Steps in the Virus Entry Pathway","volume":"92","author":"Ruedas","year":"2018","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6773","DOI":"10.1128\/JVI.00649-15","article-title":"Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques","volume":"89","author":"Alfson","year":"2015","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kugelman, J.R., Lee, M.S., Rossi, C.A., McCarthy, S.E., Radoshitzky, S., Dye, J.M., Hensley, L., Honko, A., Kuhn, J.H., and Jahrling, P.B. (2012). Ebola Virus Genome Plasticity as a Marker of Its Passaging History: A Comparison of In Vitro Passaging to Non-Human Primate Infection. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050316"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6739","DOI":"10.3390\/v7122969","article-title":"Ebola Virus Infections in Nonhuman Primates Are Temporally Influenced by Glycoprotein Poly-U Editing Site Populations in the Exposure Material","volume":"7","author":"Trefrey","year":"2015","journal-title":"Viruses"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1056\/NEJMoa1404505","article-title":"Emergence of Zaire Ebola Virus Disease in Guinea","volume":"371","author":"Baize","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S259","DOI":"10.1086\/514302","article-title":"Ebola Outbreak in Kikwit, Democratic Republic of the Congo: Discovery and Control Measures","volume":"179","author":"Kipasa","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1002\/ece3.297","article-title":"Phylogenetic assessment of filoviruses: How many lineages of Marburg virus?","volume":"2","author":"Peterson","year":"2012","journal-title":"Ecol. Evol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1586\/14760584.7.4.417","article-title":"Monovalent virus-like particle vaccine protects guinea pigs and nonhuman primates against infection with multiple Marburg viruses","volume":"7","author":"Swenson","year":"2008","journal-title":"Expert Rev. Vaccines"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mire, C.E., Geisbert, J.B., Agans, K.N., Satterfield, B., Versteeg, K.M., Fritz, E.A., Feldmann, H., Hensley, L., and Geisbert, T.W. (2014). Durability of a Vesicular Stomatitis Virus-Based Marburg Virus Vaccine in Nonhuman Primates. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094355"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Callendret, B., Vellinga, J., Wunderlich, K., Rodriguez, A., Steigerwald, R., Dirmeier, U., Cheminay, C., Volkmann, A., Brasel, T., and Carrion, R. (2018). A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196546"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1080\/21645515.2015.1039757","article-title":"Codon-Optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges","volume":"11","author":"Altamura","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dye, J.M., Warfield, K.L., Wells, J.B., Unfer, R.C., Shulenin, S., Vu, H., Nichols, D.K., Aman, M.J., and Bavari, S. (2016). Virus-Like Particle Vaccination Protects Nonhuman Primates from Lethal Aerosol Exposure with Marburgvirus (VLP Vaccination Protects Macaques against Aerosol Challenges). Viruses, 8.","DOI":"10.3390\/v8040094"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1006\/viro.1998.9367","article-title":"Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates","volume":"251","author":"Hevey","year":"1998","journal-title":"Virology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6497","DOI":"10.1128\/JVI.00069-06","article-title":"Marburgvirus Genomics and Association with a Large Hemorrhagic Fever Outbreak in Angola","volume":"80","author":"Towner","year":"2006","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Blair, P.W., Keshtkar-Jahromi, M., Psoter, K.J., Reisler, R.B., Warren, T.K., Johnston, S.C., Goff, A.J., Downey, L.G., Bavari, S., and Cardile, A.P. (2018). Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis. Viruses, 10.","DOI":"10.3390\/v10110658"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1128\/JVI.03118-12","article-title":"Mo-lecular Evolution of Viruses of the Family Filoviridae Based on 97 Whole-Genome Sequences","volume":"87","author":"Carroll","year":"2013","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7296","DOI":"10.1128\/JVI.00561-09","article-title":"Single-Injection Vaccine Protects Nonhuman Primates against Infection with Marburg Virus and Three Species of Ebola Virus","volume":"83","author":"Geisbert","year":"2009","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Warfield, K.L., Dye, J.M., Wells, J.B., Unfer, R.C., Holtsberg, F.W., Shulenin, S., Vu, H., Swenson, D.L., Bavari, S., and Aman, M.J. (2015). Homologous and Heterologous Protection of Nonhuman Primates by Ebola and Sudan Virus-Like Particles. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118881"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4952","DOI":"10.1128\/JVI.03361-12","article-title":"Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus","volume":"87","author":"Herbert","year":"2013","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/s41564-018-0227-2","article-title":"Discovery of a new ebolavirus (Bombali virus) in molossid bats in Sierra Leone","volume":"3","author":"Goldstein","year":"2018","journal-title":"Nat. Microbiol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/9\/1045\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:19Z","timestamp":1760166139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/9\/1045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,19]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["vaccines9091045"],"URL":"https:\/\/doi.org\/10.3390\/vaccines9091045","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,19]]}}}