Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail
MB-003, a plant-derived monoclonal antibody cocktail used effectively in treatment of Ebola virus infection in non-human primates, was unable to protect two of six animals when initiated 1 or 2 days post-infection. We characterized a mechanism of viral escape in one of the animals, after observation...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715009237 |
| _version_ | 1828416266801512448 |
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| author | Jeffrey R. Kugelman Johanny Kugelman-Tonos Jason T. Ladner James Pettit Carolyn M. Keeton Elyse R. Nagle Karla Y. Garcia Jeffrey W. Froude Ana I. Kuehne Jens H. Kuhn Sina Bavari Larry Zeitlin John M. Dye Gene G. Olinger Mariano Sanchez-Lockhart Gustavo F. Palacios |
| author_facet | Jeffrey R. Kugelman Johanny Kugelman-Tonos Jason T. Ladner James Pettit Carolyn M. Keeton Elyse R. Nagle Karla Y. Garcia Jeffrey W. Froude Ana I. Kuehne Jens H. Kuhn Sina Bavari Larry Zeitlin John M. Dye Gene G. Olinger Mariano Sanchez-Lockhart Gustavo F. Palacios |
| author_sort | Jeffrey R. Kugelman |
| collection | DOAJ |
| description | MB-003, a plant-derived monoclonal antibody cocktail used effectively in treatment of Ebola virus infection in non-human primates, was unable to protect two of six animals when initiated 1 or 2 days post-infection. We characterized a mechanism of viral escape in one of the animals, after observation of two clusters of genomic mutations that resulted in five nonsynonymous mutations in the monoclonal antibody target sites. These mutations were linked to a reduction in antibody binding and later confirmed to be present in a viral isolate that was not neutralized in vitro. Retrospective evaluation of a second independent study allowed the identification of a similar case. Four SNPs in previously identified positions were found in this second fatality, suggesting that genetic drift could be a potential cause for treatment failure. These findings highlight the importance selecting different target domains for each component of the cocktail to minimize the potential for viral escape. |
| first_indexed | 2024-12-10T14:01:04Z |
| format | Article |
| id | doaj.art-dc883dcf66c3464cadf39bdec67933ae |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T14:01:04Z |
| publishDate | 2015-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-dc883dcf66c3464cadf39bdec67933ae2022-12-22T01:45:49ZengElsevierCell Reports2211-12472015-09-0112122111212010.1016/j.celrep.2015.08.038Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody CocktailJeffrey R. Kugelman0Johanny Kugelman-Tonos1Jason T. Ladner2James Pettit3Carolyn M. Keeton4Elyse R. Nagle5Karla Y. Garcia6Jeffrey W. Froude7Ana I. Kuehne8Jens H. Kuhn9Sina Bavari10Larry Zeitlin11John M. Dye12Gene G. Olinger13Mariano Sanchez-Lockhart14Gustavo F. Palacios15Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAMolecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAVirology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAVirology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USAMolecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAMapp Biopharmaceutical, Inc., San Diego, CA 92121, USAVirology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USACenter for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USAMB-003, a plant-derived monoclonal antibody cocktail used effectively in treatment of Ebola virus infection in non-human primates, was unable to protect two of six animals when initiated 1 or 2 days post-infection. We characterized a mechanism of viral escape in one of the animals, after observation of two clusters of genomic mutations that resulted in five nonsynonymous mutations in the monoclonal antibody target sites. These mutations were linked to a reduction in antibody binding and later confirmed to be present in a viral isolate that was not neutralized in vitro. Retrospective evaluation of a second independent study allowed the identification of a similar case. Four SNPs in previously identified positions were found in this second fatality, suggesting that genetic drift could be a potential cause for treatment failure. These findings highlight the importance selecting different target domains for each component of the cocktail to minimize the potential for viral escape.http://www.sciencedirect.com/science/article/pii/S2211124715009237 |
| spellingShingle | Jeffrey R. Kugelman Johanny Kugelman-Tonos Jason T. Ladner James Pettit Carolyn M. Keeton Elyse R. Nagle Karla Y. Garcia Jeffrey W. Froude Ana I. Kuehne Jens H. Kuhn Sina Bavari Larry Zeitlin John M. Dye Gene G. Olinger Mariano Sanchez-Lockhart Gustavo F. Palacios Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail Cell Reports |
| title | Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail |
| title_full | Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail |
| title_fullStr | Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail |
| title_full_unstemmed | Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail |
| title_short | Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail |
| title_sort | emergence of ebola virus escape variants in infected nonhuman primates treated with the mb 003 antibody cocktail |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715009237 |
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