Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail
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
Affiliations
Jeffrey R. Kugelman
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Johanny Kugelman-Tonos
Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Jason T. Ladner
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
James Pettit
Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA
Carolyn M. Keeton
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Elyse R. Nagle
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Karla Y. Garcia
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Jeffrey W. Froude
Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Ana I. Kuehne
Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Jens H. Kuhn
Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA
Sina Bavari
Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Larry Zeitlin
Mapp Biopharmaceutical, Inc., San Diego, CA 92121, USA
John M. Dye
Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Gene G. Olinger
Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA
Mariano Sanchez-Lockhart
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
Gustavo F. Palacios
Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA
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.
