title: Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail.
abstract: 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.
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kugelman
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Johanny
authors.initials: J
authors.lastname: Kugelman-Tonos
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Ladner
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA.
authors.forename: James
authors.initials: J
authors.lastname: Pettit
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Keeton
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Elyse R
authors.initials: ER
authors.lastname: Nagle
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Karla Y
authors.initials: KY
authors.lastname: Garcia
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Froude
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Kuehne
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Kuhn
authors.affiliation: Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.affiliation: Mapp Biopharmaceutical, Inc., San Diego, CA 92121, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Zeitlin
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Mariano
authors.initials: M
authors.lastname: Sanchez-Lockhart
authors.affiliation: Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA. Electronic address: gustavo.f.palacios.ctr@mail.mil.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Palacios
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000096:biosynthesis; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000096:biosynthesis; D000914:Antibodies, Viral / Q000008:administration & dosage* / Q000096:biosynthesis; D001483:Base Sequence; D029043:Ebolavirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000401:mortality / Q000517:prevention & control / Q000821:virology*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D007116:Immunization, Passive; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis; D012189:Retrospective Studies; D016019:Survival Analysis; D014026:Nicotiana / Q000235:genetics; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D011994:Recombinant Proteins