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: 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
• Journal: Cell reports (Cell Rep) Vol. 12 Issue 12 Pg. 2111-20 (Sep 29 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26365189 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antibodies, Viral
• Epitopes
• Recombinant Proteins

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (administration & dosage, biosynthesis)
• Antibodies, Neutralizing (administration & dosage, biosynthesis)
• Antibodies, Viral (administration & dosage, biosynthesis)
• Base Sequence
• Ebolavirus (genetics, immunology, pathogenicity)
• Epitopes (chemistry, immunology)
• Hemorrhagic Fever, Ebola (immunology, mortality, prevention & control, virology)
• Humans
• Immune Evasion (genetics)
• Immunization, Passive
• Macaca mulatta
• Molecular Sequence Data
• Mutation
• Protein Binding
• Recombinant Proteins (administration & dosage, biosynthesis)
• Retrospective Studies
• Survival Analysis
• Nicotiana (genetics)
• Virus Replication