A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions.

Abstract

West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States1. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection2. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively3. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml-1, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies4. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions.

• Authors: Leslie Goo, Kari Debbink, Nurgun Kose, Gopal Sapparapu, Michael P Doyle, Alex W Wessel, Justin M Richner, Katherine E Burgomaster, Bridget C Larman, Kimberly A Dowd, Michael S Diamond, James E Crowe Jr, Theodore C Pierson
• Journal: Nature microbiology (Nat Microbiol) Vol. 4 Issue 1 Pg. 71-77 (01 2019) ISSN: 2058-5276 [Electronic] England
• PMID: 30455471 (Publication Type: Letter, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antibodies, Viral
• Viral Envelope Proteins
• West Nile Virus Vaccines
• glycoprotein E, Flavivirus

Topics

• Aedes
• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Antibodies, Neutralizing (immunology, therapeutic use)
• Antibodies, Viral (immunology, therapeutic use)
• Cell Line
• Chlorocebus aethiops
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Protein Domains (immunology)
• Vero Cells
• Viral Envelope Proteins (immunology)
• West Nile Fever (prevention & control, therapy)
• West Nile Virus Vaccines (therapeutic use)
• West Nile virus (immunology)