James Crowe
Faculty Member
Last active: 3/31/2019

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

Goo L, Debbink K, Kose N, Sapparapu G, Doyle MP, Wessel AW, Richner JM, Burgomaster KE, Larman BC, Dowd KA, Diamond MS, Crowe JE, Pierson TC
Nat Microbiol. 2019 4 (1): 71-77

PMID: 30455471 · PMCID: PMC6435290 · DOI:10.1038/s41564-018-0283-7

West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection. 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, respectively. 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, 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 antibodies. 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.

MeSH Terms (18)

Aedes Animals Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Cell Line Cercopithecus aethiops HEK293 Cells Humans Male Mice Mice, Inbred C57BL Protein Domains Vero Cells Viral Envelope Proteins West Nile Fever West Nile virus West Nile Virus Vaccines

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