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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.

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Fig. 1: Serum and mAb neutralization of WNV.
Fig. 2: Effect of virion maturation on mAb neutralization.
Fig. 3: In vitro selection of WNV-86 escape variants.
Fig. 4: Therapeutic efficacy of mAbs.

Data availability

Additional data sets generated and/or analysed during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

This study was funded by NIH grants R01 AI073755 (to M.S.D. and J.E.C.) and HHSN272201400018C (to M.S.D.), and by the intramural research program of the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases (T.C.P.). Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource, which is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). The project was supported by CTSA award no. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

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L.G., K.D., N.K., G.S., M.P.D., A.W.W., J.M.R., K.E.B., B.C.L. and K.A.D. designed and performed experiments. L.G. and T.C.P. analysed the data and wrote the manuscript. L.G., K.D., G.S., J.M.R., K.E.B., M.S.D., J.E.C. and T.C.P. edited the manuscript. M.S.D., J.E.C. and T.C.P. conceived of and supervised the study.

Corresponding authors

Correspondence to James E. Crowe Jr. or Theodore C. Pierson.

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Competing interests

M.S.D. is a consultant for Inbios and Sanofi-Pasteur and is on the Scientific Advisory Board of Moderna. J.E.C. has served as a consultant for Takeda Vaccines, Sanofi Pasteur, Pfizer and Novavax; is on the Scientific Advisory Boards of CompuVax, GigaGen, Meissa Vaccines and PaxVax; and is Founder of IDBiologics.

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Supplementary Table 1 and Supplementary Figures 1–10

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Goo, L., Debbink, K., Kose, N. et al. A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions. Nat Microbiol 4, 71–77 (2019). https://doi.org/10.1038/s41564-018-0283-7

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