Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope

Feng Long; Michael Doyle; Estefania Fernandez; Andrew S. Miller; Thomas Klose; Madhumati Sevvana; Aubrey Bryan; Edgar Davidson; Benjamin J. Doranz; Richard J. Kuhn; Michael S. Diamond; James E. Crowe; Michael G. Rossmann

doi:10.1073/pnas.1815432116

New Research In

Edited by Wah Chiu, Stanford University, Stanford, CA, and approved December 11, 2018 (received for review September 7, 2018)

Significance

Zika virus (ZIKV) has reemerged recently to cause serious human disease. However, there is no licensed vaccine or treatment currently available for ZIKV infections. Potently neutralizing antibodies are of interest due to their prophylactic and therapeutic potential. Here, we show that ZIKV-195, a potently neutralizing human monoclonal antibody, has postexposure therapeutic activity against ZIKV infection in a mouse model. We further describe the near-atomic resolution structure of the ZIKV virion in complex with ZIKV-195 Fab fragments and suggest a neutralization mechanism.

Abstract

Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.

Footnotes

↵¹To whom correspondence should be addressed. Email: mr{at}purdue.edu.

Author contributions: F.L., B.J.D., R.J.K., M.S.D., J.E.C., and M.G.R. designed research; F.L., M.D., E.F., A.S.M., A.B., and E.D. performed research; F.L., M.D., E.F., T.K., M.S., E.D., B.J.D., R.J.K., M.S.D., J.E.C., and M.G.R. analyzed data; and F.L., E.D., B.J.D., R.J.K., M.S.D., J.E.C., and M.G.R. wrote the paper.
Conflict of interest statement: 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, and Meissa Vaccines; and is Founder of IDBiologics, Inc. Vanderbilt University has a patent application pending that pertains in part to the ZIKV-195 antibody. M.S.D. is a consultant for Inbios and is on the Scientific Advisory Board of Moderna. A.B., E.D., and B.J.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular.
This article is a PNAS Direct Submission.
Data deposition: The cryo-EM map and coordinates of ZIKV in complex of Fab ZIKV-195 have been deposited in the Electron Microscopy Data Bank (accession no. EMD-9131) and the Protein Data Bank (accession no. 6MID).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815432116/-/DCSupplemental.

Published under the PNAS license.

View Full Text