Published November 6, 2018 | Published + Accepted Version + Supplemental Material

Journal Article Open

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

Creators: Keeffe, Jennifer R.; Van Rompay, Koen K. A.; Olsen, Priscilla C.; Wang, Qiao; Gazumyan, Anna; Azzopardi, Stephanie A.; Schaefer-Babajew, Dennis; Lee, Yu E.; Stuart, Jackson B.; Singapuri, Anil; Watanabe, Jennifer; Usachenko, Jodie; Ardeshir, Amir; Saeed, Mohsan; Agudelo, Marianna; Eisenreich, Thomas; Bournazos, Stylianos; Oliveira, Thiago Y.; Rice, Charles M.; Coffey, Lark L.; MacDonald, Margaret R.; Bjorkman, Pamela J.; Nussenzweig, Michel C.; Robbiani, Davide F.

Abstract

Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.

Additional Information

© 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Received 9 August 2018, Revised 15 September 2018, Accepted 5 October 2018, Available online 6 November 2018. We thank Kai-Hui Yao, Daniel Yost, and Jovana Golijanin at Rockefeller, as well as the veterinary staff, pathology staff, and the staff of Colony Management and Research Services and Clinical Laboratory at the California National Primate Center for expert assistance. We thank Alisa Voll, Tiffany Luong, and the Caltech Protein Expression Center directed by Dr. Jost Vielmetter for cloning and expression and purification of proteins and Anthony P. West, Jr., Harry B. Gristick, Beth Stadtmueller, and Christopher Barnes for help with crystallographic methods and helpful discussions. We also thank Jens Kaiser from the Molecular Observatory at the Beckman Institute at the California Institute of Technology, Ruslan Sanishvili at APS beamline 23-ID-D (Argonne National Laboratory), and the staff at beamline 12–2, Stanford Synchrotron Radiation Lightsource (SSRL), for their assistance with crystallographic data collection and processing. Operations at SSRL are supported by the US Department of Energy and NIH, and operations at APS are supported by the NIH (NIGMS and National Cancer Institute). This work was supported by the NIH (pilot awards U19AI111825 and UL1TR001866 to D.F.R.; grants R01AI037526, UM1AI100663, U19AI111825, P01AI138938, and UL1TR001866 to M.C.N.), funding by Lyda Hill (to M.C.N.), NIH grants R01AI124690 and U19AI057229 (CCHI pilot project), The Rockefeller University Development Office and anonymous donors (C.M.R. and M.R.M.), the Office of Research Infrastructure Programs/OD (grant P51OD011107), start-up funds from the Pathology, Microbiology and Immunology Department (to L.L.C.), NIH grant 1R21AI129479-01 (to K.K.A.V.R.), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation (P.J.B.). Support was also provided by the Robertson Therapeutic Development Fund (D.F.R. and M.C.N.). P.C.O. is supported by the Pew Latin American Fellows Program in the Biomedical Sciences, D.S.-B. is supported by Studienstiftung des deutschen Volkes, and M.C.N. is an HHMI Investigator. Author Contributions: J.R.K. performed biochemical experiments, solved and analyzed crystal structures, and wrote structure-related parts of the paper together with P.J.B. P.C.O., Q.W., A.G., D.-S.B., M.A., S.A.A., M.S., Y.E.L., and T.E. produced reagents, developed protocols, and conducted immunology, virology, and mouse infection experiments. S.B. performed the SPR assays. T.Y.O. analyzed data, including statistical analysis. A.S. and J.B.S. conducted qRT-PCR and sequencing experiments from macaques under supervision of L.L.C., who also edited the manuscript. J.W., J.U., and A.A. performed macaque experiments under the supervision of K.K.A.V.R., who also edited the manuscript. C.M.R. and M.R.M. supervised, interpreted experimental results, and edited the manuscript. M.C.N. supervised, designed, and interpreted experiments and wrote the paper. D.F.R. designed, supervised, and conducted experiments, interpreted experimental results, and wrote the paper. Declaration of Interests: D.F.R., M.C.N., and the Rockefeller University have filed a patent application for antibodies Z004 and Z021.

Attached Files

Published - 1-s2.0-S2211124718316073-main.pdf

Accepted Version - nihms-1512146.pdf

Supplemental Material - 1-s2.0-S2211124718316073-mmc1.pdf

Files

1-s2.0-S2211124718316073-mmc1.pdf

Files (7.8 MB)

Name	Size	Download all
1-s2.0-S2211124718316073-mmc1.pdf md5:1bcae1b2728bd1460b1943d40642ddb7	2.0 MB	Preview Download
1-s2.0-S2211124718316073-main.pdf md5:453ca27d31a95acbe797f3051351be9e	3.7 MB	Preview Download
nihms-1512146.pdf md5:1c5d4af0e50e6704a019564fb570445b	2.1 MB	Preview Download

Additional details

	All versions	This version
Views	0	0
Downloads	0	0
Data volume	0 Bytes	0 Bytes