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

Keeffe, Jennifer R. and Van Rompay, Koen K. A. and Olsen, Priscilla C. and Wang, Qiao and Gazumyan, Anna and Azzopardi, Stephanie A. and Schaefer-Babajew, Dennis and Lee, Yu E. and Stuart, Jackson B. and Singapuri, Anil and Watanabe, Jennifer and Usachenko, Jodie and Ardeshir, Amir and Saeed, Mohsan and Agudelo, Marianna and Eisenreich, Thomas and Bournazos, Stylianos and Oliveira, Thiago Y. and Rice, Charles M. and Coffey, Lark L. and MacDonald, Margaret R. and Bjorkman, Pamela J. and Nussenzweig, Michel C. and Robbiani, Davide F. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Reports, 25 (6). pp. 1385-1394. ISSN 2211-1247. PMCID PMC6268006. http://resolver.caltech.edu/CaltechAUTHORS:20181106-092448645

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2018.10.031DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268006PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
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.
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)UNSPECIFIED
NIHU19AI111825
NIHUL1TR001866
NIHR01AI037526
NIHUM1AI100663
NIHU19AI111825
NIHP01AI138938
NIHUL1TR001866
Lyda HillUNSPECIFIED
NIHR01AI124690
NIHU19AI057229
Rockefeller UniversityUNSPECIFIED
NIHP51OD011107
University of California, DavisUNSPECIFIED
NIH1R21AI129479-01
Gordon and Betty Moore FoundationUNSPECIFIED
Robertson Therapeutic Development FundUNSPECIFIED
Pew Latin American Fellows ProgramUNSPECIFIED
Studienstiftung des deutschen VolkesUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
PubMed Central ID:PMC6268006
Record Number:CaltechAUTHORS:20181106-092448645
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181106-092448645
Official Citation:Jennifer R. Keeffe, Koen K.A. Van Rompay, Priscilla C. Olsen, Qiao Wang, Anna Gazumyan, Stephanie A. Azzopardi, Dennis Schaefer-Babajew, Yu E. Lee, Jackson B. Stuart, Anil Singapuri, Jennifer Watanabe, Jodie Usachenko, Amir Ardeshir, Mohsan Saeed, Marianna Agudelo, Thomas Eisenreich, Stylianos Bournazos, Thiago Y. Oliveira, Charles M. Rice, Lark L. Coffey, Margaret R. MacDonald, Pamela J. Bjorkman, Michel C. Nussenzweig, Davide F. Robbiani, A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates, Cell Reports, Volume 25, Issue 6, 2018, Pages 1385-1394.e7, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2018.10.031. (http://www.sciencedirect.com/science/article/pii/S2211124718316073)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90664
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Nov 2018 18:21
Last Modified:03 Dec 2018 15:36

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