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A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

Van Rompay, Koen K. A. and Coffey, Lark L. and Kapoor, Tania and Gazumyanc, Anna and Keesler, Rebekah I. and Jurado, Andrea and Peace, Avery and Agudelo, Marianna and Watanabe, Jennifer and Usachenko, Jodie and Singapuri, Anil and Immareddy, Ramya and Ardeshir, Amir and Stuart, Jackson B. and Bournazos, Stylianos and Ravetch, Jeffrey V. and Balderes, Paul J. and Lorenz, Ivo C. and Esswein, Shannon R. and Keeffe, Jennifer R. and Bjorkman, Pamela J. and Wang, Qiao and Rice, Charles M. and MacDonald, Margaret R. and Nussenzweig, Michel C. and Robbiani, Davide F. (2020) A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques. Proceedings of the National Academy of Sciences of the United States of America, 117 (14). pp. 7981-7989. ISSN 0027-8424. PMCID PMC7149495. doi:10.1073/pnas.2000414117.

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Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement in vitro (ADE) and extend their half-lives. Here we report on prophylactic co-administration of the Fc-modified antibodies to pregnant rhesus macaques challenged 3 times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.

Item Type:Article
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URLURL TypeDescription Information CentralArticle Paper
Van Rompay, Koen K. A.0000-0002-7375-1337
Coffey, Lark L.0000-0002-0718-5146
Kapoor, Tania0000-0002-0396-4476
Jurado, Andrea0000-0002-4023-8000
Peace, Avery0000-0003-3074-1662
Agudelo, Marianna0000-0003-3924-6449
Watanabe, Jennifer0000-0001-9408-3991
Singapuri, Anil0000-0003-0524-0655
Immareddy, Ramya0000-0002-3612-1985
Ardeshir, Amir0000-0002-4330-4659
Stuart, Jackson B.0000-0001-9577-1737
Bournazos, Stylianos0000-0001-5466-5620
Ravetch, Jeffrey V.0000-0003-2024-9041
Lorenz, Ivo C.0000-0002-7373-1176
Esswein, Shannon R.0000-0002-5142-0190
Keeffe, Jennifer R.0000-0002-5317-6398
Bjorkman, Pamela J.0000-0002-2277-3990
Wang, Qiao0000-0001-6416-1733
Rice, Charles M.0000-0003-3087-8079
MacDonald, Margaret R.0000-0001-5177-2068
Nussenzweig, Michel C.0000-0003-0592-8564
Robbiani, Davide F.0000-0001-7379-3484
Additional Information:© 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by Michel C. Nussenzweig, February 25, 2020 (sent for review January 22, 2020; reviewed by Sonja Best and Guido Silvestri). PNAS first published March 24, 2020. We thank Kai-Hui Yao and Daniel Yost at Rockefeller University, as well as A. Gibbons, M. Allen, V. Bakula, M. Christensen, I. Cazares, W. von Morgenland, the veterinary staff, pathology staff, and the staffs of Colony Management and Research Services and the Clinical Laboratory at the California National Primate Center for expert assistance. We also thank Mohsan Saeed (Boston University) for construction of plasmid pZIKV/HPF/CprM*PRVABC59E. This work was supported by awards from NIH, U19AI111825, P01AI138938, and UL1TR001866 (to D.F.R.), R01AI037526, UM1AI100663, U19AI111825, P01AI138938, and UL1TR001866 (to M.C.N.); funding from Lyda Hill Philanthropies (to M.C.N.); grants R01AI124690 and U19AI057229 (CCHI pilot project); The Rockefeller University Development Office, and anonymous donors (to 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.); and grant R21AI129479-S (to K.K.A.V.R.). Support was also provided by the Robertson Therapeutic Development Fund (to D.F.R. and M.C.N.) and a scholarship from the Studienstiftung des Deutschen Volkes (to T.K.). S.R.E. is supported by NIH National Research Service Award Fellowship F30AI147579 and NIH National Institute of General Medical Sciences Training grant T32-GM008042 through the University of California, Los Angeles-Caltech Medical Scientist Training Program. M.C.N. is a Howard Hughes Medical Institute Investigator. Data Availability: All data are available in SI Appendix. Author contributions: M.C.N. and D.F.R. designed research; T.K., A.G., A.J., A.P., M.A., J.W., J.U., A.S., R.I., A.A., J.B.S., S.B., S.R.E., and Q.W. performed research; S.B., J.V.R., P.J. Balderes, and I.C.L. contributed new reagents/analytic tools; K.K.A.V.R., L.L.C., T.K., R.I.K., S.B., J.R.K., P.J. Bjorkman, C.M.R., M.R.M., M.C.N., and D.F.R. analyzed data; M.C.N. and D.F.R. wrote the paper; K.K.A.V.R. interpreted the data and supervised J.W., J.U. and R.I. in the laboratory management of the macaque experiments; L.L.C. supervised A.S. and J.B.S. in viral load determination and sequencing of virus escape mutations; T.K. cloned plasmids to produce mutant ZIKV RVPs, performed RVP neutralization experiments together with Q.W., and measured human IgG in macaque plasma together with M.A.; A.G. produced and purified antibodies for macaque, mouse, and in vitro experiments; R.I.K. performed necropsies and histopathological evaluations; A.A. assisted with data analysis/graphing; J.R.K. and P.J. Bjorkman performed in silico structural analysis; and C.M.R. and M.R.M. supervised and interpreted experimental results. Reviewers: S.B., National Institutes of Health, Rocky Mountain Laboratory; and G.S., Emory University. Competing interest statement: The Rockefeller University, D.F.R., and M.C.N. have filed a patent application for antibodies Z004 and Z021. This article contains supporting information online at
Funding AgencyGrant Number
Lyda Hill PhilanthropiesUNSPECIFIED
Rockefeller UniversityUNSPECIFIED
University of California, DavisUNSPECIFIED
Robertson Therapeutic Development FundUNSPECIFIED
Studienstiftung des deutschen VolkesUNSPECIFIED
NIH Predoctoral FellowshipT32-GM008042
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Fc domain modifications; Zika virus; macaque pregnancy model; antibody-dependent enhancement; congenital Zika syndrome
Issue or Number:14
PubMed Central ID:PMC7149495
Record Number:CaltechAUTHORS:20200203-091204189
Persistent URL:
Official Citation:A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques. Koen K. A. Van Rompay, Lark L. Coffey, Tania Kapoor, Anna Gazumyan, Rebekah I. Keesler, Andrea Jurado, Avery Peace, Marianna Agudelo, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Ramya Immareddy, Amir Ardeshir, Jackson B. Stuart, Stylianos Bournazos, Jeffrey V. Ravetch, Paul J. Balderes, Ivo C. Lorenz, Shannon R. Esswein, Jennifer R. Keeffe, Pamela J. Bjorkman, Qiao Wang, Charles M. Rice, Margaret R. MacDonald, Michel C. Nussenzweig, Davide F. Robbiani. Proceedings of the National Academy of Sciences Apr 2020, 117 (14) 7981-7989; DOI: 10.1073/pnas.2000414117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101052
Deposited By: Tony Diaz
Deposited On:03 Feb 2020 17:26
Last Modified:15 Feb 2022 23:20

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