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Published April 7, 2020 | Supplemental Material + Submitted + Published
Journal Article Open

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

Abstract

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.

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 https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2000414117/-/DCSupplemental.

Attached Files

Published - 7981.full.pdf

Submitted - 2020.01.31.926899v1.full.pdf

Supplemental Material - pnas.2000414117.sapp.pdf

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Additional details

Created:
August 22, 2023
Modified:
December 22, 2023