Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico
Abstract
Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.
Additional Information
© 2017 Elsevier Inc. Received 3 April 2017, Revised 17 April 2017, Accepted 17 April 2017, Available online 4 May 2017. We would especially like to thank the members of the Santa Maria Mixtequilla and Pau da Lima communities who agreed to participate in this study, as well as the Fiocruz community research team and staff of Hospital Geral Roberto Santos for their assistance with the clinical protocols. We thank members of the Nussenzweig and Rice labs for helpful discussions and suggestions. A particular thank you to Lotta von Boehmer, Christian Mayer, Yotam Bar-On, Irina Shimeliovich, and Julio Cetrulo Lorenzi for sharing expertise, protocols, and reagents. We thank Ted Pierson for plasmids pWNVII-Rep-REN-IB and pZIKV/HPF/CprME, Aaron Brault (CDC) for ZIKV PRVABC59, Bob Tesh for DENV1 PUO-359, Matt Evans for ZIKV MR766 cDNA, and Greg Ebel, James Weger, and Brian Geiss for ZIKV PRVABC59 cDNA. We are grateful to Laura Kramer (NYSDOH) and Robert Lanciotti (CDC) for PRNT advice and protocols, Kimberly Dowd for RVP advice, and Muhammad Arshad for cloning assistance. We thank Barbara Johnson, Ann Powers, Christin Goodman, Claire Huang, Brandy Russell (CDC), and Claudia Duarte dos Santos for sharing ZIKV information early on. Moreover, we are thankful to Mary Ellen Castillo for facilitating virus work in the cell culture core, Alison Ashbrook for help with PRNT assays, Natalia Frias-Staheli for generation of the DENV1 stock, Corrine Quirk for assistance with mouse colonies, Tiffany Luong, Alisa Voll, and the Caltech Protein Expression Center for cloning, expression, and purification of proteins for crystallography, and Christopher Barnes and Beth Stadtmueller for help with crystallographic methods. This work was supported by NIH pilot awards U19AI111825 (to D.F.R.) and UL1TR001866 (to D.F.R. and L.B.), grants R01AI037526, UM1AI100663, U19AI111825, and UL1TR001866 (to M.C.N.), grants R01AI121207, R01TW009504, R25TW009338, and U01AI088752 (to A.I.K.), grants R01AI124690 (to C.M.R.) and U19AI057229 (CCHI Opportunity Fund Project to C.M.R. and M.R.M.), donors to the Zika Fund at Rockefeller University and anonymous donors (to C.M.R.), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation (P.J.B.). Operations at the Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and the NIH. Support was also provided by the Robertson Therapeutic Development Fund (to 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. by Studienstiftung des deutschen Volkes, L.F.K.U. by the Austrian Marshall Plan Foundation, and E.E.S.-R. is partly supported by Red INMUNOCANEI-Conacyt. M.C.N. is an HHMI Investigator. In connection with this work, D.F.R. and M.C.N. have a provisional patent application with the U.S. Patent and Trademark Office (62/483,001). The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies or individuals.Attached Files
Accepted Version - nihms869847.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.xlsx
Supplemental Material - mmc3.xlsx
Files
Additional details
- PMCID
- PMC5492969
- Eprint ID
- 77442
- Resolver ID
- CaltechAUTHORS:20170515-095254627
- U19AI111825-01
- NIH
- UL1TR001866
- NIH
- R01AI037526
- NIH
- UM1AI100663
- NIH
- U19AI111825
- NIH
- UL1TR001866
- NIH
- R01AI121207
- NIH
- R01TW009504
- NIH
- R25TW009338
- NIH
- U01AI088752
- NIH
- R01AI124690
- NIH
- U19AI057229
- NIH
- CCHI Opportunity Fund
- Rockefeller University Zika Fund
- Gordon and Betty Moore Foundation
- Department of Energy (DOE)
- Robertson Therapeutic Development Fund
- Pew Latin American Fellows Program in the Biomedical Sciences
- Studienstiftung des deutschen Volkes
- Austrian Marshall Plan Foundation
- Consejo Nacional de Ciencia y Tecnología (CONACYT)
- Created
-
2017-05-16Created from EPrint's datestamp field
- Updated
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2022-03-28Created from EPrint's last_modified field