Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

Rajeshwer S. Sankhala, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Vincent Dussupt, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Gina Donofrio, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Gregory D. Gromowski, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Rafael A. De La Barrera, Pilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Rafael A. Larocca, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Letzibeth Mendez-Rivera, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Anna Lee, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Misook Choe, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Weam Zaky, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Grace Mantus, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Jaime L. Jensen, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Wei-Hung Chen, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Neelakshi Gohain, Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Hongjun Bai, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Michael K. McCracken, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Rosemarie D. Mason, Vaccine Research Center, NIH, Bethesda, MD 20852, USA.
David Leggat, Vaccine Research Center, NIH, Bethesda, MD 20852, USA.
Bonnie M. Slike, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Ursula Tran, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Ningbo Jian, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Peter Abbink, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Rebecca Peterson, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Eric Araujo Mendes, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Rafael Freitas de Oliveira Franca, Oswaldo Cruz Foundation Institute Aggeu Magalhães, Recife, PE 50740-465, Brazil.
Guilherme Amaral Calvet, Oswaldo Cruz Foundation, Evandro Chagas National Institute of Infectious Diseases, Rio de Janeiro, RJ 21040-360, Brazil.
Ana Maria Bispo de Filippis, Oswaldo Cruz Foundation, Oswaldo Cruz Institute, Rio de Janeiro, RJ 21041-300, Brazil.
Adrian McDermott, Vaccine Research Center, NIH, Bethesda, MD 20852, USA.
Mario Roederer, Vaccine Research Center, NIH, Bethesda, MD 20852, USA.
Mayda Hernandez, Integral Molecular, Philadelphia, PA 19104, USA.
Amie Albertus, Integral Molecular, Philadelphia, PA 19104, USA.
Edgar Davidson, Integral Molecular, Philadelphia, PA 19104, USA.

Document Type

Journal Article

Publication Date

8-29-2023

Journal

Cell reports

Volume

42

Issue

8

DOI

10.1016/j.celrep.2023.112942

Keywords

CP: Immunology; X-ray crystallography; Zika virus; dengue virus; flavivirus; monoclonal antibodies; neutralizing antibodies; rhesus macaque; structural biology

Abstract

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.

Department

Microbiology, Immunology, and Tropical Medicine

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