Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

Rajeshwer S Sankhala; Vincent Dussupt; Gina Donofrio; Gregory D Gromowski; Rafael A De La Barrera; Rafael A Larocca; Letzibeth Mendez-Rivera; Anna Lee; Misook Choe; Weam Zaky; Grace Mantus; Jaime L Jensen; Wei-Hung Chen; Neelakshi Gohain; Hongjun Bai; Michael K McCracken; Rosemarie D Mason; David Leggat; Bonnie M Slike; Ursula Tran; Ningbo Jian; Peter Abbink; Rebecca Peterson; Erica Araujo Mendes; Rafael Freitas de Oliveira Franca; Guilherme Amaral Calvet; Ana Maria Bispo de Filippis; Adrian McDermott; Mario Roederer; Mayda Hernandez; Amie Albertus; Edgar Davidson; Benjamin J Doranz; Morgane Rolland; Merlin L Robb; Rebecca M Lynch; Dan H Barouch; Richard G Jarman; Stephen J Thomas; Kayvon Modjarrad; Nelson L Michael; Shelly J Krebs; M Gordon Joyce

doi:10.1016/j.celrep.2023.112942

Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

Cell Rep. 2023 Aug 29;42(8):112942. doi: 10.1016/j.celrep.2023.112942. Epub 2023 Aug 9.

Authors

Rajeshwer S Sankhala¹, Vincent Dussupt², Gina Donofrio², Gregory D Gromowski³, Rafael A De La Barrera⁴, Rafael A Larocca⁵, Letzibeth Mendez-Rivera², Anna Lee⁶, Misook Choe¹, Weam Zaky⁶, Grace Mantus⁷, Jaime L Jensen¹, Wei-Hung Chen¹, Neelakshi Gohain¹, Hongjun Bai⁶, Michael K McCracken³, Rosemarie D Mason⁸, David Leggat⁸, Bonnie M Slike⁶, Ursula Tran⁶, Ningbo Jian⁶, Peter Abbink⁵, Rebecca Peterson⁵, Erica Araujo Mendes⁵, Rafael Freitas de Oliveira Franca⁹, Guilherme Amaral Calvet¹⁰, Ana Maria Bispo de Filippis¹¹, Adrian McDermott⁸, Mario Roederer⁸, Mayda Hernandez¹², Amie Albertus¹², Edgar Davidson¹², Benjamin J Doranz¹², Morgane Rolland⁶, Merlin L Robb¹³, Rebecca M Lynch⁷, Dan H Barouch¹⁴, Richard G Jarman³, Stephen J Thomas³, Kayvon Modjarrad¹⁵, Nelson L Michael¹⁶, Shelly J Krebs¹⁷, M Gordon Joyce¹⁸

Affiliations

¹ 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.
² 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.
³ Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
⁴ Pilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
⁵ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁶ 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.
⁷ George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
⁸ Vaccine Research Center, NIH, Bethesda, MD 20852, USA.
⁹ Oswaldo Cruz Foundation Institute Aggeu Magalhães, Recife, PE 50740-465, Brazil.
¹⁰ Oswaldo Cruz Foundation, Evandro Chagas National Institute of Infectious Diseases, Rio de Janeiro, RJ 21040-360, Brazil.
¹¹ Oswaldo Cruz Foundation, Oswaldo Cruz Institute, Rio de Janeiro, RJ 21041-300, Brazil.
¹² Integral Molecular, Philadelphia, PA 19104, USA.
¹³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
¹⁴ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
¹⁵ Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹⁶ Center of Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹⁷ 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. Electronic address: skrebs@hivresearch.org.
¹⁸ 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. Electronic address: gjoyce@eidresearch.org.

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.

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

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Dengue Virus*
Dengue*
Epitopes
Humans
Macaca mulatta
Mice
Viral Envelope Proteins / chemistry
Viral Vaccines* / therapeutic use
Zika Virus Infection*
Zika Virus*

Substances

Antibodies, Neutralizing
Epitopes
Antibodies, Viral
Antibodies, Monoclonal
Viral Vaccines
Viral Envelope Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding