The epitope arrangement on flavivirus particles contributes to Mab C10's extraordinary neutralization breadth across Zika and dengue viruses

Arvind Sharma; Xiaokang Zhang; Wanwisa Dejnirattisai; Xinghong Dai; Danyang Gong; Wiyada Wongwiwat; Stéphane Duquerroy; Alexander Rouvinski; Marie-Christine Vaney; Pablo Guardado-Calvo; Ahmed Haouz; Patrick England; Ren Sun; Z Hong Zhou; Juthathip Mongkolsapaya; Gavin R Screaton; Felix A Rey

doi:10.1016/j.cell.2021.11.010

The epitope arrangement on flavivirus particles contributes to Mab C10's extraordinary neutralization breadth across Zika and dengue viruses

Cell. 2021 Dec 9;184(25):6052-6066.e18. doi: 10.1016/j.cell.2021.11.010. Epub 2021 Nov 30.

Authors

Arvind Sharma¹, Xiaokang Zhang², Wanwisa Dejnirattisai³, Xinghong Dai⁴, Danyang Gong⁵, Wiyada Wongwiwat³, Stéphane Duquerroy⁶, Alexander Rouvinski¹, Marie-Christine Vaney¹, Pablo Guardado-Calvo¹, Ahmed Haouz⁷, Patrick England⁷, Ren Sun⁸, Z Hong Zhou⁹, Juthathip Mongkolsapaya¹⁰, Gavin R Screaton¹¹, Felix A Rey¹²

Affiliations

¹ Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France.
² Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France; Interdisciplinary Center for Brain Information, the Brain Cognition and Brain Disease Institute, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong 518055, China.
³ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France; Université Paris-Saclay, Faculté des Sciences, F-91405 Orsay, France.
⁷ Institut Pasteur, Université de Paris, CNRS UMR 3528, Center for Technological Resources and Research, 75015 Paris, France.
⁸ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
¹¹ Division of Medical Sciences, University of Oxford, Oxford, UK. Electronic address: gavin.screaton@medsci.ox.ac.uk.
¹² Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France. Electronic address: felix.rey@pasteur.fr.

Abstract

The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.

Keywords: Dengue virus; Flaviviruses; X-ray crystallography; Zika virus; broadly neutralizing antibodies; cryo-EM; vaccine design.

Publication types

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

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing* / immunology
Antibodies, Neutralizing* / metabolism
Antibodies, Viral / immunology
Cell Line
Chlorocebus aethiops
Cross Reactions / immunology
Dengue Virus* / immunology
Dengue Virus* / physiology
Dengue* / immunology
Dengue* / virology
Drosophila melanogaster
HEK293 Cells
Humans
Protein Binding
Protein Conformation
Vero Cells
Viral Envelope Proteins* / chemistry
Viral Envelope Proteins* / immunology
Viral Envelope Proteins* / metabolism
Zika Virus Infection* / immunology
Zika Virus Infection* / virology
Zika Virus* / immunology
Zika Virus* / physiology

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Viral Envelope Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding