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

Abstract

SummaryThe 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.

Highlights

Flaviviruses are the most important arthropod-borne viral pathogens for humans, causing severe disease around the world (Collins and Metz, 2017)
The concentration of bivalent C10 required for 50% reduction of infection (IC50) of Zika virus (ZIKV) and DENV1–DENV4 was in the range of 0.1–4 nM
The monovalent Fab IC50 remained in this range for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4, for which it was nearly two logs higher (Figure 1C)

Summary

Introduction

Flaviviruses are the most important arthropod-borne viral pathogens for humans, causing severe disease around the world (Collins and Metz, 2017). Among them is the highly teratogenic and neurotropic Zika virus (ZIKV), which re-emerged recently (Pierson and Diamond, 2018), and the worldwide distributed dengue viruses of serotype 1-4 (DENV1–DENV4), which impose a very high toll on public health, with 50–100 million cases yearly. The four DENVs cause $500,000 hospitalizations annually (Bhatt et al, 2013) of individuals with a hemorrhagic syndrome resulting from vascular leakage (Halstead, 2007). The neutralizing antibodies induced during a DENV or ZIKV infection target the envelope (E) protein (Fibriansah and Lok, 2016) and, with a few exceptions, are serotype specific. Cross-reactive antibodies are elicited, which, in general, are poorly neutralizing and have.

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Conclusion