Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement.

Matthew Mccallum,Nadine Czudnochowski,Tristan I Croll,Cameron Stewart,Kevin Hauser,Anshu Joshi,Josh R Dillen,Davide Corti,Jay Nix,Samantha K Zepeda,Herbert W Virgin,John E Bowen,Alexandra C Walls,Laura E Rosen,David Veesler,Gyorgy Snell,Abigail E Powell

doi:10.1126/science.abn8652

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.

Highlights

The Omicron receptor-binding domain (RBD) and the N-terminal domain (NTD) contain 15 and 11 mutations, respectively, which lead to severe dampening of plasma neutralizing activity in previously infected or vaccinated individuals [7,8,9,10,11]
To provide a structural framework for the observed Omicron immune evasion and altered receptor recognition, we determined cryoEM structures of the prefusionstabilized SARS-CoV-2 Omicron S ectodomain trimer bound to S309 and S2L20 (NTD-specific monoclonal antibody (mAb)) Fab fragments
We evaluated the binding of clinical mAbs to the Omicron receptor-binding domain (RBD) and S ectodomain trimer using surface plasmon resonance (SPR)

Summary

Introduction

The Omicron receptor-binding domain (RBD) and the N-terminal domain (NTD) contain 15 and 11 mutations, respectively, which lead to severe dampening of plasma neutralizing activity in previously infected or vaccinated individuals [7,8,9,10,11]. To provide a structural framework for the observed Omicron immune evasion and altered receptor recognition, we determined cryoEM structures of the prefusionstabilized SARS-CoV-2 Omicron S ectodomain trimer bound to S309 and S2L20 (NTD-specific mAb) Fab fragments

Results

Conclusion