Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Katherine G Nabel,Pan Yang,Richelle C Charles,Anca Clabbers,Regina C Larocque,Sanjat Kanjilal,Guohai Zhou,Sundaresh Shankar,Nicole V Tolan,Anhdao T Darcy,Jane Seagal,Michaël Desjardins,Junhua Pan,Edward T Ryan,Lindsey R Baden,Davide Tavella,Vesna Brusic,Jonathan Abraham,Casey Tylek,Adrian Coscia,Sarah A Clark,Anand S Dighe ,Anthony John Griffiths ,Joel Cohen‐Solal ,Yao Shan Fan ,Haley H Varnum ,Lars Clark ,Sarah E Turbett ,Ivan Correia ,Amy C Sherman ,Lindsay Mckay

doi:10.1126/science.abl6251

Abstract

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.

Highlights

While previously studied VOCs contain one to three receptor binding domain (RBD) mutations that at times overlap [1], the potential for composite variants is being closely monitored
A virus recently sequenced from travelers returning from Tanzania contained a previously undocumented combination of RBD mutations (E484KRBD, T478RRBD, and R346KRBD) with N-terminal domain (NTD) deletions that would likely alter the spike protein antigenic surface and result in antibody escape
Structure of an evolved receptor binding domain angiotensin-converting enzyme 2 (ACE2) complex We previously generated two SARS-CoV-2 spike proteins that each contain six RBD changes that were detected during persistent infection of an immunocompromised individual infected with a SARS-CoV-2 strain containing the D614GS mutation [14,15,16]. This individual received treatment with REGN-COV2 [17, 18], but several of the RBD substitutions had occurred even prior to administration of this therapeutic antibody cocktail [14,15,16]. Lentivirus pseudotypes bearing these spike proteins, denoted day 146* and day 152* (Fig. 1A and table S2), were refractory to neutralization by VH3-53-heavy chain gene-derived neutralizing antibodies, a potent class of neutralizing antibodies that have been repeatedly isolated from convalescent donors [19,20,21,22,23,24,25]

Summary

Introduction

While previously studied VOCs contain one to three RBD mutations that at times overlap [1], the potential for composite variants is being closely monitored. The B.1.617.2 (Delta) variant can acquire the K417NRBD mutation found in the B.1.351 (Beta) variant, generating the Delta AY. variant, for a total of three RBD mutations (Fig. 1A). As shown in recently deposited sequences from samples collected in Angola, the Beta variant can acquire the L452RRBD mutation found in the Delta and B.1.429/427 (Epsilon) variants, for a total of four RBD mutations (Fig. 1A and table S1). A virus recently sequenced from travelers returning from Tanzania contained a previously undocumented combination of RBD mutations (E484KRBD, T478RRBD, and R346KRBD) with NTD deletions that would likely alter the spike protein antigenic surface and result in antibody escape (table S1). We investigate the structural plasticity of the SARSCoV-2 spike protein RBD and its capacity to evade neutralizing antibodies

Methods

Results

Conclusion