Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Abstract

The zoonotic spillover of SARS-CoV-2 has resulted in a global pandemic causing over 266 million infections and more than 5.2 million fatalities as of December 2021. Continued SARS-CoV-2 evolution leads to the emergence of variants of concern (VOC) that are characterized by higher transmissibility, immune evasion or disease severity. For pandemic preparedness, we need pan-sarbecovirus countermeasures, such as vaccines and therapeutics that are effective against all SARS-CoV-2 variants and divergent zoonotic sarbecoviruses (1).The coronavirus spike glycoprotein (S) promotes viral entry into host cells and is the main target of neutralizing antibodies elicited by infection or vaccination (2-7). S comprises an S1 subunit, which recognizes host cell receptors, and an S 2 subunit that drives viral-cell membrane fusion. The S 1 subunit includes the N-terminal domain and the receptor-binding domain (RBD) and two additional domains designated C and D (6). For SARS-CoV and SARS-CoV-2, the RBD interacts with angiotensin-converting enzyme 2 (ACE2) to allow virus entry into host cells (4,(8)(9)(10)(11)(12)(13)(14)(15)(16). The RBD is also the main target of serum neutralizing activity elicited by infection (17) and vaccination (7, 18) and exposes multiple antigenic sites that are recognized by broadly neutralizing sarbecovirus antibodies (Abs) (19-25) (fig. S1). However, a large fraction of Abs in polyclonal sera ( 17) and most monoclonal Abs (mAbs) selected for therapeutic development ( 26) target a subset of epitopes that overlap the ACE2-contact surface [designated the receptor-binding motif (RBM)]. The marked genetic divergence and plasticity of the RBM among SARS-CoV-2 variants and sarbecoviruses has thus far limited the breadth of Abs recognizing this region and they are readily escaped by mutations (20,(27)(28)(29)(30)(31)(32).To identify broadly neutralizing sarbecovirus Abs, we isolated SARS-CoV-2 S-specific (IgG) memory B cells from one symptomatic COVID-19 convalescent individual (who was not hospitalized) 35 days after symptoms onset. We identified one mAb, designated S2K146 (IGHV3-43; IGL1-44), which did not compete with S309 (site IV) (21) or S2X259 (site II) (19) but competed with S2E12 (site I), a potent RBM mAb with neutralization breadth against SARS-CoV-2-related

Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron

“…These correlates clearly explain why mutations at these positions would not be selected. In line with our findings, several ACE2-mimic antibodies have already been shown to broadly cross-neutralize sarbecoviruses (Cameroni et al, 2021;Park et al, 2021). The conserved and structurally constrained region for ACE2 recognition revealed in this study would rationalize the development of broad-spectrum vaccine and antibody therapeutics.…”

Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies

“…This suggests S2K146 as a potentially effective alternative to equals 14.2 and 12.6 ng/ml for the wt and the Omicron variant, respectively (Cameroni et al, 2021). Such broadly binding capacity has also been experimentally shown both for the wildtype, as well as the Alpha, Beta, Delta, Epsilon, and Kappa variants, (Park et al, 2022) and Omicron (Cameroni et al, 2021). The neutralization power of S2K146 was experimentally measured for the wt and some variants (IC 50 equals 10 ng/ml for the wt, 9 ng/ml for Alpha, 9 ng/ml for Delta, and 30 ng/ml for Kappa (Park et al, 2022) Yet, this predicted result for 4A8 does not totally agree with the experimental findings.…”

“…Such broadly binding capacity has also been experimentally shown both for the wildtype, as well as the Alpha, Beta, Delta, Epsilon, and Kappa variants, (Park et al, 2022) and Omicron (Cameroni et al, 2021). The neutralization power of S2K146 was experimentally measured for the wt and some variants (IC 50 equals 10 ng/ml for the wt, 9 ng/ml for Alpha, 9 ng/ml for Delta, and 30 ng/ml for Kappa (Park et al, 2022) Yet, this predicted result for 4A8 does not totally agree with the experimental findings. 4A8 is known to bind to the NTD with high affinity (K D = 92.7 nM) and a weaker affinity for the RBD (EC 50 > 10,000 ng/ml in an ELISA experiment) (Chi et al, 2020).…”

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

“…The RBD is the main target of plasma neutralizing activity in convalescent and vaccinated individuals and comprises several antigenic sites recognized by neutralizing Abs with a range of neutralization potencies and breadth (12,13,21,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) (Fig. 3A).…”