A broad and potent neutralization epitope in SARS-related coronaviruses

Abstract

Many neutralizing antibodies (nAbs) elicited to ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through natural infection and vaccination have reduced effectiveness to SARS-CoV-2 variants. Here, we show that therapeutic antibody ADG20 is able to neutralize SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize a broad range of VOCs, albeit with reduced potency against Omicron. Thus, this conserved and vulnerable site can be exploited for the design of universal vaccines and therapeutic antibodies.

Deconstructing SARS‐CoV‐2 neutralization: A modular molecular framework for computational design and comparison of antibodies and nanobodies targeting the spike RBD

“…More in detail, it is observed that among the investigated ab or nb, m396 (2dd8.pdb, 28 ), REGN10987 (6xdg.pdb, 15 ), and ADG20 (7u2d.pdb, 31 ) bind the stern/stern* portion of the boat‐shaped spike RBD (Table 2 and Figure 5C). The ab Ly‐CoV488 (7kmh.pdb, 26 ), Ly‐CoV481 (7kmi.pdb, 26 ), CT‐P59 (7cm4.pdb, 16 ), and the nb VHH_E (7kn5.pdb), 27 ab Ly‐CoV555 (7kmg.pdb, 26 ), and nb Ty1 (6zxn.pdb), 17 and H11‐H4 (6zh9.pdb), 25 bind the hull/hull* portion of the boat‐shaped spike RBD (Table 2 and Figure 5D).…”

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

“…Understanding how SARS-CoV-2 mAbs achieve broad neutralization or are rendered ineffective by viral mutations provides insight not only about natural immunity, but is critical to develop broadly effective therapeutic mAbs and guide vaccine design. 6 , 13 , 22 , 23 , 24 Moreover, defining antibody-antigen interactions is critical for the rapid re-evaluation of existing antibody-based therapeutics toward continuously emerging SARS-CoV-2 variants. This, overlaid with the immuno-genetic makeup of the antibodies shared by a large population further informs our understanding of the public immune response and their antigenic drift from variants.…”

“… 6 , 7 , 13 Such information can be collectively used to fine-tune the immune response focused on broad and potent neutralizing epitopes through antigen design for a universal vaccine. 22 , 24 Recently, based on the information from shared public clonotypes of HIV-1 bnAbs, a V2-apex region-specific immunogen has been successfully designed. 25 …”

Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift

“…Most SARS-CoV-2 RBD antibodies target three regions: the RBS, the CR3022 site, and the S309 site (Figure 6A). Antibodies targeting the RBS generally exhibit higher frequency and higher neutralization potency due to direct competition with receptor 29 . Almost all commercially available therapeutic neutralizing antibodies (except for Sotrovimab) for COVID-19 treatment target the RBS.…”

“…These nAbs exhibit limited cross-reactivity with related coronaviruses and are easily escaped by SARS-CoV-2 variants 26,27 . Class 3 and 4 RBD nAbs are less potent and are less frequently elicited in humans but target relatively more conserved regions of the RBD and exhibit cross-reactivity with VOCs and diverse sarbecoviruses 3,26,[28][29][30][31][32][33][34][35][36][37][38] . Elicitation of nAb responses that target class 3 and 4 RBD sites or the nearby overlapping nAb epitopes are thus more desirable for broad sarbecovirus vaccine strategies.…”