Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

Abstract

The global spread of the SARS-CoV-2 virus has resulted in emergence of lineages which impact the effectiveness of immunotherapies and vaccines that are based on the early Wuhan isolate. All currently approved vaccines employ the spike protein S, as it is the target for neutralizing antibodies. Here we describe two SARS-CoV-2 isolates with unusually large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis shows that the deletions result in complete reshaping of the NTD supersite, an antigenically important region of the NTD. For both spike variants the remodeling of the NTD negatively affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite. For one of the variants, we observed a P9L mediated shift of the signal peptide cleavage site resulting in the loss of a disulfide-bridge; a unique escape mechanism with high antigenic impact. Although the observed deletions and disulfide mutations are rare, similar modifications have become independently established in several other lineages, indicating a possibility to become more dominant in the future. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2.

Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

“…The predicted NTD pocket residues overlap with the experimentally known NTD supersite formed by residues 14-20, residues 140-158 (the supersite b-hairpin), and residues 245-264 (the supersite loop). NTD-neutralizing monoclonal antibodies target the same antigenic supersite, providing examples of convergent solutions to NTD-targeted monoclonal antibody neutralization [57]. The favorable pocket propensity scores for the NTD residues were also found for the 1RBD-up S-BA.1 conformations (Figure 6D-F).…”

“…Our analysis captured this experimentally validated pocket and ranked it as the most probable pocket for ligand binding in the closed and open forms of the S-BA.1 trimer (Supplementary Materials, Figure S5). The latest studies highlight the conformational plasticity of the NTD regions where mutations and/or deletions not only change the architecture but also alter the surface properties, leading to a remodeling of the binding pockets, major antigenic changes in the NTD supersite, and a loss of antibody binding [57,136].…”

“…Moreover, due to the generally conserved and yet plastic nature of the epitope, the antibody maintains binding to VOCs, including the Omicron BA.1 variant [56]. Other recent studies highlighted the conformational plasticity of the NTD regions in which mutations/deletions not only change the architecture but also alter the surface properties, leading to the remodeling of the binding pockets, major antigenic changes in the NTD supersite, and a loss of antibody binding [57]. These studies supported the notion that the NTD can serve as an adaptable antigenic surface on the S protein capable of unlocking and redistributing cryptic binding pockets which may enable the virus to divert the host's immune responses away from the RBD regions [40].…”

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features

“…The Virology Laboratory at the University of Washington, Department of Laboratory Medicine and Pathology (“UW Virology”) conducted next-generation sequencing of SARS-CoV-2 Spike sequences with the Swift Biosciences SNAP workflow version 2.0 on Illumina platforms 17 , 54 . Only Spike gene sequence information was obtained, and the assignment of WHO-labeled variants was based on profiles of predefined and characteristic amino acid substitutions in the Spike protein relative to the reference sequence [GenBank accession number NC_045512 ( https://www.ncbi.nlm.nih.gov/nuccore/1798174254 )].…”