Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

Abstract

Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

“…However, our results suggest that reduced NAb binding to the NTD is one potential mechanism that deserves further investigation. The G142D mutation is located in close proximity to the alterations of E156G and DEL157-158 reported in all Delta VOC that is part of the N3 loop of the NTD 'super site' epitope recognized by NTD-directed NAbs and associated with reduced viral neutralization (28)(29)(30)(31)(32). Despite the well-known challenges of in-silico protein structure e prediction on the spike protein (e.g., preand post-fusion conformation, the impact of D614G and P681R mutations on furin cleavage structure, and native spike conformation vs various mutated spike protein and their effect on antibody binding to different NTD or RBD epitopes) all of our structural predictions modelled against different templates (native, NTD-or RBD antibody-bound) consistently predicted that G142D and T95I mutations contribute to significant changes in the NTD secondary structure, including the potential conversion of β -strand to α -helix around aa159-167 and 183-190 regions, hydrogen-bond changes due to altered residue charge at G142D, an enlarged pocket at T95I, and overall three dimensional NTD surface topography that is unfavorable to NAb binding in the presence of other Delta VOC signature mutations.…”

Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

“…36 The other study on S-Delta focuses on the binding by the NTDand RBD-specific nAbs. 37 In this case, a highly engineered HexaPro variant is used, which may alter the propensity of RBD up/down conformations. The common finding from these studies, including ours, is the reorganization of the NTD loop structure of S-Delta, accompanied by the reposition of the N-glycan on N149 (Fig.…”

“…Although the reported ACE2 binding affinities vary considerably depending on the construct designs of ACE2 (monomeric versus dimeric Fc-fusion 36 or GFP-fusion used herein) and S proteins (full-length, trimeric ectodomain or monomeric RBD 36,37,39,40 , our self-consistent BLI analysis showed a strong correlation between the free energy derived from the Kd values and the size of the ACE2 binding interface area (Fig. 4D) based on the high-resolution cryo-EM structures of individual S variants (Fig.…”

“…NTD mutations in the Beta, Gamma, Delta and Kappa variant considerably attenuate various NTD-specific nAbs and completely abolish their neutralizing activities in many cases 15,17,20,21,27,36,37 . Therefore, nAbs that target the RBD remain a preferred route for success, and several RBD-specific nAbs are currently approved for emergency use to treat COVID-19 patients 12 .…”

Demographic characteristics of SARS-CoV-2 B.1.617.2 (Delta) variant infections in Indian population

“…Delta variant of SARS-CoV-2 (B.1.617.2) has caused recent COVID-19 waves and spikes in multiple countries and it is now a globally dominant strain 1 . Structural and functional analyses of the lineage characterizing mutations in the spike glycoprotein have predicted potential alterations in virus-host interactions and masking of the antibody binding sites leading to increased transmissibility, lethality, and immune escape capabilities for this variant [2][3][4] , which were further validated in recent animal model 5,6 and human studies [7][8][9][10] . Available studies precisely indicate that delta is at least 50-60% more transmissible than alpha variant (B.1.1.7) 11 and are capable of immune escape against the natural infections with previous SARS-CoV-2 strains, the COVID-19 vaccines, and therapeutically used monoclonal antibodies 5,11 .…”