N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Abstract

Highlights d NTD-targeting antibodies are a key part of immunity to SARS-CoV-2 d NTD neutralizing antibodies target a single antigenic site of vulnerability d Neutralizing NTD antibodies protect hamsters from SARS-CoV-2 challenge d Variants of concern have mutations in the NTD that escape neutralization

The ongoing evolution of variants of concern and interest of SARS-CoV-2 in Brazil revealed by convergent indels in the amino (N)-terminal domain of the Spike protein

“…Although NTD indels Δ189-190 and ins214ANRN did not affect the NTD antigenic-supersite, they occur at putative epitope regions covering residues 168/173-188 and 209-216 ( Appendix Table 2 ) and leads to conformational changes in exterior loops (Figure S1 G-H) which might affect Ab binding outside the antigenic-supersite. These findings suggest that NTD deletions Δ144, Δ141-143, and Δ242-244 here detected probably abrogate the binding of NAb directed against the NTD antigenic-supersite and confirm that deletions at RDRs 2/4 are an essential mechanism for SARS-CoV-2 immune evasion 3,14 .…”

“…Moreover, in vitro co-incubation of SARS-CoV-2 with highly neutralizing plasma form COVID-19 convalescent patient, has revealed an incremental resistance to neutralization followed by the stepwise acquisition of indels at N3/N5 loops 31 . Notably, SARS-CoV-2 challenge in hamsters previously treated with anti-NTD mAbs revealed selection of two escape mutants harboring NTD deletions Δ143-144 and Δ141-144 14 . Thus, NTD indels might represent a mechanism of ongoing adaptive evolution of VOC and VOI circulating in Brazil to escape from dominant neutralizing antibodies directed against the NTD antigenic-supersite.…”

“…Several SARS-CoV-2 variants with mutations in the RBD have been described in Brazil, including the VOC P.1 15 and the VOIs P.2 16 and N.9 17 . The VOC P.1 also displayed NTD mutations (L18F) that abrogate binding of some anti-NTD mAbs 14 , but none of those variants displayed indels in the NTD. Importantly, although VOC P.1 showed reduced binding to RBD-directed antibodies, it is more susceptible to anti-NTD mAbs than other VOCs 9–14 .…”

“…The VOC P.1 also displayed NTD mutations (L18F) that abrogate binding of some anti-NTD mAbs 14 , but none of those variants displayed indels in the NTD. Importantly, although VOC P.1 showed reduced binding to RBD-directed antibodies, it is more susceptible to anti-NTD mAbs than other VOCs 9–14 . In this study, we monitored and characterized the emergence of RDR variants within VOC and VOI circulating in Brazil that were genotyped by the Fiocruz COVID-19 Genomic Surveillance Network between November 2020 and February 2021.…”

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…Spike mutations of emerging mutant variants mainly accumulate in three regions: 1) RBD, 2) NTD, and 3) around the S1/S2 cleavage site (Figure 6). RBD and NTD play essential roles as target sites for nAbs, directed in >90% of cases against RBD, complemented by lower percentage nAb activity against NTD [191,208,301,302]. Consequently, these sites are also prominent sites for nAb escape mutations.…”