Abstract
A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based mRNA vaccine or convalescent individuals exhibited neutralizing titers, which were reduced 2-3.5 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The L452R mutation reduced neutralizing activity of 14 out of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 out of 10 NTD-specific mAbs since the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and formation of a new disulphide bond, as revealed by mass spectrometry and structural studies.

The incidence of the B.1.427/B.1.429 lineages is increasing rapidly
The SARS-CoV-2 B.1.427/B.1.429 variant was reported for the first time at the beginning of 2021 in California and as of May 2021 has been detected in 34 additional countries (41, 42). The two lineages B.1.427 and B.1.429 (belonging to clade 20C according to Nextstrain designation) share the same S mutations (S13I, and W152C in the NTD and L452R in the RBD), but harbor different mutations in other SARS-CoV-2 genes (42). Molecular clock analysis suggest that the progenitor of both lineages emerged in May 2020, diverging to give rise to the B.1.427 and B.1.429 lineages in June-July 2020 (42). The fast rise in the number of cases associated with the B.1.427/B.1.429 lineages led to their classification as a VOC by the US Center for Disease Control

These findings show that the three mutations present in the B1.427/B.1.429 S glycoprotein decrease the neutralizing activity of vaccine-elicited and infection-elicited Abs, suggesting that these lineage-defining residue substitutions are associated with immune evasion. However, these data also underscore the higher quality of Ab responses induced by vaccination compared to infection and their enhanced resilience to mutations found in VOC.

Collectively, these findings demonstrate that the S13I and W152C mutations found in the B.1.427/B.1.429 S variant are jointly responsible for escape from NTD-specific mAbs, due to deletion of the SARS-CoV-2 S two N-terminal residues and overall rearrangement of the NTD antigenic supersite. Our data support that the SARS-CoV-2 NTD evolved a compensatory mechanism to form an alternative disulfide bond and that mutations of the S signal peptide occur in vivo in a clinical setting to promote immune evasion. The SARS-CoV-2 B.1.427/B.1.429 S variant therefore relies on an indirect and unusual neutralization-escape strategy.