SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

Abstract

SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

Amino acids 484 and 494 of SARS-CoV-2 spike are hotspots of immune evasion affecting antibody but not ACE2 binding

“…However, we observed a reduction in some sera to mutation N439K (0.530.45) as reported in (40), which was not observed when Δ69-70 was added (Fig. 2H), and also, as reported in (59), in mutation L452R (0.480.23) that is associated with the most recent variants of concern B.1.427/9. Importantly, we tested BNT162b2-elicited plasma (collected after the first and second dosage of the Pfizer-BioNTech vaccine) for their capacity to neutralize the spike-pseudotyped particles, expressing WT spike protein or mutants bearing all defining mutations of the variants of concern B.1.1.7, B.1.351 and P.1.…”

Comparison of 10 emerging SARS-CoV-2 Variants: infectivity, animal tropism, and antibody neutralization

“…Pseudoviruses of multiple variants and single mutants at RBD sites presumably related to these variants were examined for their ability to infect four SARS-CoV-2 susceptible cells. No signi cant enhancements of infectivity were observed among the tested variants, compared with the D614G reference strain, while the L452R mutation and B.1.429 variant exhibited slightly increased infectivity; these ndings were consistent with the reports by MaCallum et al 16 . In addition, we also found slight enhancements of infectivity involving the B.1.525, B.1.526-2, and B.1.1.318 variants, suggesting that these variants should receive close attention.…”

Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India

“…A recent report revealed that the L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific mAbs including three clinical stage mAbs. 21 Another recent study 22 has demonstrated that the mutation L452R can escape from human leukocyte antigen (HLA)-24-restricted cellular immunity and can also increase viral infectivity, potentially promoting viral replication. Hence the double mutant combination noted in this study that may result in neutralization escape of specific mAbs needs to be further experimentally validated.…”