The Rise and Fall of a Local SARS-CoV-2 Variant with the Spike Protein Mutation L452R

Abstract

Emerging SARS-CoV-2 variants may threaten global vaccination efforts and the awaited reduction in outbreak burden. In this study, we report a novel variant carrying the L452R mutation that emerged from a local B.1.362 lineage, B.1.362+L452R. The L452R mutation is associated with the Delta and Epsilon variants and was shown to cause increased infection and reduction in neutralization in pseudoviruses. Indeed, the B.1.362+L452R variant demonstrated a X4-fold reduction in neutralization capacity of sera from BNT162b2-vaccinated individuals compared to a wild-type strain. The variant infected 270 individuals in Israel between December 2020 and March 2021, until diminishing due to the gain in dominance of the Alpha variant in February 2021. This study demonstrates an independent, local emergence of a variant carrying a critical mutation, L452R, which may have the potential of becoming a variant of concern and emphasizes the importance of routine surveillance and detection of novel variants among efforts undertaken to prevent further disease spread.

Keywords: SARS-CoV-2; mutation; neutralization; sequencing; variant.

Figure 1

Characterization of the B.1.362+L452R variant in Israel and within the global B.1.362 lineage. (A) Phylogenetic tree representing random samples sequenced in Israel from December 2020 to May 2021 (n = 3870). The genotype at the S protein in locations 452 and 1063 is indicated, with the different amino acid substitutions in these locations denoted by different colors: wild type in green (L/L: positions 452 and 1063 are Leucine (L)) and B.1.362+L452R variant in yellow (R/F: positions 452 and 1063 were substituted to arginine (R) and phenylalanine (F), respectively). Additional variants which have a mutation in the 452 positions are apparent in the tree, including a B.1.617.2 variant cluster with R/L in blue and a C.37 variant cluster with Q/L in orange. (B) Global SARS-CoV-2 genomes from of the B.1.362 lineage only (n = 441). The wide type genotype (L/L) is indicated in green and the B.1.362+L452R variant cluster (R/F) in yellow. The B.1.362+L452R variant cluster is composed of Israeli viruses only. Phylogenetic trees were created with Nextstrain Augur pipeline and visualized with Auspice [26]. Non-Israeli B.1.362 lineage sequences were downloaded from GISAID [25] and identified with Pangolin [6].

Figure 2

Prevalence of the B.1.362+L452R variant and other lineages in Israel. The prevalence of the B.1.362+L452R variant is denoted in blue (right y-axis); the Alpha variant is denoted in orange (left y-axis); the B.1.362 lineage is denoted in grey (left y-axis).

Figure 3

Neutralization capacity of the B.1.362+L452R variant. Neutralization assays were carried out with VERO-E6 cells infected with the B.1.362+L452R variant, the Alpha variant and a local WT strain, using sera from individuals obtained at least 30 days following the second dose of the Pfizer-BioNTech vaccine. Bars represent the log geometric mean titer (GMT) and 95% confidence intervals. A dilution equal to 1:10 or above was considered neutralizing (dashed line).