Antibody-Mediated Neutralization of Authentic SARS-CoV-2 B.1.617 Variants Harboring L452R and T478K/E484Q

Abstract

The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.

Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and Monoclonal Antibodies

“…After 48 h CPE formation was evaluated microscopically. Evaluation of monoclonal antibodies was quantified using Spark Cyto 400 multimode imaging plate reader (Tecan) as described before 6,11 .…”

Genetic Analysis of SARS-CoV-2 Variants in Mexico during the First Year of the COVID-19 Pandemic

“…Of these, two amino acid changes in S have been reported to have phenotypic effects. S:T478K was reported to increase receptor binding affinity and viral entry [10], and S:P681H [9] was reported to increase spike cleavage efficiency. To gain better insight into the evolution of B.1.1.519, we reconstructed a phylogeny using available sequences of lineages B.1.1.222 and B.1.1.519 from samples collected through February 2021.…”

“…Additionally, changes close to the furin cleavage site, such as the S:P681H change, increase spike cleavage and possibly enhance virus infectivity [9]. In some lineages, these changes are coupled with mutations that permit the virus to escape from neutralizing antibodies (S:E484K, S:L452R) [10][11][12] elicited from previous infection or vaccination. These viruses are referred to as variants of concern (VOC) by the World Health Organization (WHO), posing an increased threat to global public health.…”

The Global Epidemic of the SARS-CoV-2 Delta Variant, Key Spike Mutations and Immune Escape

“…Wilhelm A et al. ( 31 ) found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, the neutralization activity of convalescent sera against Delta was reduced by 5.33-fold.…”

“…Even at high concentrations, imdevimab was not effective against Delta, indicating high resistance. However, neutralization of Delta was moderately reduced with the clinically approved combination of casirivimab/imdevimab ( 31 ). In addition, another pseudovirus simulation showed that the L452R mutation could enhance the immune escape ability of the virus against convalescent plasma ( 32 ) and monoclonal antibodies (SARS2-01, SARS2-02, LY-CoV555, SARS2-32, X593, P2B2F6) ( 33 ).…”