Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants.

Rafael Bayarri-Olmos,Susanne Dam Nielsen,Finn Matthiesen,Cecilie Bo Hansen,Jais Rose Bjelke,Ida Jarlhelt,Ruth Frikke-Schmidt,Laust Bruun Johnsen,Charlotte Helgstrand,Peter Garred,Kasper Karmark Iversen,Mikkel-Ole Skjoedt,Henning Bundgaard,Sisse Rye Ostrowski

doi:10.3389/fimmu.2021.757197

Abstract

The recent identification and rise to dominance of the P.1 and B.1.351 SARS-CoV-2 variants have brought international concern because they may confer fitness advantages. The same three positions in the receptor-binding domain (RBD) are affected in both variants, but where the 417 substitution differs, the E484K/N501Y have co-evolved by convergent evolution. Here we characterize the functional and immune evasive consequences of the P.1 and B.1.351 RBD mutations. E484K and N501Y result in gain-of-function with two different outcomes: The N501Y confers a ten-fold affinity increase towards ACE-2, but a modest antibody evasion potential of plasma from convalescent or vaccinated individuals, whereas the E484K displays a significant antibody evasion capacity without a major impact on affinity. On the other hand, the two different 417 substitutions severely impair the RBD/ACE-2 affinity, but in the combined P.1 and B.1.351 RBD variants, this effect is partly counterbalanced by the effect of the E484K and N501Y. Our results suggest that the combination of these three mutations is a two-step forward and one step back in terms of viral fitness.

Highlights

The continuous genetic drift resulting in immune adaptation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has received international attention since the first identification of new emerging variants in the spring of 2020 [1]
We produced recombinant receptor-binding domain (RBD) from SARS-CoV-2 wild type, B.1.351 strain [20], and P.1 strain [21], as well as RBDs containing the individual mutations found in B.1.351 and P.1 strains (Figure 1A)
This resulted in a net reduction of the thermal stability of the N_K_Y RBD (B.1.351 strain) (−2.8°C), and mild a net increase of T_K_Y RBD (P.1 strain) (+1°C)

Summary

Introduction

The continuous genetic drift resulting in immune adaptation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has received international attention since the first identification of new emerging variants in the spring of 2020 [1]. A specific focus has been on mutations in the spike gene, and in particular the residue changes that affect the receptor-binding domain Some of the key residues involved directly in ACE-2 binding have evolved independently at different continents by convergent evolution. The consequences of these residue changes are being studied intensively and the growing VOC group, which includes to date the strains B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), has rapidly replaced the parent SARS-CoV-2 strain in the regions where they have been introduced. The VOC B.1.351, P.1, and B.1.617.2, and VOI B.1.525, B.1.617.1, B.1.620, and B.1.621 all have a glutamic acid residue at position 484 changed, which has been suggested to be a key residue for B-cell recognition and could affect the immunity level of vaccinated and convalescent individuals [16]

Methods

Results

Conclusion