SARS-CoV-2 variants, spike mutations and immune escape

Abstract

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

Interpretable modeling of genotype-phenotype landscapes with state-of-the-art predictive power

“…This region of latent mutational effect space poses a potential clinical threat, as it represents genetically stable SARS-CoV-2 infectivity through strong affinity between the RBD and ACE2. Variants in this region may then have more mutational flexibility to evade immune response while maintaining infectivity (Hie et al 2021;Atlani-Duault et al 2021;Harvey et al 2021).…”

“…This region of latent mutational effect space poses a potential clinical threat, as it represents genetically stable SARS-CoV-2 infectivity through strong affinity between the RBD and ACE2. Variants in this region may then have more mutational flexibility to evade immune response while maintaining infectivity(Hie et al 2021;Atlani-Duault et al 2021;Harvey et al 2021).To similarly quantify additivity in multiple dimensions, we add the curvature across each dimension to compute the Laplacian (∆f (z), Fig6e). A value of zero for the Laplacian indicates a constant rate of change in all dimensions and constitutes multidimensional additivity.…”

Emergence of immune escape at dominant SARS-CoV-2 killer T-cell epitope

“…Genome sequencing has shown extensive nonsynonymous mutations occurred within the SARS-CoV-2 genome during 2020. Some of these mutations alter viral fitness 30 while others have been shown to diminish the binding of antibodies 31 . To date, there has been limited study of T-cell escape and a broad brush-approach of examining T-cell recognition of key transmission variants failed to reveal any evidence that escape was occurring 32 .…”

Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections

“…Mutations could also lead to vaccine breakthrough 4 . The spike protein's RBD is immunodominant 5 , targeted by convalescent sera and vaccine-elicited antibodies (Pfizer BNT162b2 6 ), though evidence suggest substantial role of the amino-terminal domain (NTD).…”