SARS-CoV-2 variant biology: immune escape, transmission and fitness

Abstract

In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.

Fig. 1. Properties of amino acid substitutions or deletions in selected SARS-CoV-2 variants of concern.

Black boxes denote the presence of each mutation in the variant of concern. Epitope residues are coloured to indicate the amino-terminal domain (NTD) supersite or the receptor-binding domain (RBD) class. For RBD residues, the results of deep mutational scanning (DMS) studies show the escape fraction (that is, a quantitative measure of the extent to which a mutation reduced polyclonal antibody binding) for each mutant averaged across plasma (‘plasma avg’) and for the most sensitive plasma (‘plasma max’), illustrating consistency or variation in the effect of a mutation depending on differences in the antibody repertoire of individuals. Mutations in the furin cleavage site are highlighted. Orange shading indicates the distance to angiotensin-converting enzyme 2 (ACE2)-contacting residues that form the receptor-binding site (RBS). Note that the RBS is defined as residues with an atom <4 Å from an ACE2 atom in the structure of the RBD bound to ACE2 (RCSB Protein Data Bank ID 6M0J). Finally, ACE2-binding scores representing the binding constant (Δlog₁₀ K_D) relative to the wild-type reference amino acid from DMS experiments are shown in shades of red or blue.

Fig. 2. Furin cleavage site and variant success.

a, Comparison of S1–S2 cleavage site sequences in wild-type (WT) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Alpha, Delta and Omicron variants of concern compared with other coronaviruses: SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus OC43 (HCoV-OC43), HCoV-HKU1, HCoV-NL63 and HCoV-229E. A slash indicates the putative furin/serine protease cleavage site. Amino acids contributing to monobasic or polybasic cleavages sites are shaded. b, Diagrammatic representation of estimated relative optimization of the S1–S2 furin cleavage site (FCS) for the variants of concern. The mutations affecting FCS function are indicated. Note that non-concordant results have been observed for Omicron, as indicated. The level of FCS optimization for future variants is uncertain. Data on Alpha from refs. ^,,, data on Delta from refs. ^,, and data on Omicron from refs. ^,,.

Fig. 3. Potential impact of SARS-CoV-2 variants on T cell responses and innate immunity.

a, Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, CD4⁺ T cell and CD8⁺ T cell responses are generated against 30–40 epitopes across the virus genome (epitopes are shown in red and blue). b, An example of how an amino acid change within one epitope might impact epitope-specific cytotoxic T cell responses, thereby inhibiting the elimination of virus-infected cells. T cell evasion of SARS-CoV-2 has been shown to be the consequence of impaired peptide binding to the major histocompatibility complex (MHC) or poor binding of the T cell receptor (TCR) to the peptide–MHC complex. c, Although the T cell response to vaccination is focused on the spike protein alone, even the multiple spike mutations in the Omicron variant of concern reduce the vaccine-induced spike-specific T cell response only by less than 30%, with considerable interindividual variability^,. M, membrane protein; N, nucleocapsid protein.

Fig. 4. Dominant SARS-CoV-2 variants, vaccinations, infections and deaths since early 2020 in the UK.

a, Waves of dominant variants in the UK (B.1, B.1.1.7/Alpha, B.1.617.2/Delta, AY.4.2/Delta and Omicron sublineages BA.1, BA.2, BA.4 and BA.5), proportion of the UK population with one or two doses and with one booster vaccination, number of COVID-19 cases and number of reported COVID-19-related deaths. Data from COG-UK Mutation Explorer and GOV.UK. b, Diagrammatic visualization of the dynamic relationship between variant transmissibility, antigenicity, virulence and fitness. As population immunity derived from infection and vaccination increases, the fraction of completely immunologically naive hosts declines (gradient blue lines). Consequently, the importance of antigenic novelty in determining variant fitness increases. Antigenic distance to previously circulating variants becomes an increasingly key determinant of variant transmissibility, increasing the potential for intrinsic and real-world transmissibility to diverge. Similarly, antigenic distance influences a variant’s potential to infect and cause disease in immune hosts, increasing the potential for a variant’s intrinsic virulence to diverge from its real-world clinical impact. VOC, variant of concern.