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

Since its initial emergence in Wuhan in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 641 million cases of COVID-19 and more than 6.6 million deaths as of December 2022. SARS-CoV-2 (along with SARS-CoV, the cause of SARS) is a member of the species Severe acute respiratory syndrome-related coronavirus, the sole member of a subgenus of viruses, Sarbecovirus, primarily found in horseshoe bats. Like other coronaviruses, SARS-CoV-2 possesses a large RNA genome, comprising ~30,000 nucleotides, whose replication is mediated by RNA-dependent RNA polymerase (RdRP) and an associated proofreading enzyme exoribonuclease (ExoN). This, combined with the discontinuous nature of coronavirus transcription, has resulted in coronaviruses with high rates of recombination, insertions and deletions, and point mutations (although the rates are lower than for other RNA viruses due to the proofreading). The success of novel genetic variants generated, although prone to stochastic sampling processes, will be very dependent on natural selection; in particular, positive selection associated with mutations that are beneficial to the virus in which they occur. SARS-CoV-2 has proven to be a highly capable human pathogen, but also a generalist in terms of host tropism, establishing infections in a variety of mammalian species, including infections in farmed mink, a stable reservoir in white-tailed deer and incidental infections of many other animal species. Once SARS-CoV-2 was in humans, the first months of SARS-CoV-2 evolution were characterized by limited adaptation and phenotypic change relative to its later evolution. The first notable change, a single spike substitution (D614G), arose early in the pandemic and conferred an ~20% growth advantage relative to preceding variants. A lineage defined by D614G (PANGO lineage B.1) quickly became dominant in Europe, giving an early indication of the potential for SARS-CoV-2 to increase its transmissibility in humans. From October 2020 onwards, novel, more heavily mutated SARS-CoV-2 variants began to emerge. These variants were distinguished by higher numbers of non-synonymous mutations principally in the spike protein—particularly the case for Omicron—and distinct phenotypic properties, including altered transmissibility and antigenicity. To date, five SARS-CoV-2 variants have been declared variants of concern (VOCs) by the World Health Organization on the basis that they exhibit substantially altered transmissibility or immune escape, warranting close monitoring. Each VOC showed transmission advantages over preceding variants and became dominant, either regionally in the cases of Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1), or globally, in the cases of Delta (B.1.617.2/AY sublineages) and the many Omicron sublineages (B.1.1.529/BA sublineages). In contrast to the expectation that viruses undergo rapid host adaptation following spillover, selection analysis indicates that SARS-CoV-2 lacked notable levels of observable adaptation early in the pandemic. It subsequently became clear that SARS-CoV-2 is a generalist virus capable of using a variety of mammalian ACE2 membrane proteins for cell entry, enabling infection of a wide range of mammals. The sarbecoviruses are transmitted frequently between different horseshoe bat species and non-bat species with ACE2-binding capability (the inferred ancestral trait in sarbecoviruses), which happens to include humans. The SARS-CoV-2 spike protein contains important properties that are responsible and required for efficient human-to-human transmission, in particular human ACE2 binding and the polybasic furin cleavage site (FCS) at the S1–S2 junction.

This Review synthesizes extensive literature on SARS-CoV-2 variant biology, covering: (1) relative transmissibility and antigenicity of VOCs (Alpha, Beta, Gamma, Delta and Omicron) and sublineages; (2) the role of spike mutations, especially at the furin cleavage site (FCS), and contributions of non-spike proteins (N, M, E, and ORF1ab components like NSP6) to fitness; (3) recombination among lineages (e.g., XD, XE, XAY, XBB) and its phenotypic consequences; (4) immune escape across humoral, T cell, and innate pathways, including antigenic distance, preserved but variably reduced T cell responses, and enhanced innate immune antagonism; (5) changing population immunity from infection and vaccination, its waning, and implications for vaccine effectiveness; and (6) the complex relationship among transmissibility, antigenic novelty, and virulence, including epidemiological and animal model findings on severity across variants.

This is a narrative review. The authors collate and interpret findings from published and preprint studies spanning virology experiments (including pseudovirus and reverse genetics systems), deep mutational scanning, structural biology, animal models, immunology (neutralization assays, T cell epitope mapping), epidemiology (household transmission, vaccine effectiveness), genomic surveillance (PANGO lineage tracking, recombinant identification), and population-level analyses. No new primary experimental or clinical data are generated; conclusions derive from comparative synthesis of the cited literature and surveillance datasets.

- Step changes in SARS-CoV-2 adaptation produced VOCs with higher transmissibility and/or immune escape that became regionally or globally dominant. - Early D614G conferred ~20% growth advantage and rapidly dominated (B.1 lineage). - Spike furin cleavage site (FCS) is a key determinant of efficient transmission; mutations adjacent to the FCS (e.g., P681H in Alpha/Mu/Omicron; P681R in Delta; N679K in Omicron) enhance cleavage in some contexts and contributed to fitness, with Alpha and Delta estimated to have 65% and 55% higher relative transmissibility than the variants they replaced. - Omicron’s success is decoupled from simple FCS optimization: it shows an altered entry phenotype favoring endosomal priming (cathepsins) over TMPRSS2 dependence, markedly reduced fusogenicity, and substantial immune escape enabling reinfections and breakthrough infections. - Omicron sublineages (BA.1, BA.2, BA.4/BA.5, BA.2.75 and descendants) exhibit pronounced antigenic shifts; most first-generation vaccine-induced or pre-Omicron infection-derived antibodies poorly neutralize them. Booster doses are required to maintain vaccine effectiveness against infection, which wanes over time; effectiveness against severe disease remains higher but also wanes after boosters. - Therapeutic monoclonal antibodies show broad loss of efficacy against Omicron; bebtelovimab retained activity against all tested variants at the time of review. - Recombinants have increased with co-circulation (e.g., XD—Delta×BA.1; XE—BA.1×BA.2 with >2,500 genomes in the UK; XAY—BA.2×Delta; XBB—recombinant between BA.2 sublineages BJ.1 and BA.2.75 with many RBD mutations and substantial neutralization escape). - Non-spike mutations contribute to infectivity and fitness: N protein R203K/G204R (Alpha, Gamma, Omicron) or convergent R203M/T205I (Delta/Beta) increase infectivity via mechanisms including altered phosphorylation, novel transcription regulatory sites, and expression of truncated products (N*, N.iORF3). BA.1 M and E substitutions can reduce VLP entry, compensated by S and N changes. NSP6 Δ106–108 (conserved in VOCs except Delta) may enhance replication organelle formation. - T cell immunity is generally preserved across VOCs despite some epitope losses (overall <30% reduction in total spike-specific CD4+ and CD8+ responses to Omicron on average, with interindividual variability); specific mutations (e.g., L452R, P272L, P13L) can abrogate certain HLA-restricted responses. - VOCs, including Alpha and Omicron BA.4/BA.5, show enhanced innate immune evasion (e.g., increased expression of ORF6, ORF9b, N; downregulation of MHC-I via ORF8/ORF7a/ORF3a), and variable sensitivity to IFITM restrictions associated with entry pathways. - Antigenic distance increasingly determines variant fitness as population immunity grows; Omicron BA.4/BA.5 exhibit additional RBD mutations (e.g., L452R, F486V) facilitating escape even from prior Omicron immunity (particularly BA.1). - Relative virulence trends have been inconsistent across waves: Alpha and then Delta were associated with increased severity compared to predecessors, while Omicron showed reduced severity relative to Delta in co-circulation periods, influenced by both intrinsic factors (reduced fusogenicity, altered tropism) and population immunity; animal models generally recapitulate reduced Omicron pathogenicity but have limitations.

The Review integrates virological, immunological, and epidemiological evidence to explain variant fitness as a moving target shaped by both intrinsic viral properties and the evolving immune landscape. Early gains in transmissibility (e.g., D614G, FCS optimization with ACE2 affinity enhancements) dominated when populations were largely naive. As immunity accrued through vaccination and infection, antigenic novelty and immune evasion became the primary drivers of successful variants, exemplified by Omicron and its sublineages. The authors highlight that non-spike genes, regulatory elements, and innate immune antagonism meaningfully contribute to fitness, while T cell responses, though affected at specific epitopes, remain broadly preserved and likely underpin continued protection against severe disease. The altered entry route and reduced fusogenicity of Omicron decouple some prior associations between FCS enhancement, fusogenicity, and transmissibility. Recombination can combine advantageous features from distinct lineages but, up to XBB’s emergence, had limited epidemiological impact. The dynamic between antigenic distance, transmissibility, and virulence indicates that future variant trajectories and disease burden are hard to predict; real-world transmissibility and severity may diverge from intrinsic properties due to population immunity. Sustained and equitable genomic and phenotypic surveillance remains essential to detect and characterize new variants rapidly.

SARS-CoV-2 continues to adapt to humans via diverse and often convergent pathways affecting spike and non-spike regions, enabling enhanced transmissibility, immune evasion (humoral, cellular, and innate), and altered entry mechanisms. As population immunity rises, antigenic novelty becomes the predominant determinant of variant fitness; consequently, future variants may be antigenically and phenotypically distinct from early Omicron, yet with mitigated real-world severity due to accumulated immunity. The likely origin of VOCs in chronic infections underscores the role of prolonged intra-host evolution in stepwise antigenic shifts. While recombination offers routes to aggregate advantageous traits, its pandemic impact has been limited to date. Ongoing global genomic surveillance, functional characterization of non-spike adaptations, and next-generation vaccine strategies (including variant-updated, mucosal, and universal approaches) are crucial to manage future waves. Future research should prioritize dissecting non-spike contributions to fitness and innate immune antagonism, mapping cross-protection across emerging antigenic spaces, and improving correlates of protection beyond neutralizing antibodies.

- As a narrative review, conclusions depend on the quality, heterogeneity, and timing of underlying studies (including preprints) and may be affected by publication bias. - Experimental findings vary by systems used (live virus vs pseudovirus, cell types, animal models), leading to inconsistent results (e.g., Omicron S1–S2 cleavage efficiency, IFITM effects). - Non-spike mutations and regulatory adaptations are under-characterized due to technical challenges (reverse genetics, limited in vitro systems), constraining mechanistic inferences. - Epidemiological severity estimates are confounded by changing population immunity, interventions, and healthcare practices; cross-wave comparisons may not capture intrinsic virulence. - Animal models may not fully recapitulate human disease, and ongoing human adaptation may reduce model relevance. - Reduced or uneven genomic surveillance can delay detection of emerging variants and limit global generalizability. - T cell escape data are limited, with small samples and HLA-specific findings that may not extrapolate to diverse populations.