In a recent report published in Virological*, a discussion forum for the analysis of virus genomes, researchers summarized the mechanisms through which new Omicron sublineages of severe acute respiratory syndrome coronavirus 2 are evolving ( SARS-CoV-2).
Study: SARS-CoV-2 evolution, post-Omicron. Image credit: Jezper/Shutterstock
background
Over time, SARS-CoV-2 has demonstrated a unique evolutionary feature called saltation: the ability to produce variants characterized by long phylogenetic branch lengths and no genetic intermediates. These new Omicron subvariants resemble older than contemporary SARS-CoV-2 strains, such as norovirus strains, but unlike other common respiratory viruses.
Results of the study
The research community hypothesized this type of evolution as a consequence of the re-emergence of viruses that evolved during long-term chronic infections. The prolonged duration of chronic SARS-CoV-2 infection and a likely transmission bottleneck allowed these variants to rapidly accumulate mutations. Most of the SARS-CoV-2 variants of concern (VOCs) (eg, Alpha, Beta, Gamma, and Omicron) that evolve from their pre-variant progenitors are “first-generation” salting variants.
In the case of SARS-CoV-2, this evolutionary pattern continued in 2022, giving rise to the second generation of salting variants, all of which are Omicron subvariants; e.g. eg, derivatives BA.2, BA.2.75, BA.2.3.20, BJ.1, BS.1, BA.2.83, BA.2.10.4, BP.1 and DD.1. Primarily, these evolved as a result of a seeding event in late 2021 or early 2022.
These Omicron subvariants have numerous non-synonymous mutations nested within the receptor-binding domain (RBD) and N-terminal domain (NTD) of the SARS-CoV-2 (S) spike glycoprotein. So far, BA.2.75 has been the most widespread, although BA.2.3.20 has also seen appreciable growth in recent months.
SARS-CoV-2, like all coronaviruses, is highly susceptible to recombination between lineages. Consequently, by November 2022, researchers had identified 54 Pango-designated cross-lineage recombinants of SARS-CoV-2, all denoted by the X- prefix. In particular, these recombinants between divergent variants often acquire several advantageous mutations from both parents. However, they outperformed their parental lineages only when they were on a steep decline trajectory while the next variant was still evolving.
To date, XBB, probably a recombinant between BJ.1 and a derivative of BA.2.75, BM.1.1.1, is the best-known cross-lineage recombinant. It has inherited the 5′ and 3′ parts of its genome from the first and second, respectively, with only one breakpoint within the S RBD. Its single S breakpoint allowed XBB to possess the most potent RBD antigenic mutations, making it relatively more distant (antigenically) from any previous variant. XBD and XBF are two other recognized contemporary recombinant lineages, which are recombinants between the Omicron BA.5 and BA.2.75 sublines.
Complex recombinants, such as XAY, XBA, XWA and XBC, have appeared due to recombination events between non-co-circulating lineages, such as Delta and BA.2. Unlike simple recombinants, they contain three to eight breakpoints and a higher number of private mutations. They have not acquired these mutations from any parental lineage. Surprisingly, XAY and XBA are complex recombinants that share parts of their genomes and even private mutations, suggesting that they probably arose from the same parental strains.
The researchers believe that the “complex” recombinants have also arisen from chronic infections in individuals who first contracted Delta coronavirus disease 2019 (COVID-19) and subsequently BA.2 super-reinfection. Although XBC and XAY appear to be the most widespread at present, both lineages had fewer RBD antigenic mutations than the co-circulating and rapidly growing BQ.1.1 or XBB lineages; therefore, it is unlikely to be sustained in the long term.
Effect of antigenic drift and convergent mutations in SARS-CoV-2
BA.5 accumulated potent antigenic mutations sequentially unlike BA.2, the earlier Omicron-derived skip variant, which acquired these mutations in one go to replace the latter by mid-2022 globally. Another rapidly growing lineage was BQ.1.1, a derivative of BQ.1, which contains three more antigenic mutations in its S RBD. Other examples include BA.2.75.2, which also had several more antigenic RBD mutations than the parental BA.2.75. In general, this drift-like evolutionary pattern resembles sequential antigenic drift in seasonal influenza viruses.
Skipping, drifting, and recombinant SARS-CoV-2 variants also have extraordinary convergent evolution, especially at RBD antigenic sites. They showed substitutions, such as R346X, K444X, and reversions, such as F490X and R493Q. In addition, they had multiple deletions in the ~144 NTD region, appearing in multiple phylogenetic branches. However, it is unclear whether these mutations would continuously accumulate over time at less dominant sites or slow down due to their adverse effects on virus fitness.
Conclusions
Currently, BQ.1.1, XBB and CH.1.1 are probably the fastest growing SARS-CoV-2 variants globally and may cause new waves of COVID-19 in the coming months together or individually. However, it is possible that, unless a fitter SARS-CoV-2 variant emerges, they may all co-circulate albeit transiently. Despite sharing viral, epidemiological and clinical properties with their parent lineages, all these lineages are more distant from the earlier Omicron lineages, both genetically and antigenically.
Another “Omicron-like event” could only give rise to a new variant with orthogonal antigenicity of these circulating lineages. While it’s not clear how likely that is, it would be nice to have strategies to combat it if that were to happen. However, the most threatening would be the appearance of a salinization variant of the Delta VOC. As Delta sequences continue to be sampled by genome sequencing methods globally, most with multiple private mutations, the threat of a potentially large Delta reservoir is real.
In conclusion, the researchers emphasized the continued need for surveillance and genomic analysis of SARS-CoV-2 in an equitable manner on a global scale; currently, it is either missing or inconsistent. Policymakers could end other pandemic response measures, but SARS-CoV-2 continues to evolve, using unpredictable mechanisms. These surveillance measures would ensure a rapid response to emerging variants of SARS-CoV-2.
*Important news
Virological is a discussion forum for the analysis and interpretation of the molecular evolution and epidemiology of viruses. The reports are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.