The evolutionary trajectories and mechanisms driving the emergence of post-Omicron SARS-CoV-2 lineages

In a recent report posted on Virological*, a discussion forum for analysis of virus genomes, researchers summarized the mechanisms through which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) new Omicron sublineages are evolving.

Study: SARS-CoV-2 evolution, post-Omicron. Image Credit: Jezper/Shutterstock
Study: SARS-CoV-2 evolution, post-Omicron. Image Credit: Jezper/Shutterstock

Background

Over time, SARS-CoV-2 has shown a unique evolutionary feature termed saltation – the ability to produce variants characterized by long phylogenetic branch lengths and no genetic intermediates. These new Omicron subvariants resemble older rather than contemporary SARS-CoV-2 strains like norovirus strains but unlike other common respiratory viruses.

Study findings

The research community hypothesized this kind of evolution to be the consequence of the re-emergence of viruses that evolved during long-term chronic infections. The prolonged duration of SARS-CoV-2 chronic infection and a probable transmission bottleneck allowed these variants to accumulate mutations rapidly. Most SARS-CoV-2 variants of concern (VOCs) (e.g., Alpha, Beta, Gamma, and Omicron) evolving from its pre-variant progenitors are 'first-generation' saltation variants.

In the case of SARS-CoV-2, this evolutionary pattern continued in 2022, giving rise to the second generation of saltation variants, all of which are Omicron subvariants; e.g., BA.2-derivatives, BA.2.75, BA.2.3.20, BJ.1, BS.1, BA.2.83, BA.2.10.4, BP.1, and DD.1. Majorly, these evolved as a consequence of a seeding event at the end of 2021 or beginning of 2022.

These Omicron subvariants have numerous non-synonymous mutations nested inside the receptor-binding domain (RBD) and N-terminal domain (NTD) of the SARS-CoV-2 spike (S) glycoprotein. So far, BA.2.75 has been the most widespread, though BA.2.3.20 have also shown appreciable growth in the past few months.

SARS-CoV-2, like all coronaviruses, is highly susceptible to inter-lineage recombination. Consequently, by November 2022, researchers had identified 54 Pango-designated inter-lineage recombinants of SARS-CoV-2, all denoted by the X- prefix. Notably, these recombinants between divergent variants typically acquire several advantageous mutations from both parents. However, they outcompeted their parental lineages only when they were on a steep decline trajectory while the next variant was still evolving.

So far, XBB, likely a recombinant between BJ.1 and a BA.2.75-derivative, BM.1.1.1, is the most renowned inter-lineage recombinant. It has inherited the 5’ and 3' parts of its genome from the former and the latter, respectively, with just one breakpoint within the S RBD. Its single S breakpoint allowed XBB to possess the most potent antigenic RBD mutations, making it relatively farther (antigenically) from any prior variant. XBD and XBF are two other renowned contemporary recombinant lineages, which are recombinants between the Omicron BA.5 and BA.2.75 sublineages.

Complex recombinants, such as XAY, XBA, XWA, and XBC, have come into existence due to recombinant 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 either parental lineage. Remarkably, XAY and XBA are complex recombinants that share parts of their genomes and even private mutations, suggesting they likely arose from the same parental strains.

Researchers believe ‘complex’ recombinants have also likely arisen from chronic infections in individuals who first contracted coronavirus disease 2019 (COVID-19) from Delta and later super reinfection from BA.2. Although XBC and XAY appear most widespread at present, both these lineages had lesser antigenic RBD mutations than co-circulating and rapidly growing BQ.1.1 or XBB lineages; thus, unlikely will sustain in the long term.

Effect of antigenic drift and convergent mutations in SARS-CoV-2

BA.5 accumulated potent antigenic mutations sequentially as opposed to BA.2, the preceding Omicron-derived saltation variant, which acquired these mutations in one go to replace the latter in mid-2022 globally. Another rapidly growing lineage was BQ.1.1, a derivative of BQ.1, containing three further antigenic mutations in its S RBD. Other examples include BA.2.75.2, which also had several more antigenic RBD mutations than parental BA.2.75. Overall, this drift-like evolutionary pattern resembles sequential antigenic drift in seasonal influenza viruses.

The saltation, drift, and recombinant SARS-CoV-2 variants also have an extraordinary convergent evolution, especially at antigenic RBD sites. They showed substitutions, such as R346X, K444X, and reversions, such as F490X and R493Q. Additionally, they had several deletions in the ~144 NTD region, appearing on multiple phylogenetic branches. Yet, it is unclear if such 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 likely the fastest-growing SARS-CoV-2 variants globally and might drive new COVID-19 waves in the coming months together or individually. However, it is possible that unless a fitter SARS-CoV-2 variant emerges, these all might co-circulate albeit transiently. Despite sharing viral, epidemiological, and clinical properties with their parent lineages, all these lineages are farther away from earlier Omicron lineages, both genetically and antigenically.

Another 'Omicron-like event’ might only give rise to a new variant with orthogonal antigenicity from these circulating lineages. Though it is unclear how likely it is, it would be good to have strategies to combat it if this were to occur. However, the most threatening would be the emergence of a saltation variant from the Delta VOC. As Delta sequences continue to be sampled via genome sequencing methods globally, most with multiple private mutations, the threat of a potentially sizable reservoir of Delta is real.

To conclude, the researchers emphasized the continuous need for SARS-CoV-2 genomic surveillance and analysis equitably on a global scale; at present, it is either missing or inconsistent. Policymakers might terminate other pandemic intervention measures, but SARS-CoV-2 continues to evolve, using unpredictable mechanisms. Such surveillance measures would ensure rapid response to emerging SARS-CoV-2 variants.

*Important notice

Virological is a discussion forum for the analysis and interpretation of virus molecular evolution and epidemiology. Reports are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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