How the Omicron variant altered the biology of SARS-CoV-2

The current coronavirus disease 2019 (COVID-19) pandemic was caused by the rapid onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several worrying variants of SARS-CoV-2 (COV) have emerged; however, the Omicron variant possesses a significantly different phenotype compared to previous variants, such as Beta or Delta variants.

In a recent Natural microbiology study, researchers discuss how immune evasion and reduced virulence are a novel mechanism of endocytic entry and a significant antigenic shift in the spike protein of novel SARS-CoV-2 COVs like the Omicron variant.

Study: Omicron: a change in the biology of SARS-CoV-2. Image Credit: natatravel / Shutterstock.com

Background

When the SARS-CoV-2 Omicron variant was first identified in South Africa, it exhibited significant changes, particularly in the spike protein, which raised concerns about a new global wave of infection . There was also significant uncertainty about vaccine efficacy, as all vaccines had been developed based on the spike protein from the original strain of SARS-CoV-2.

In the UK, SARS-CoV-2 has been monitored by members of the COVID-19 Genomics UK (COG-UK) consortium and public health agencies by high-throughput sequencing. These scientists determined that the Omicron variant had replaced the previously dominant circulating Delta variant at a rapid rate; however, early analyzes showed that this variant caused less severe disease.

In the current study, researchers are analyzing the immune evasion characteristics of the Omicron variant through the use of immune function analyzes and estimates of overall vaccine effectiveness. To better understand the causes of the reduction in the severity of the disease, the researchers also studied the biological properties of the virus. in vitro.

Study results

Samples were collected from people who received vaccines as part of the Deployed COVID-19 Vaccine Cohort Study (DOVE). From these samples, researchers quantified spike-specific T cells and neutralizing antibodies to estimate vaccine efficacy in the Evaluation of Variants Affecting Deployed COVID-19 Vaccine (EVADE) study.

Significantly reduced neutralization of Omicron BA.1 and BA.2 variants was observed. Reduced neutralization was observed in the sera of those who had received two or three doses of the COVID-19 vaccine; however, T cell responses were relatively preserved. These results were consistent with the marked reduction in overall vaccine efficacy, which was somewhat restored after the booster vaccination.

To determine the causes of immune evasion, researchers analyzed the virological properties of the Omicron variant in vitro. To this end, unlike previous variants, Omicron did not induce cell-cell fusion.

Normally, cell-cell fusion occurs due to activation of spike protein by cell surface transmembrane serine protease 2 (TMPRSS2) at the cell membrane. However, the Omicron variant enters cells through an endosomal entry pathway independent of TMPRSS2, resulting in altered cell tropism of the virus.

The researchers also conducted experiments using chimeric spike proteins and observed that the altered cell-cell fusion was caused by certain changes in the receptor binding domain (RBD) of the spike protein. Additional endosomal entry was found to be associated with changes in the S2 domain. These major changes in the biology of the virus are responsible for the global spread of the Omicron variant and its reduced virulence.

Future prospects

Genetic sequencing was able to correctly predict Omicron’s immune evasion characteristics. It is likely that future vaccines using large-scale genomic data will encapsulate multivalent designs. These multivalent designs would incorporate the genetic variation of variants circulating at the time or could also strive to stimulate responses to target more conserved epitopes.

The researchers reported that the sequencing data does not predict the change in viral entry mechanism. This was inferred from several laboratory observations of reduced syncytia formation in cell culture.

After in vitro studies are needed to better understand the mechanisms governing alterations in cell tropism and the severity of clinical disease. As new recombinant variants emerge, experiments with chimeric spike proteins could be particularly useful.

Future research may provide better insights into key mutations in the RBD and S2 regions of the spike protein and their roles in determining cell entry and cell fusion. Since the evolution of SARS-CoV-2 is likely to present further challenges in the future, such studies will provide crucial insights into the virulence of newly emerging variants.

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