Study Finds Why Omicron Variant Is Highly Transmissible

Washington [US]: A study comparing four variants of SARS-CoV-2 shows how the Omicron variant is adept at entering cells and escaping neutralization from existing vaccines or prior infection, potentially contributing to the variant’s high transmissibility.

Published in the journal ‘Proceedings of the National Academy of Sciences’ (PNAS) on July 19, a study suggests that Omicron mutations increase the infectivity of SARS-CoV-2 virus-like particles and decrease antibody neutralisation. Researchers examine the virus using virus-like particles (VLPs) that imitate the SARS-CoV-2 proteins’ structural characteristics. VLPs of the B.1, B.1.1, Delta, and Omicron variants were evaluated against antisera samples from 38 COVID-19 survivors, both vaccinated and unvaccinated, by Jennifer Doudna, Melanie Ott, and colleagues.

In contrast to the original B.1 strain, antisera from the same individual who had received two vaccinations were up to 15 times less effective at neutralising Omicron in vitro. Nevertheless, the in vitro neutralising activity against Omicron was significantly increased in sera from participants who had received a third mRNA vaccine within 16 to 21 days. The in vitro neutralising potency of four currently available monoclonal antibody therapies–casirivimab, imdevimab, sotrovimab, and bebtelovimab–was then assessed by the authors. They discovered that only bebtelovimab was significantly effective against Omicron. According to the findings, the authors hypothesise that Omicron may be particularly contagious in part because it is a harder strain to neutralise. The researchers also found an existing monoclonal antibody that might in vitro neutralise the variation.

Effective vaccine and treatment development depends on an understanding of the molecular factors that influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral fitness. The advent of viral variations such as Delta and Omicron highlighted the need to evaluate infectivity and antibody neutralisation, although research on intact SARS-CoV-2 is being conducted slowly due to biosafety level 3 handling requirements. The impact of mutations outside the S gene cannot be determined by lentiviruses pseudotyped with the SARS-CoV-2 spike (S) protein, despite the ability to assess S-mediated cell binding and entrance via the ACE2 and TMPRSS2 receptors (1, 2).

To overcome these obstacles, the researchers created SARS-CoV-2 virus-like particles (SC2-VLPs), which combine the S, N, M, and E structural proteins with messenger RNA (mRNA) that contains a packaging signal to generate RNA-loaded capsids that are capable of spike-dependent cell transduction (3). This approach allowed for quick testing of SARS-CoV-2 structural gene variants for their impact on both infection efficiency and antibody or antiserum neutralisation. It correctly represents the impact of changes in structural proteins that are reported in infections with viral isolates.

In conclusion, SARS-CoV-2 VLPs that transduce reporter mRNA into ACE2- and TMPRSS2-expressing cells allowed for a quick and thorough evaluation of the impact of structural protein (S, E, M, N) variants on both particle infectivity and antibody-neutralisation. Using this approach, the researchers discovered that, in comparison to ancestral viral variations, such as Delta, the S and N Omicron versions increase VLP infectivity.

Omicron continues to carry the N mutational hotspot mutations that have been found to significantly increase VLP infectivity in the past. Surprisingly, Omicron M and E gene variations seem to reduce the virus’ ability to infect, at least when compared to ancestral forms of the other structural genes. This suggests that genes like S and N take precedence over less-effective forms of M, E, and maybe other genes in the whole virus. Monitoring the evolution of the S and N genes and figuring out why the N gene has such a strong impact on the infectiousness of viral particles may lead to the creation of more accurate diagnostic tools, broadly neutralising vaccines, and maybe new treatments. Notably, compared to ancestral variants, including Delta, all antisera from vaccine recipients or convalescent sera from COVID-19 survivors demonstrated lower neutralisation of Omicron VLPs, with mRNA vaccines substantially outperforming a viral vector vaccine or natural infection in initial potency. The T cell-based immunity brought on by immunisation or prior infection is not taken into consideration in these results. The researchers also discovered that Omicron S mutations entirely negate the ability of several commercially available therapeutic antibodies to bind to Class 1 and Class 3 monoclonal antibodies. These findings imply that, prior to vaccine boosting, the efficacy of antibodies produced by mRNA vaccines against Omicron is 15-18 times lower, and that the Johnson & Johnson vaccine only generates a small amount of neutralising antibodies against any SARS-CoV-2 type. Booster shots raise Omicron’s neutralisation titers, but they are still significantly lower than for earlier types. These results support the use of mRNA vaccination boosters to improve antibody-based protection against Omicron infection instead of vaccines specifically designed to protect against Omicron itself, which is consistent with evidence from previous pseudovirus neutralisation trials (5, 6).

The researchers’ approach to analyzing the impact of mutations in structural proteins has a few limitations. They assume that mutations in the structural proteins act independently of each other and of the other non-structural genes of the virus. The results are consistent with additive effects of N, M, E, and S mutations, but this may not be the case when combined with other viral proteins. It would be interesting to see if similar results would be obtained in infectious clones incorporating the entire genome and testing these mutations combinatorially, but this is infeasible due to a large number of mutations. In addition, The researchers believe that infectious VLPs cannot be separated from defective particles and exosomes, which may affect the interpretations of our conclusions regarding the compositions of VLPs.

However, the Researchers think that their method for evaluating the effects of structural protein changes has some drawbacks. It is assumed that the structural protein mutations function independently of one another and the virus’s other non-structural genes. Our findings support the cumulative impact of N, M, E, and S mutations, but when paired with additional viral proteins, this may not hold true. Although this is impractical because of the sheer number of mutations, it would be intriguing to investigate if similar results could be produced in infectious clones that included the full genome and tested these mutations in combination. Additionally, the researchers are unable to distinguish between infectious VLPs and defective particles and exosomes, which could have an impact on how our findings about the composition of VLPs are interpreted.

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