Research discovers what makes Omicron highly transmissible

A research that compared four SARS-CoV-2 variations found that the Omicron variant is excellent at entering cells and evading neutralisation from current vaccines or past infection, likely contributing to the variant’s high transmissibility.

A research published on July 19 in the journal ‘Proceedings of the National Academy of Sciences’ (PNAS) reveals that Omicron mutations boost the infectivity of SARS-CoV-2 virus-like particles while decreasing antibody neutralisation.

The virus is being studied using virus-like particles (VLPs) that mimic the structural properties of the SARS-CoV-2 proteins. Jennifer Doudna, Melanie Ott, and colleagues tested VLPs of the B.1, B.1.1, Delta, and Omicron variants against antisera samples from 38 COVID-19 survivors, both vaccinated and unvaccinated.

Antisera from the same individual who had had two vaccines were up to 15 times less efficient at neutralising Omicron in vitro than the initial B.1 strain. Nonetheless, sera from subjects who received a third mRNA vaccination within 16 to 21 days exhibited considerably higher in vitro neutralising activity against Omicron. The authors next evaluated the in vitro neutralising power of four presently available monoclonal antibody therapies: casirivimab, imdevimab, sotrovimab, and bebtelovimab. Only bebtelovimab was shown to be considerably effective against Omicron.

According to the data, the authors hypothesise that Omicron is especially infectious because it is a more difficult strain to neutralise. The researchers also discovered an existing monoclonal antibody that may be able to neutralise the mutation in vitro.

Understanding the molecular mechanisms that govern the viral fitness of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the development of effective vaccines and treatments. Because of biosafety level 3 handling restrictions, research on intact SARS-CoV-2 is being undertaken slowly. Despite the capacity to assess S-mediated cell binding and entry via the ACE2 and TMPRSS2 receptors, lentiviruses pseudotyped with the SARS-CoV-2 spike (S) protein cannot detect the impact of mutations outside the S gene (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).

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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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