A new study has revealed why the omicron variant is highly transmissible

Washington: A study comparing four strains of SARS-CoV-2 shows how Omicron The variant is adept at entering cells and evading neutralization from existing vaccines or previous infections, potentially contributing to the variant’s high transmissibility.
Published on July 19 in the journal ‘Proceedings of the National Academy of Sciences’ (PNAS), a study suggests that the Omicron mutation increases the infectivity of SARS-CoV-2 virus-like particles and reduces antibody neutralization.
Researchers examine the virus using virus-like particles (VLPs) that mimic the structural features of the SARS-CoV-2 protein. VLPs of B.1, B.1.1, delta and omicron variants were evaluated against antisera samples from 38 Covid-19 survivors, both vaccinated and unvaccinated. Jennifer Doudna, Melanie Ottand colleagues.
Unlike the original B.1 strain, antisera from the same individual receiving two vaccines were 15-fold less effective at neutralizing Omicron in vitro. However, there was a significant increase in in vitro neutralizing activity against Omicron in sera from participants who received the third mRNA vaccine at 16 to 21 days. The in vitro neutralizing potency of four currently available monoclonal antibody therapies – cacirivimab, imdevimab, Sotrovimaband bebtelovimab — were then evaluated by the authors.
They found that only bebtelovimab was significantly effective against Omicron. According to the findings, the authors hypothesize that Omicron may be particularly infectious because it is a hard strain to neutralize. Researchers have also found a monoclonal antibody that can neutralize the variant in vitro.
The development of effective vaccines and treatments depends on understanding the molecular factors that influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral fitness. The advent of viral variants such as delta and omicron highlighted the need to assess infectivity and antibody neutralization, although research on intact SARS-CoV-2 is being conducted slowly due to biosecurity level 3 handling requirements. Despite the ability to assess S-mediated cell binding and entry through the ACE2 and TMPRSS2 receptors (1, 2), the effect of mutations outside the S gene could not be determined by lentivirus pseudotyped with the SARS-CoV-2 spike (S) protein. .
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 the packaging signal to generate the RNA. -loaded capsid capable of spike-dependent cell transduction (3). This approach allowed rapid testing of SARS-CoV-2 structural gene variants for both their efficiency of infection and their effect on antibody or antiserum neutralization. It correctly represents the effect of changes in structural proteins reported in infections with viral isolates.
In conclusion, SARS-CoV-2 VLPs that transfected reporter mRNA into ACE2- and TMPRSS2-expressing cells allowed rapid and complete assessment of the effect of structural protein (S, E, M, N) variants on both particle infectivity and antibody. Giving. – Neutrality. Using this approach, the researchers discovered that, compared to delta-like progenitor viral variants, the S and N Omicron variants enhance VLP infectivity. Omicron N continues to carry mutational hotspot mutations that significantly increased VLP infectivity in the past. Surprisingly, the omicron M and E gene variants reduced the infectivity of the virus, at least when compared to ancestral forms of other structural genes.
This suggests that genes such as S and N take precedence over less-effective forms of M, E, and perhaps other genes throughout the virus. Monitoring the evolution of the S and N genes and discovering why the N gene has such a strong effect on the infectivity of viral particles could lead to the creation of more accurate diagnostic tools, broadly inactivated vaccines, and perhaps new treatments. Notably, all antisera from vaccine recipients or healthy sera from Covid-19 survivors showed lower inactivation of omicron VLPs, compared to progenitor types including delta, with mRNA vaccines significantly outperforming viral vector vaccines or natural infection in the initial pot.
These results do not take into account T cell-based immunity induced by immunization or previous infection. The researchers also discovered that Omicron S mutations completely negate the ability of many commercially available therapeutic antibodies to bind to class 1 and class 3 monoclonal antibodies. These findings suggest that, prior to vaccine boosting, the efficacy of antibodies elicited by mRNA vaccines against omicron is 15-18 times lower, and that the Johnson & Johnson vaccine elicits only small amounts of neutralizing antibodies against any SARS-CoV-2 variant. . Booster shots increase Omicron’s neutralization titers, but they are still significantly lower than previous types. These results support the use of mRNA vaccination boosters to improve antibody-based protection against omicron infection rather than vaccines specifically designed to protect against omicron, consistent with evidence from previous pseudovirus neutralization trials (5, 6).
The researchers’ approach to analyzing the effect of mutations in structural proteins has a few limitations. They assume that mutations in structural proteins act independently of each other and of other non-structural genes of the virus. The results are consistent with additive effects of the 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 by incorporating the entire genome into infectious clones and testing combinations of these mutations, but this is unlikely due to the large number of mutations. In addition, the researchers believe that infectious VLPs cannot be separated from defective particles and exosomes, which may affect the interpretation of our conclusions regarding the composition of VLPs.
However, the researchers believe that their method of assessing the effects of structural protein changes has some drawbacks. Structural protein mutations are believed to act independently of each other and of other non-structural genes of the virus. Our findings support a cumulative effect 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 interesting to investigate whether similar results could be produced in infectious clones that included the entire genome and tested these mutations in combination. In addition, researchers are unable to distinguish between infectious VLPs and defective particles and exosomes, which may affect how our findings about VLP composition are interpreted.


Source link

Leave a Comment