Harvard And US FDA Study Finds That SARS-CoV-2 Omicron BA.2 Sublineage To Be More Immune Evasive, More Fusogenic, More Transmissible And Replicates Faster!
A new study lead by researchers from Harvard Medical School, Boston Children’s Hospital, the United States Food and Drug Administration (US FDA), Brigham and Women’s Hospital, Beth Israel Deaconess Medical Cente and also Georgetown University has found that the Harvard And US FDA Study finds that the SARS-CoV-2 Omicron BA.2 sublineage and all its emerging subvariants to be more immune evasive, more fusogenic, more transmissible and replicates faster than the BA.1 variant!
Note that Thailand Medical
News has already been issuing warnings about this since early February 2022!
At present the Omicron subvariant BA.2 has become the dominant circulating strain of the SARS-CoV-2 virus in many countries but is fast being displaced by various BA.2 subvariants including the BA.2.12.1 and BA.2.3 and also the newly emerging BA.4 and BA.5 variants.
The study team characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants.
It was found that the BA.2 Spike proteins can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants.
Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes.
As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.04.28.489772v1
The various SARS-CoV-2 variants of concern (VOCs) are often designated so for their propensity to spread and escape host immunity. The SARS-CoV-2 Delta and Alpha VOCs surpassed the circulating viruses at that moment during the preceding COVID-19 waves. This was mainly due to their increased transmissibility when a significant part of the population had yet to acquire immunity from vaccination or natural infection, and adaptive immunity had begun to dwindle.
Thereafter, the Omicron lineages arose with a substantially higher number of mutations in the S gene than the preceding VOCs. The Omicron BA.1 subvariant quickly displaced Delta, trailed by a progressive replacement of the seemingly more contagious Omicron BA.2 sublineage.
The study team profiled the full-length SARS-CoV-2 Omicron BA.2 sublineage S protein and analyzed its structure relative to a native sequence using cryogenic electron microscopy (cryo-EM).
It was found that the structural, antigenic, and functional features of BA.2 S protein and the replication of the authentic virus in animal models and cell culture were contrasted to previously prevale
nt SARS-CoV-2 variants. This was to gain molecular insights into this significantly transmissible SARS-CoV-2 mutant.
The study team infected cytokeratin 18 promoter (K18)-human angiotensin-converting enzyme 2 (hACE2) or transgenic mice with authentic SARS-CoV-2 viruses.
The team next used Deoxyribonucleic acid (DNA) fragments to assemble the full-length S protein gene from the Omicron BA.2 variant.
The study team carried out the purification and expression of the full-length S protein. In addition, an anti-SARS-CoV-2 S antibody was used to perform a Western blot.
The research findings indicated that the mutations in the S protein-induced substantial reconfigurations of the antigenic structure and surface of the N-terminal domain (NTD) and receptor-binding domain (RBD), respectively, in both the Omicron BA.2 and BA.1 sublineages.
These changes resulted in high robust resistance levels to neutralizing antibodies in BA.2 and BA.2 subvariants, not detected in earlier SARS-CoV-2 variants. Despite its higher ACE2 binding affinity, numerous studies suggested that the elevated mutations in BA.1 S protein might have impaired its fusogenic capacity in return for its ability to elude host immunity.
The study team illustrated that the BA.1 S needed a significantly higher ACE2 level on the host cells for successful membrane fusion, mainly due to the N856K mutation.
However, this mutation was not identified in the BA.2 S, which was more fusogenic than BA.1 throughout a wide range of ACE2 levels, while its S was still weaker than other VOCs. As a result, the evidence reported herein revealed a molecular foundation for BA.2's higher transmissibility than BA.1.
The study team also discovered that pulmonary viral ribonucleic acid (RNA) copy counts were 100 to 1000 times greater in the Omicron- and Delta-infected mice than in the wildtype G614-infected during the initial 24 hours after infection. This was because the intranasal administration forced the viruses straight into the lung. Despite their reduced viral entrance exhibited in cell culture, both BA.2 and BA.1 may multiply in the lungs of vulnerable animals as quickly as the Delta variant and far faster than the G614 virus before host immune responses arise.
Alarmingly, the study team noted that the potential of the BA.2 and BA.1 virus to spread into extrapulmonary organs was not correlated with receptor ACE2 levels.
It was thought that it was likely controlled by other host variables or post-infection reactions. These results imply that both replicative benefits by the replication machinery and immune elusions by the S protein might result in elevated Omicron sublineages' transmissibility.
It was also found that with just seven residue modifications, the BA.2 sublineage has evolved a method different from the previous variants to remodel the NTD. It maintained the entire RBD structure, despite 16-point mutations, due to the functional relevance of receptor adherence.
Importantly, nearly all RBD mutations were found towards the borders of the RBD-1 and 3 epitopic areas. On the contrary, there were multiple alterations in the core of the RBD-2 region, which directly intersects the ACE2 binding domain.
The study data also suggests that the BA.2's RBD-1 and 3 surfaces were drastically conserved.
Hence, the study team mentioned that targeting the immunogenic core of the RBD-1 or 3 regions might be a potential immunogen design technique for producing widely neutralizing antibody responses that can defend against present and perhaps future SARS-CoV-2 variants.
The research data also demonstrated that the Omicron BA.2 S protein could fuse membranes more proficiently than Omicron BA.1 because of the absence of a BA.1-specific mutation that might slow down receptor engagement, yet was less efficient than other SARS-CoV-2 variants.
It was found that without pre-existing immunity, both the Omicron BA.2 and BA.1 variants reproduced far quicker in animal lungs than the early SARS-CoV-2 G614 or B.1 strain, presumably explaining their enhanced transmissibility despite their functionally impaired Ss.
Mutations in the BA.2 S, like in BA.1, rearrange its antigenic domains, resulting in high resistance toward neutralizing antibodies.
The study findings on the whole imply that both replicative benefit and immune escape might play a role in the increased transmissibility of the SARS-CoV-2 Omicron BA.2 sublineages.
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