SARS-CoV-2: The Next Concerning Variants Will Be The BU And BQ

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A leading researcher from University of Missouri-School of Medicine-USA who has been involved in wastewater surveillance of SARS-CoV-2 variants for the last two years predicts that the newly emerging BU and BQ variants are most likely to be the next concerning SARS-CoV-2 variants in the next waves after the various BA.2.75 sub-lineages that are expected to dominate this fall and early winter.

Professor Dr Marc Johnson, a molecular virologist predicted that the BU an BQ variants would be the next dominant VOCs in coming months.
https://twitter.com/SolidEvidence/status/1571579049738117122

Professor Johnsons twitter thread can be found here.
https://threadreaderapp.com/thread/1571578981824057344.html
 
The BU lineages starts with the BU.1 variant ie BA.5.2.16.1 with spike mutations S:444M & S460K
https://github.com/cov-lineages/pango-designation/issues/1065

The BW.1 (BA.5.6.2.1) sub-lineage with spike mutations 444T and 460K could also become a concerning variant the next few months.
 
It should be noted that Chinese researchers are already warning indirectly that the current SARS-CoV-2 Omicron variants are all rapidly evolving and mutating at an unprecedented rate and are managing to not only evade both natural immunity from previous infections and vaccine induced immunity but also the last few various monoclonal therapeutics available.
https://www.biorxiv.org/content/10.1101/2022.09.15.507787v1
 
Studies have also showed that both the BA.2.75 variant and its emerging sub-lineages like the BA.2.75.2 sub-lineage are already displaying a trend to evade all existing monoclonal therapeutics.
https://www.biorxiv.org/content/10.1101/2022.09.16.508299v1
 
https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(22)00419-X
 
The BQ lineage starts with the BQ.1 variant ie B.1.1.529.5.3.1.1.1.1.1 or BA.5.3.1.1.1.1.1. It is evolving rapidly and is still spawning lots of sub-lineages with interesting spike mutations and also nucleocapsid mutations.
https://github.com/cov-lineages/pango-designation/issues/1082

The BQ.1 is already showing a great growth advantage over the BA.2.75 lineage. https://cov-spectrum.org/collections/24

But let’s not forget that …. another variant is creating great concerns ….

The Omicron sub-variant BA.4.6

The Omicron sub-variant BA.4.6 is a recent cause for concern because of its rapid expansion despite the presence of the other widespread sub-variant BA.5. Furthermore, the two new mutations, R346T and N658S, in the receptor binding domain (RBD) of the BA.4.6 spike protein indicate its potential to evade the therapeutic monoclonal antibodies currently being used to combat COVID-19.

A similar mutation (R346K) in the BA.1.1 sub-variant had resulted in antibody evasion. Two other sub-variants, BA.4.7 and BA.5.9 have also been detected at low frequencies, with mutations R346S and R346I, respectively. The efficacy of the existing repertoire of monoclonal antibodies needs to be tested against these mutated subvariants to ensure immunity against the rapidly emerging and evolving sub-variants of SARS-CoV-2.

About the study

The present study compared the spike protein binding affinity of the Omicron sub-variants BA.4.6, BA.4.7, and BA.5.9 against that of the globally dominant BA.5 sub-variant. The assays included the spike proteins from the lineages carrying R346T, R346S, and N658S point mutations and the spike proteins of the BA.4 and B.4 sub-lineages.

The researchers tested the antibody evasion properties of the three Omicron sub-variants by subjecting the corresponding pseudoviruses to neutralization using serum samples from vaccinated individuals who had received their second booster shot (three doses in total) and mRNA-vaccinated individuals who had BA.1 or BA.2 infections.

A panel of 23 monoclonal antibodies was used to measure the sensitivity of BA.4.6, BA.4.7, and BA.5.9 to neutralization. The 23 monoclonal antibodies were selected based on effectiveness against earlier Omicron subvariants and diversity of the target epitope clusters on the RBD of the spike protein. The neutralization assays also included monoclonal antibodies currently in clinical use.

Results

The study results showed that Omicron sub-variants BA.4.6, BA.4.7, and BA.5.9 exhibited similar binding affinities to the dimeric human angiotensin-converting enzyme 2 (hACE2) receptor compared to the BA.5 subvariant. The pseudoviruses carrying point mutations also displayed binding affinities similar to BA.4.6.

The three subvariants were equally resistant to the serum from vaccinated individuals with booster shots. The pseudoviruses carrying point mutations for R346T, R346S, and N658S showed a similar trend. The sub-variants BA.4.6, BA.4.7, and BA.5.9 also exhibited equivalent resistance to the serum from vaccinated BA.1-infected patients. However, BA.4.6 was significantly more resistant to the serum from vaccinated BA.2-infected patients than BA.5.

In the neutralizing assays, the monoclonal antibodies that target epitope cluster class 3 of the RBD showed reduced neutralization potency against BA.4.6, BA.4.7, and BA.5.9. The authors believe this reduction in efficacy is due to the R346T and R346S mutations but not the N658S mutation. The R346T and R346S mutations were seen to weaken or remove the salt bridges or hydrogen bonds which aid in the R346 residue binding to the RBD class 3 monoclonal antibodies.

Additionally, the therapeutic monoclonal antibody combination of cilgavimab and tixagevimab was found to be ineffective against all three newly emergent mutated sub-variants.

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