Scientist Find That Newer Omicron Variants Like BA.4.6, BA.4.7 and BA.5.7 Are More Immune Evasive Than BA.5, Making Even Evusheld Ineffective!

Researchers from Columbia University Vagelos College of Physicians and Surgeons, New York-USA and the from the School of Medicine-National Taiwan University-Taiwan have found that the new Omicron variants like BA.4.6, BA.4.7 and BA.5.7 are even more immune evasive than the BA.5 variant and that even the monoclonal combination known as Evusheld is ineffective.


 
Evushed is a combination of the monoclonal antibodies Tixagevimab and Cilgavimab and is one of the last therapeutic ‘armaments’ left in the fight against the emerging SARS-CoV-2 variants besides another monoclonal therapeutic called Bebtelovimab.
 
But even then, other scientist are already warning that there are even newer emerging strains such as the 2.75.2 variant that is even able to breakthrough Bebtelovimab, creating a possible scenario this coming fall and winter that is extremely bleak and a possibility of increased mortality rates we have yet to have witness since the start of the COVID-19 pandemic. https://www.thailandmedical.news/news/sars-cov-2-ba-2-75-variant-is-evolving-rapidly,-spawning-many-sub-lineages-like-the-ba-2-75-2-that-is-now-the-most-immune-evasive-variant-known
 
Thailand Medical News predicts that even with the advent of the new boosters featuring the spike proteins of the newer Omicron variants, the current observed rapid rate of the SARS-CoV-2 evolution and amount of mutations arising which has been unprecedented in field of virology so far, the emergence and dominance of  variants that are going to be more pathogenic and lethal is unavoidable.
 
The BA.4.6, BA.4.7 and BA.5.7 are already found in countries like the United States, Canada and in many countries in Europe with the BA.4.6 already playing a key role in current surges.
 
Interestingly, compared to BA.5, these new sub-variants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion.
 
The American and Taiwanese researchers compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance.
 
The stud team also performed VSV-based pseudo virus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs).
 
The study findings showed that compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera.
 
Worryingly, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of Tixagevimab and Cilgavimab completely lost neutralizing activity against these three subvariants.
 
The loss of activity of Tixagevimab and Ci lgavimab against BA.4.6 leaves the world with just Bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2 so far.
 
The study team warned that as the virus continues to evolve, the current arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.09.05.506628v1
 
The BA.4.6 Omicron sub-variant has been 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.
 
It was already found that a similar mutation (R346K) in the BA.1.1 sub-variant had resulted in antibody evasion.
 https://pubmed.ncbi.nlm.nih.gov/35016198/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385487/
 
Another two other Omicron sub-variants, BA.4.7 and BA.5.9 have also been detected at low frequencies, with mutations R346S and R346I, respectively.
 
The study team hence found that 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.
 
The 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 study team tested the antibody evasion properties of the three Omicron sub-variants by subjecting the corresponding pseudo viruses 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 total of 23existing 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.
 
The research findings 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.
 
Also, the pseudo viruses carrying point mutations also displayed binding affinities similar to BA.4.6.
 
The study findings showed that the three subvariants were equally resistant to the serum from vaccinated individuals with booster shots. The pseudo viruses carrying point mutations for R346T, R346S, and N658S showed a similar trend.
 
Importantly, the sub-variants BA.4.6, BA.4.7, and BA.5.9 exhibited equivalent resistance to the serum from vaccinated BA.1-infected patients.
 
Alarmingly, BA.4.6 was however significantly more resistant to the serum from vaccinated BA.2-infected patients than BA.5.
 
Furthermore, 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 study team believes this reduction in efficacy is due to the R346T and R346S mutations but not the N658S mutation.
 
Both 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.
 
It was also worryingly found that the therapeutic monoclonal antibody combination of Cilgavimab and Tixagevimab was found to be ineffective against all three newly emergent mutated sub-variants.
 
The study finds suggest that the spread of the newly emergent SARS-CoV-2 Omicron subvariant BA.4.6 cannot be attributed to the R346T and N658S spike protein mutations increasing its receptor binding affinity. Moreover, the resistance of the BA.4.6 sub-variant to the serum from vaccinated BA.2-infected patients was significantly higher than that of the other sub-variants but not large enough to explain the worldwide expansion of BA.4.6 conclusively.
 
The study team warns that the loss of neutralization activity of a widely used combination of monoclonal antibodies Tixagevimab and Cilgavimab (Evusheld) is concerning.
 
At present, Bebtelovimab is the only potent therapeutic monoclonal antibody against all the circulating SARS-CoV-2 variants and sub-variants.
 
Concerningly, the resistance of the new sub-variants to the monoclonal antibodies in clinical use leaves a large population of immunocompromised individuals vulnerable to the rapidly mutating sub-variants of SARS-CoV-2.
 
We should expect to see the emergence of more worryingly immune-evasive SARS-CoV-2 Omicron sub-variants in coming weeks.
 
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