COVID-19 News: Japanese Study Finds That BQ.1.1 Variant Has Enhanced Binding Affinity To Human ACE2 Receptor And Greater Fusogenicity Than BA.5!

COVID-19 News: A new study led by Japanese researchers from world famous Sato lab at the Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo and also involving scientists from the Department of Microbiology and Immunology, Faculty of Medicine, Hokkaido University has found that the current predominant SARS-CoV-2 Omicron subvariant that is circulating in many countries at present ie BQ.1.1,  has enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 subvariant!


 
In late 2022, although the SARS-CoV-2 Omicron subvariants have highly diversified, some lineages have convergently acquired amino acid substitutions at five critical residues in the spike protein.
 
As covered by many COVID-19 News coverages, these five recent convergent mutations are spike mutations R346T, K444T, L452R, N460K, or F486V.
 
The study team illuminated the evolutionary rules underlying the convergent evolution of Omicron subvariants and the properties of one of the latest lineages of concern, BQ.1.1.
 
Their detailed phylogenetic and epidemic dynamics analyses suggest that Omicron subvariants independently increased their viral fitness by acquiring the convergent substitutions. Particularly, BQ.1.1, which harbors all five convergent substitutions, shows the highest fitness among the viruses investigated.
 
Worryingly, neutralization assays show that BQ.1.1 is more resistant to breakthrough BA.2/5 infection sera than BA.5.
 
Furthermore, the BQ.1.1 spike exhibits enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 spike.
 
It was found however, the pathogenicity of BQ.1.1 in hamsters is comparable to or even lower than that of BA.5.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.12.05.519085v1

The SARS-CoV-2 Omicron BA.1 rapidly supplanted the Delta variant, and shortly after, Omicron BA.2 was the predominant variant.
 
After that, numerous BA.2 descendants emerged, including BA.2.75 and BA.5.
 
At present there are more than 500 SARS-CoV-2 variants and sub-lineages that have emerged with many having the right viral fitness and are circulating and spreading in various regions and countries around the world.
https://cov-spectrum.org/collections/24
 
Though both the BA.2.75 and BA.5 subvariants diverged from BA.2, they are phylogenetically independent, and recent studies report similar evolutionary patterns in the spikes of BA.2.75 and BA.5 sub-variants.
 
The research team in past studies reported an increase in the pathogenicity of BA.2.75 and BA.5 sub-variants in a hamster model relative to the BA.2 sub-variant, suggesting that the sub-variants evolved to enhance intrinsic pathogenicity. Despite the emergence of several new sub-variants after BA.5, they have failed to outcompete BA.5.
 
The emergent sub-variants instead appear to be under convergent evolution, acquiring amino acid substitutions at the same site.
 
Interestingly, the BQ.1.1 sub-variant, a descendant of BA.5, harbors five convergent substitutions (R346T, K444T, L452R, N460K, and F486V) and has been classified as a variant under monitoring by the World Health Organization (WHO).
 
The study team explored the evolutionary characteristics underlying the convergent evolution of SARS-CoV-2 Omicron lineages.
 
The study team first constructed phylogenetic trees for Omicron sub-variants to identify where convergent substitutions occurred.
 
It was found that the L452 residue had the highest substitution frequency in the BA.2 lineage.
 
Also, it was revealed that substitution events were relatively more frequent in newer lineages than BA.1/2.
 
The study team next modeled the relationship between spike substitutions and viral epidemic dynamics to assess the impact of substitutions on viral fitness. They analyzed a dataset of more than 300,000 Omicron sequences collected between March 1, 2022, and October 15, 2022, that included 254 spike haplotypes. The five convergent substitutions positively affected the effective reproductive number (Re).
 
Interestingly, the spike haplotype corresponding to the BQ.1.1 sub-variant had the highest Re.
 
Subsequent investigations indicated that viral fitness increased independently in multiple Omicron lineages during BA.5 diversification.
 
The detailed analysis also suggested that BQ.1.1 increased its fitness by serially acquiring K444T, N460K, and R346T substitutions.
 
The study team also examined the immune resistance of SARS-CoV-2 Omicron BQ.1.1 using pseudoviruses and observed that BA.5 and BQ.1.1 were markedly resistant to neutralization by Omicron BA.2 breakthrough infection sera.
 
Notably, BQ.1.1 showed 2.7-fold increased resistance to breakthrough infection sera relative to BA.5. Similarly, BQ.1.1 was 5.6-fold more resistant to BA.5 infection sera than BA.5.
 
Also, sera from hamsters infected with BA.2, BA.2.75, or BA.5 exhibited high antiviral activity against the infecting variant but lacked cross-reactivity against other variants.
 
YSD or Yeast surface display assay showed that the dissociation constant (KD) of BQ.1.1 spike’s receptor-binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2) was significantly lower than that of BA.5 spike RBD, implying a higher affinity of BQ.1.1 spike to hACE2 than BA.5 spike.
 
The study findings implicated the N460K and R346T substitutions in BQ.1.1 spike with significantly enhanced binding affinity.
 
Importantly, BQ.1.1 pseudovirus showed higher infectivity than BA.2 or BA.5 pseudovirus. The R346T and N460K substitutions of the BQ.1.1 spike was responsible for the increased infectivity. Syrian hamsters were infected with clinical isolates of Delta, BA.5, or BQ.1.1.
 
Next, the pulmonary function of hamsters was determined based on the ratio of time to peak expiratory flow relative to total expiratory time (Rpef) and enhanced pause (Penh). Delta infection caused significant changes in these parameters than BA.5 infection, suggesting that Delta was more pathogenic than BA.5.
 
It was found that the Rpef and Penh of BQ.1.1-infected hamsters were significantly higher and lower than those of BA.5-infected animals, respectively. This meant that the pathogenicity of BQ.1.1 was comparable to or even lower than that of BA.5. Viral RNA load in the lungs of BA.5-infected hamsters was similar to that of hamsters infected with Delta or Omicron BQ.1.1.
 
Lastly, the study team examined the intrinsic pathogenicity of SARS-CoV-2 Omicron BQ.1.1 by analyzing the right lung of infected hamsters and scoring five histopathological features/parameters – 1) bronchitis/bronchiolitis, 2) hemorrhage with congestive edema, 3) alveolar damage, 4) hyperplasia of type II pneumocytes, and 5) the area of hyperplasia.
 
It was found that delta-infected hamsters had a significantly higher cumulative histopathological score than BA.5-infected animals.
 
In contrast, the aggregate scores were comparable between hamsters infected with BA.5 and BQ.1.1, although BQ.1.1-infected animals showed enhanced bronchitis/bronchiolitis and more type II pneumocytes.
 
In summary, the study tea uncovered the convergent evolution of sub-Omicron variants, highlighting the frequent substitutions at five sites in the viral spike protein that improved viral fitness and Re.
 
The SARS-CoV-2 Omicron BQ.1.1, which harbors all five convergent substitutions, showed the highest Re. The BQ.1.1 sub-variant was also highly resistant to neutralization by BA.2 or BA.5 breakthrough infection sera and showed high binding affinity to hACE2 and greater fusogenicity than BA.5.
 
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