BREAKING! COVID-19 News: Ohio State University Study Discovers That XBB.1.5, CH.1.1 And CA.3.1 Variants Have Increased Fusogenicity Than BA.2!

COVID-19 News: A new study led by researchers from Ohio State University-USA has found that the current SARS-CoV-2 subvariants that are predominant in circulation in various parts of the world ie XBB.1.5 alias Kraken, CH.1.1 and CA.3.1 are far more fusogenic than the BA.2 variant with the potential to increase the risk of disease severity in those infected!


 
Worryingly, the study also found that the Ch.1.1 and CA.3.1 sub-lineages were more highly resistant to the current monovalent and bivalent COVID-19 shots!
 
While much is already known about the XBB.1.5 and CH.1.1 variants that are circulating around at the moment and causing massive infections in various countries as covered in various COVID-19 News coverages, the CA.3.1 sub-lineage is a new variant that emerged in the United States in late December 2022 and carries the critical mutation, L452R and many researchers are warning that this sub-lineage need to be monitored as it is most likely to become a dominant variant after the XBB.1.5, Ch.1.1, XBF, BR.2, BF.7.14, BF.7.15, BA.5.2.48, BA.5.2.49, BF.5.1 and BF.5.2 surges.
 
According to the study team, newly emerging Omicron subvariants continue to emerge around the world, presenting potential challenges to current vaccination strategies.
 
The study team investigated the extent of neutralizing antibody escape by these new subvariants XBB.1.5, CH.1.1, and CA.3.1, as well as their impacts on spike protein biology.
 
The study findings demonstrated a nearly complete escape of these variants from neutralizing antibodies stimulated by three doses of mRNA vaccine, but neutralization was rescued by a bivalent booster. However, CH.1.1 and CA.3.1 variants were highly resistant to both monovalent and bivalent mRNA vaccinations.
 
The study team also assessed neutralization by sera from individuals infected during the BA.4/5 wave of infection and observed similar trends of immune escape. In these cohorts, XBB.1.5 did not exhibit enhanced neutralization resistance over the recently dominant BQ.1.1 variant.
 
Worryingly, the study findings also showed that the spike proteins of XBB.1.5, CH.1.1, and CA.3.1 all exhibited increased fusogenicity compared to BA.2, correlating with enhanced S processing.
 
The study team warned that continued surveillance of Omicron subvariants is warranted.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2023.01.16.524244v1
 
In order to investigate the biological function of the S proteins of these new Omicron subvariants, the study team investigated the fusogenicity, surface expression and processing.
 
All the subvariants tested exhibited reduced syncytia formation compared to the ancestral D614G (p < 0.0001), but with a clear increase in fusion relative to BA.2.
 
Like BQ.1.1 and BA.2.75.217, subvariants XBB.1.5, CH.1.1 and 170 CA.3.1 also showed enhanced fusogenicity compared to BA.4/5.
 
However, relati ve to the parental XBB, the XBB.1.5 subvariant and its two single mutants XBB.1 containing G252V and XBB-S486P did not demonstrate obvious differences in S fusogenicity.
 
The syncytia formation efficiency of CH.1.1 and 173 CA.3.1 were comparable to that of BA.2.75.2-N1199D but seemed much lower than the parental BA.2.75.2.
 
Importantly, differences in fusogenicity could not be attributed to differences in surface expression, as demonstrated by comparable levels of signal on cells expressing individual S proteins measured by flow cytometry.
 
Next, the study team investigated the S processing of these Omicron subvariants using pseudotyped viral producer cell lysates by immunoblotting. While the expression levels of these Omicron S proteins were comparable, all XBB subvariants, including XBB.1.5, CH.1.1 and CA.3.1, showed increased S processing compared to D614G; this was evidenced by increased S1/S and S2/S ratios, which was also true for BQ.1.1 and BA.2.75.2.
 
Importantly, S processing for XBB.1.5 remained comparable to that for XBB, though a notable increase in S processing for XBB-S486P mutant was noticed, which was consistent with its relatively higher cell-cell fusion activity. No obvious differences in S processing for CH.1.1 185 and CA.3.1 were seen as compared to their parental BA.2.75.2 subvariant.
 
The study findings also found that the bivalent mRNA vaccine recipients exhibit approximately 2~8-fold higher nAb titers, depending on variants tested, as compared to monovalent booster recipients, and the results are consistent with enhanced vaccine efficacy for the bivalent formula.
 
The nearly complete escape of 3-dose sera and BA.4/5 215 wave infection exhibited by all Omicron subvariants, especially XBB subvariants and CH.1.1 and CA.3.1, was remarkable and this is supported by some recent studies.
https://pubmed.ncbi.nlm.nih.gov/36495917/
 
https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-2151062
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9725777/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9747694/
 
https://www.biorxiv.org/content/10.1101/2023.01.03.522427v2
 
Importantly, XBB.1.5 did not exhibit enhanced neutralization resistance over the recently dominant BQ.1.1 variant, which itself caused no notable surge in cases or hospitalizations compared to prior Omicron subvariants.
 
Due to the fact that most samples fell below the limit of nAb detection, it is difficult to compare the neutralization titers between the different subvariants for this cohort. However, it is clear that CH.1.1 and CA.3.1 have a consistently stronger neutralization resistance than XBB, XBB.1 and XBB.1.5, which is astonishing and warrants continuous monitoring and further investigations.
 
Interestingly, one finding of this study is the modestly but consistently enhanced infectivity of Omicron XBB variants in CaLu-3 cells, especially XBB.1.5, as compared to the prototype Omicron BA.1/BA.1.1 and subsequently emerged Omicron subvariants including BQ.1.1 and BA.2.75.2.
 
One possible explanation is the increased binding of XBB.1.5 to the ACE2 receptor, as recently shown by a recent study which also supported by the structural modeling.
https://www.biorxiv.org/content/10.1101/2023.01.03.522427v2
 
The initial mutation F486S in XBB is predicted to cause decreased affinity between the S protein and ACE2 due to the introduction of energetically unfavorable contacts between the polar residue and a hydrophobic patch. The subsequent mutation S486P largely reverses this effect, increasing the propensity for hydrophobic interactions with ACE2 and the flexibility of this region of the S protein, thus allowing it to settle further into the binding groove on ACE2.
 
Consistent with the predicted improvement in ACE2 utilization, the study team observed a corresponding increase in cell-cell fusion and S processing for XBB subvariants, especially the single point mutant XBB-S486P.
 
Considering that all prior Omicron subvariants have been shown to exhibit low infectivity in CaLu-3 cells, which correlated with their notably lower pathogenicity and a shift in tissue tropism toward the upper airway, in vivo experiments investigating these aspects of the virus are necessary for XBB subvariants.
 
The study team’s structural modeling of the spike protein interacting with its receptor and neutralizing antibodies provide insights for understanding Omicron subvariant evolution.
 
Intriguingly, the structural analysis suggests a sophisticated two-step strategy for XBB lineage to evade immune suppression and likely outcompete other Omicron subvariants through mutations on the spike residue at position 486. F486 has a bulky hydrophobic side chain and is a hotspot for establishing protective immunity against the virus, while F486S mutation greatly facilitates evasion of antibody recognition.
 
But this F486S mutation reduces the efficiency of receptor utilization which must be counteracted with receptor-affinity gaining mutations, such as N460K and R493Q, to preserve the viral fitness.
 
Hence, it makes sense that once the XBB circulation is established, S486 is further mutated into P486 as present in XBB.1.5, thus regaining higher receptor affinity while still maintaining similar immune escape.
 
Such a combination of enhanced antibody escape and receptor affinity therefore likely enables, and has facilitated, the current dominance of the XBB.1.5 strain.
 
In the cases of subvariants CH.1.1 and CA.3.1, it is clear that these variants have used the same strategy as other Omicron variants including BA.4/5 and BQ.1, by mutating the L452 and K444 sites of vulnerability frequently recognized by class I and II neutralizing antibodies to evade neutralization, again underscoring the convergent viral evolution.
 
Importantly, the study findings highlight the continued waning of 3-dose mRNA booster efficacy against newly emerging Omicron subvariants.
 
While this effect can be partially saved by administration of a bivalent booster, escape by some subvariants, particularly CH.1.1 and CA.3.1, is still prominent.
 
The study team stresses that continued refinement of current vaccination strategies or investigation of new ones remains necessary. They also warned that the biology of the S protein of Omicron subvariants, notably those of the XBB lineage, also continues to change, emphasizing the importance of continued surveillance of emerging variants
 
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