SARS-CoV-2 Omicron XBB.1.5, CA.3.1, and CH.1.1 show significant antibody resistance

In a recent study posted on Bio Rxiv* In a preprint server, Ohio State University researchers examined the extent Neutralizing antibody (nAb) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evasion by Omicron XBB.1.5, CA.3.1, and CH.1.1 subvariants.

study: Aberrant evasion of neutralizing antibody responses by Omicron XBB.1.5, CH.1.1, and CA.3.1 variantsImage credit: Design_Cells / Shutterstock

Several subvariants have emerged from the SARS-CoV-2 Omicron, some exhibiting relatively high immune evasion and threatening vaccination EffectivenessThe BQ.1.1 subvariant was most prevalent several months after BA.5 predominated in the United States. Nevertheless, it is rapidly being superseded by XBB.1.5. The XBB strain was first detected in India as a recombinant of BA.2.75 and BA.2.10.1.1. Its emergence was alarming as it contained numerous mutations with well-established immune escape properties.

The efficacy of monoclonal antibodies (mAbs), monovalent or bivalent vaccines, and challenged immunity was reduced against XBB. The XBB lineage acquired two additional substitutions in the spike, resulting in subvariants of XBB.1 and XBB.1.5, but their impact remains unclear. Moreover, Omicron CA.3.1 and CH.1.1 subvariants have recently attracted attention because they retain the L452R substitution previously found in Delta and Omicron BA.4/5 variants in the spike.

Research and Findings

In the present study, researchers evaluated the spike protein biology of emerging SARS-CoV-2 Omicron subvariants XBB.1.5, CA.3.1, and CH.1.1. First, they assessed the infectivity of spike-pseudotyped lentiviruses in his HEK293T-ACE2 cells and Calu-3 cell lines expressing human angiotensin-converting enzyme 2 (ACE2). XBB.1 and XBB.1.5 were highly infective, increasing titers nearly 2-fold over SARS-CoV-2 D614G in HEK293T-ACE2 cells.

The infectivity of the XBB subvariant was not significantly different from that of D614G in this cell line. In contrast, the CA.3.1 and CH.1.1 subvariants showed almost 2.5-fold less infectivity than Calu-3’s D614G. The team then examined among these novel subvariants sera from 14 of her health care workers (HCW) who received two to four doses of the monovalent mRNA vaccine followed by a boost with the bivalent vaccine. tested the sum.

Sera were obtained after a median of 66 days after bivalent vaccination. CA.3.1, CH.1.1, and XBB.1.5 subvariants are 4.6- to 17.7-fold lower nAb titers than BA.4/5 and are more resistant to neutralization by serum than BA.4/5. showed endurance. Interestingly, XBB.1.5 had slightly higher nAb titers than the parental line (XBB).

Of note, BQ.1.1 exhibited higher neutralization resistance than any of the XBB subvariants and 12.8 lower nAb titers than BA.4/5. CA.3.1 and CH.1.1 subvariants were much more resistant to neutralization by bivalent sera. Neutralization experiments were then repeated using sera from HCW vaccinated three times with the monovalent mRNA vaccine.

Samples were taken 2-13 weeks after vaccination. Mean nAb titers in 3-vaccinated sera against SARS-CoV-2 D614 and Omicron (BA.2 and BA.4/5) were up to 5.6-fold lower than bivalent sera. nAb titers were significantly reduced in the CA.3.1, CH.1.1, and XBB.1.5 subvariants. Overall, the trend of triple-vaccinated sera in subvariant neutralization was comparable to that of bivalent sera.

In addition, the team examined the subvariant’s neutralizing resistance to sera from BA.4/5-infected individuals. They observed strong and near-complete neutralization resistance against CA.3.1, CH.1.1, and XBB.1.1 subvariants, with nAb titers 2.6–4.1 fold lower than BA.4/5 .In addition, researchers determined fusogenicity, surface expression, and processing spike protein of subvariants.

Reduced syncytium formation was evident in all subvariants compared to D614G. XBB.1 and XBB.1.5 did not differ in spike confluency compared to XBB. The syncytia formation efficiency of CA.3.1 and CH.1.1 was lower than that of BA.2.75.2. The XBB subvariants, BQ.1.1 and BA.2.75.2, showed higher spiking than D614G. There were no differences in spiking of CA.3.1 and CH.1.1 subvariants compared to parent BA.2.75.2.

Finally, we performed homology modeling of XBB lineage spikes complexed with ACE2 or nAbs. The P486 residue of XBB.1.5 is more hydrophobic than the S486 residue of XBB/XBB.1, leading to better interaction with residues of ACE2 and allowing better receptor utilization. Residue 486 is a hotspot for class I nAb recognition, and mutation at this site in XBB subvariants completely abolishes interaction with therapeutic mAb AZD8895. Mutations of K444 and L452 residues found in CA.3.1 and CH.1.1 also affect interaction with class II nAbs.

Conclusion

Taken together, the findings suggest that bivalent mRNA vaccines induce up to 8-fold higher nAbs than monovalent vaccines. The XBB subvariants, CA.3.1 and CH.1.1, were almost completely escaped from neutralization by triple vaccination or BA.4/5 infected sera. Moreover, XBB.1.5 did not show enhanced immune escape compared to his BQ.1.1. The CA.3.1 and CH.1.1 subvariants were consistently more resistant to neutralization than the XBB subvariants and thus required continued monitoring and further analysis.

*Important Notices

Bio Rxiv We publish a non-peer-reviewed, preliminary scientific report and should not be taken as conclusive, to guide clinical practice/health-related actions, or to be treated as established information.