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

In a recent study published on bioRxiv* preprint server, Ohio State University researchers examined the degree of neutralizing antibody (nAb) Evasion by Omicron XBB.1.5, CA.3.1 and CH.1.1 subvariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

To study: Extraordinary evasion of neutralizing antibody response by Omicron variants XBB.1.5, CH.1.1 and CA.3.1. Image Credit: Design_Cells / Shutterstock

Several subvariants have emerged from SARS-CoV-2 Omicron, some showing relatively higher immune evasion, threatening vaccination efficiency. The BQ.1.1 subvariant was the most prevalent after months of BA.5 predominance in the United States. Nevertheless, it is quickly replaced by XBB.1.5. The XBB line 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 established immune evasion characteristics.

The efficacy of monoclonal antibodies (mAbs), mono- or bivalent vaccines, and infection-induced immunity were reduced against XBB. Lineage XBB acquired two additional substitutions in the peak, resulting in subvariants XBB.1 and XBB.1.5, and their impact remains unknown. Additionally, the CA.3.1 and CH.1.1 sub-variants of Omicron have been notable lately, as they carry the L452R substitution in the tip, previously discovered in the Delta and Omicron BA.4/5 variants.

The study and the conclusions

In the current study, researchers assessed 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 HEK293T-ACE2 cells expressing human angiotensin-converting enzyme 2 (ACE2) and the Calu-3 cell line. XBB.1 and XBB.1.5 had higher infectivity, with titers almost twice as high as SARS-CoV-2 D614G in HEK293T-ACE2 cells.

The infectivity of XBB subvariants was not significantly different from that of D614G in this cell line. In contrast, the CA.3.1 and CH.1.1 subvariants had almost 2.5 times lower infectivity than D614G in Calu-3. Next, the team tested the neutralization of these emerging subvariants by the sera of 14 healthcare workers (HCWs) boosted with a bivalent vaccine after two to four doses of monovalent mRNA vaccine.

Sera were obtained after a median of 66 days after the bivalent vaccination. The CA.3.1, CH.1.1 and XBB.1.5 subvariants showed strong resistance to neutralization by sera compared to BA.4/5, with nAb titers 4.6 to 17.7 times lower than those of BA.4/5. Interestingly, XBB.1.5 had slightly higher nAb titers than its parent line (XBB).

Of note, BQ.1.1 showed higher knockout resistance than any of the XBB subvariants, with nAb titers 12.8 lower than BA.4/5. The CA.3.1 and CH.1.1 subvariants showed much higher resistance to neutralization by bivalent sera. Then, neutralization experiments were repeated using sera from healthcare workers vaccinated three times with monovalent mRNA vaccines.

Samples were obtained 2 to 13 weeks after vaccination. Mean nAb titers of SARS-CoV-2 D614 and Omicron triply vaccinated sera (BA.2 and BA.4/5) were up to 5.6 times lower than those of bivalent sera. The nAb titers were markedly reduced for the CA.3.1, CH.1.1 and XBB.1.5 subvariants. Overall, the trends of the triple-vaccinated sera in the neutralizing subvariants were comparable to those of the bivalent sera.

In addition, the team examined the neutralization resistance of the subvariants to sera from individuals infected with BA.4/5. They observed potent and nearly complete knockout resistance for the CA.3.1, CH.1.1, and XBB.1.1 subvariants, with nAb titers 2.6-4.1 times lower than those of BA.4/ 5. Additionally, researchers determined the fusogenicity, surface expression and processing of peak proteins subvariants.

Reduced syncytia formation was evident for all subvariants compared to D614G. XBB.1 and XBB.1.5 showed no difference in tip fusogenicity compared to XBB. The syncytia formation efficiency of CA.3.1 and CH.1.1 was lower than BA.2.75.2. The XBB, BQ.1.1, and BA.2.75.2 subvariants featured higher peak processing than D614G. There was no difference in tip processing for the CA.3.1 and CH.1.1 subvariants compared to the parent BA.2.75.2.

Finally, homology modeling of XBB line tips complexed with ACE2 or nAbs was performed. Residue P486 in XBB.1.5 was more hydrophobic than residue S486 in XBB/XBB.1, resulting in favorable interactions with residues in ACE2, allowing for better receptor utilization. Residue 486 is a hotspot for class I nAb recognition, and mutations at this site in XBB subvariants completely abolish interactions with the therapeutic mAb, AZD8895. Mutations at residues K444 and L452 found in CA.3.1 and CH.1.1 also affect interactions with class II nAbs.

conclusion

Taken together, the results suggest that bivalent mRNA vaccines induce up to eight times more nAb than monovalent vaccines. The XBB subvariants, CA.3.1 and CH.1.1, showed almost complete escape from neutralization by the triply vaccinated or BA.4/5 infection sera. Additionally, XBB.1.5 did not show enhanced immune evasion compared to BQ.1.1. The CA.3.1 and CH.1.1 subvariants have consistently shown greater resistance to knockout than the XBB subvariants, warranting continued monitoring and additional analysis.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.