Study investigates the antigenic and viral receptor-binding properties of major Omicron BA.2.75 subvariants

By Tarun Sai LomteReviewed by Lily Ramsey, LLMMar 28 2023

In a recent study posted to bioRxiv* preprint server, researchers in the United States (US) examined the neutralization evasion and receptor affinity properties of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron BA.2.75 sub-variants.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

SARS-CoV-2 Omicron has evolved, resulting in several sub-variants. The Omicron BA.2.75 variant has spread rapidly, competing with the BQ and XBB sub-variants.

Further, BA.2.75-derived sub-variants are relatively diverse and have different evolutionary pathways. CH.1.1 and BN.1 are the most frequently observed sub-variants of Omicron BA.2.75.

CH.1.1 dominates in American and European countries, while BN.1 is in Asian countries. The BA.2.75 sub-lineage features several convergent mutations observed in other Omicron variants and three new substitutions (K356T, R403K, and D574V), which raise concerns about their impact on therapeutics and vaccines.

The study and findings

In the present study, researchers evaluated receptor affinity and neutralization evasion features of SARS-CoV-2 Omicron BA.2.75 sub-variants. Firstly, they measured the binding affinity of BA.2.75 sub-variants and other variants to the human angiotensin-converting enzyme 2 (hACE2) by surface plasmon resonance (SPR). They observed higher binding affinities of BA.4/5, BQ.1, XBB.1.5, BQ.1.1, and BF.7 relative to the D614G strain.

Several BA.2.75 sub-variants, including DS.1, CH.1, and CH.1.1, exhibited lower affinity than BA.2.75. Additional single substitutions in the BA.2.75 spike (R346T, K356T, L452R, R403K, or D574V) enhanced binding affinity.

BN.1 showed the highest affinity among BA.2.75 sub-variants. Next, the researchers examined the neutralization profile of spike-pseudotyped viruses against 30 monoclonal antibodies (mAbs).

Twenty-seven mAbs were those targeting the receptor-binding domain (RBD) epitopes, and three targeted the N-terminal domain (NTD) or its sub-domains (SD1 and SD2). The neutralizing activity of class 4 RBD and non-RBD mAbs was generally not impaired against BA.2.75 sub-variants.

BN.1 was relatively resistant to a few class 3 RBD mAbs. Notably, CH.1.1, CH.1, DS.1, BM.4.1.1, and BA.2.75.2 were highly resistant to neutralization by class 1 and class 2 RBD mAbs and most class 3 mAbs.

Furthermore, the team assessed human sera's neutralization of the BA.2.75 sub-variants. Samples were collected from four clinical cohorts – recipients of three wild-type (WT) mRNA vaccine doses, individuals primed with three WT mRNA doses and boosted with one bivalent vaccine dose, and individuals who had a breakthrough infection with BA.2 or BA.4/5 variants.

The Omicron BA.2.75 was over seven-fold more resistant to neutralization by sera from individuals vaccinated with three WT mRNA vaccines. These individuals also had significantly lower neutralization titers against BA.2.75 sub-variants than BA.2.75. Strikingly, CH.1.1 had almost a 12-fold decline in neutralization susceptibility.

Besides, BM.4.1, BM.4.1.1, CH.1, BN.1, DS.1, and BL.1 sub-variants significantly impaired neutralizing activity. The authors observed a similar trend for sera from bivalent vaccine recipients and BA.2 and BA.4/5 breakthrough cohorts. CH.1, DS.1, and CH.1.1 displayed substantially stronger evasion, while BN.1, BA.2.75.2, BL.1, BM.4.1.1 exhibited moderately higher evasion than BA.2.75.

Next, the team used antigen cartography of neutralization results of bivalent vaccine-boosted sera to visualize the antigenic relationship of the sub-variants. BA.4/5 and BA.2.75 had a similar antigenic distance.

The point mutations D574V, F486S, L452R, K356T, and R346T in BA.2.75.1, BA.2.75.7, BA.2.75.4, BA.2.75.5, and BA.2.75.6 increased antigenic distance by 1.02, 1.47, 0.92, 1.14, and 0.3 antigen units (AUs), respectively, relative to BA.2.75.

BA.2.75.2 was 5.07 AUs from bivalent vaccine-boosted sera and 1.96 AU away from BA.4/5, suggesting an evasion advantage over BA.4/5. In addition, DS.1, CH.1.1, and CH.1 were 6.4, 6.75, and 6.09 AUs from the bivalent sera, respectively, similar to that for XBB.1.5 (6.39 AUs). The BA.2.75 sub-variants formed two antigenically distinct clusters; one set clustered with BQ sub-variants and the other with XBB sub-variants. 

Finally, the team plotted fold increases in receptor-binding affinity against those in antibody evasion to identify common trends. This revealed two phenotypic combinations. One group had a significantly higher affinity with a moderate increase in antibody evasion, while the other showed a substantial increase in resistance to neutralization but lower receptor affinity.

Conclusions

The findings suggest that the evolution of BA.2.75 sub-variants diverged into two trajectories – one with higher neutralization evasion but lower receptor affinity and the other with higher receptor affinity but moderately high antibody evasion.

Interestingly, the most dominant SARS-CoV-2 variants are also the most evasive to neutralization, suggesting that this ability to escape from antibody pressure could be the major determinant of viral transmissibility.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.