The antibody evasion properties of the SARS-CoV-2 Omicron subvariant BA.2.75

In a recent study posted to the bioRxiv* preprint server, researchers evaluated all the features, especially the antigenic properties and transmission potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sub-variant BA.2.75.

Study: Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75. Image Credit: Mayboon/Shutterstock
Study: Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75. Image Credit: Mayboon/Shutterstock

Background

BA.2.75 recently emerged from India and subsequently has been identified in 25 countries worldwide. Though a descendent of Omiron sub-variant BA.2, it contains some unique mutations in its spike (S) protein, including five N-terminal domain (NTD) and four receptor-binding domain (RBD) substitutions, viz., K147E, W152R, F157L, I210V, G257S, and D339H, G446S, N460K, and R493Q, respectively. Some of these mutations might be hampering the RBD-angiotensin-converting enzyme 2 (ACE2) binding, which, in turn, could alter this variant's neutralization sensitivity.

Two RBD substitutions, D339H and N460K are also particularly noteworthy because studies have not documented their presence in other SARS-CoV-2 variants, and their impact is unknown. The emergence of newer variants, such as BA.2.75, raises concerns that SARS-CoV-2 is continuously evolving to escape from neutralization by vaccination or infection-induced antibodies and monoclonal antibodies (mAbs) in clinical use. Thus, there is an urgent need to evaluate and characterize the antibody evasion and transmission potential of BA.2.75.

About the study

In the present study, researchers produced pseudotyped vesicular stomatitis viruses (VSV) of Omicron sub-variants - BA.2, BA.2.12.1, and BA.4/5. They assessed their neutralization sensitivity to sera from three cohorts, where the first group comprised individuals who had received a booster shot of a messenger ribonucleic acid (mRNA)-based SARS-CoV-2 vaccine. The second and third groups had patients with BA.1 or BA.2 breakthrough infection after vaccination.

The team performed serum neutralization assays to evaluate the effect of new mutations found in BA.2.75. They also assessed the neutralization resistance of BA.2.75 to a panel of 23 mAbs which targeted epitopes in the S protein. Further, the researchers identified the BA.2.75 mutations that conferred the observed antibody resistance profile. Furthermore, they performed structural modeling to investigate the impact of its G446S and N460K mutations. Additionally, the team assessed the role of receptor binding affinity of BA.2.75 in its transmissibility. They used surface plasmon resonance (SPR) to quantify the binding affinity of purified S trimer to dimeric human ACE2 (hACE2).

Study findings

The study results showed that the neutralization or 50% inhibitory dose (ID50) titers of the sera from boosted individuals were markedly lower against BA.2, BA.2.12.1, and BA.4/5 than D614G (4.9-, 7.8-, and 14.8-folds, respectively). The ID50 against BA.2.75 was similar to against BA.2.12.1, but 8.7-fold and 1.8-fold lower than D614G and BA.2, respectively. However, ID50  values for BA.2.75 were 1.7-fold higher than BA.4/5. They observed a similar trend among two cohorts of the BA.1 and BA.2 breakthrough infections.

Six mutations viz., W152R, F157L, I210V, G257S, D339H, and N446K altered the neutralization titers of sera from all three cohorts against BA.2 by 0.8-fold to 1.3-fold. Conversely, K147E and N460K impaired the sera neutralization activity by 1.6-fold to 1.8-fold and 1.5-fold to 2.4-fold, respectively. The R493Q reversion mutation moderately enhanced the neutralization by 1.8- to 3.0-fold.

The authors noted that the class I antibodies (e.g., Omi-18) and class III antibodies (e.g., LY-CoV1404) lost neutralization activity against BA.2.75 compared to BA.2. The loss in neutralization activity against class I antibodies Omi-3 and Omi-18 were apparent in the background of BA.2 but not D614G. Conversely, class II antibodies, such as REGN10933, showed higher neutralization sensitivity against BA.2.75 relative to BA.2. Overall, this data could help interpret the observations made during polyclonal serum neutralization. Notably, LY-CoV1404 ( bebtelovimab) was the only clinical mAb that retained potent neutralizing activity against all Omicron subvariants, including BA.2.75, with an IC50 below 0.01 µg/ml. It showed a 3.7-fold loss in neutralization against BA.2.75.

While G446S impaired or abolished the neutralizing activity of class III mAbs, such as JMB2002, the N460K substitution provided neutralization resistance to all the class I mAbs and one class II mAb (ZCB11) tested. The NTD mutation K147E had no significant impact on polyclonal sera, indicating that this mutation may be acting through non-RBD antibodies. Interestingly, BA.2.75 had the highest receptor binding affinity among all Omicron sub-variants, with dissociation constant (KD) values seven- and 2.4-fold lower than BA.2 and BA.4/5 values, respectively. BA.2.75 was also slightly more sensitive to hACE2 than the other pseudoviruses.

Conclusions

The systematic evaluation of the antigenic properties of the new SARS-CoV-2 Omicron subvariant BA.2.75 revealed that it had a higher resistance to vaccine-induced and infection-induced serum neutralizing activity than BA.2 sub-variant. However, it did not show higher immune evasion from polyclonal sera than the BA.4/5 subvariant. Although NTD antibodies contribute a fraction of the serum virus-neutralizing activity, it is intriguing why SARS-CoV-2 added five new NTD mutations in Omicron subvariant BA.2.75.

*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.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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