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In a recent study posted to the bioRxiv* preprint server, researchers examined antibody escape and cross-domain stabilization in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron spike (S) protein.

Study: Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein. Image Credit: Naeblys/Shutterstock

The widespread mortality and morbidity caused by rampant coronavirus disease 2019 (COVID-19) transmission have resulted in the emergence of novel SARS-CoV-2 variants of concern (VOCs).

However, the interactions of the new mutations in these VOCs against the Omicron mutational background need extensive research.

About the study

The researchers in the present study characterized the expression, cell receptor affinity, and antibody binding of the SARS-CoV-2 S extracellular domains (ECDs) using cell surface display of the S protein. The team also assessed the impact of all SARS-CoV-2 Omicron mutations on human angiotensin-converting enzyme-2 (hACE-2) binding, the stability of the S protein, and the evasion of monoclonal antibodies (mAbs).

The team used a mammalian cell surface display and compared the expression and antigenicity of the Omicron BA.1 and BA.2 ECDs to other VOCs. They expressed S variants on human embryonic kidney (HEK293T) cells. The S proteins were subsequently immunostained to evaluate the expression, Ab binding, lisinopril métabolite and hACE2 affinity via two-color flow cytometry.

S proteins were first cloned from SARS-CoV-2 Alpha, Beta, Delta, Gamma, and Omicron BA.1 and BA.2 VOCs and Epsilon variant of interest (VOI). The team incorporated the D614G mutation and prefusion stabilizing prolines into the variants to improve surface expression. Each variant was assayed for the expression and the potential of escaping a set of 21 mAbs. These MAbs included nine N-terminal domain (NTDs)-targeting mAbs and 12 neutralizing receptor-binding domain (RBDs)-targeting mAbs. Furthermore, clinically used mAbs like REGN10987 (imdevimab) and REGN10933 (casirivimab), and S309 (sotrovimab) and LY-CoV555 (bamlanivimab) were also included in the study.

The team conducted microneutralization assays on the BA.1 variant along with 10 mAbs, whose neutralization ability against the Wuhan-Hu-1 (WHU1) lineage was known. Furthermore, they examined four NTD-targeting mAbs, each belonging to the four classes of binding mAbs. Subsequently, the team screened the WHU1 S protein variant that contained each mutation found in the BA.1 and BA.2 variants. Also, the impact of RBD substitutions on mAbs was assessed by screening the WHU1 S protein using RBD-targeting mAbs.  

Results

The study results showed that the SARS-CoV-2 Omicron BA.1 and BA.2 variants had increased Ab escape potential compared to other variants. BA.1 effectively evaded a majority of the Abs tested in the present study, including almost all the NTD-targeting mAbs. On the other hand, BA.1 S protein was refractory to several RBD-targeting mAbs and displayed a strong escape potential against all class II binders, half of the total class III binders, and all of the quaternary binders.

Moreover, BA.2 exhibited a substantial level of Ab escape potential; however, it showed susceptibility towards the class I NTD-targeting mAbs and the class III RBD-targeting mAbs. 

In comparison to the WHU1, the BA.1 variant effectively evaded neutralization by class I, class II, and class IV mAbs. This evasion could be attributed to the series of contiguous mutations found on the variant. Interestingly, BA.1 escaped the same Abs as those observed in the mammalian cell surface assay. This indicated that the BA.1 and BA.2 S protein variants were antigenically distinct.

Furthermore, the team observed that the class I mAbs had lowered Ab binding due to the Y145D mutation while the class III and class IV had increased binding that was more susceptible to mutations.

Notably, the BA.2 variant was sensitive toward some of the NTD-binding mAbs. Also, the mutations in BA.2 showed slightly reduced bindings toward class II, III, and IV mAbs. Moreover, with the G142D mutation, BA.2 effectively escaped recognition by Ab at this site.

Among the mAbs tested in this study, a class I mAb, called S2X35, had slightly decreased Ab binding because of the E484A mutation. Furthermore, class II Abs including C002, LY-CoV555, and C144 and the quaternary binder 2-43 were found to be the most influenced by the mutations at E484A and Q493R. The class III mAb REGN10987 also displayed lowered binding due to both N440K and G446S mutations, while C135 was affected by the N440K and Q498R mutations.

Conclusion

Overall, the study findings showed that the continuous emergence of mutations in SARS-CoV-2 variants will further lead to an altered conformational equilibrium, allowing for the formation of more stable and virulent mutations. The researchers believe that the strategy employed in the present study can be extended to develop future therapeutic approaches and vaccine formulations.

*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:
  • Kamyab Javanmardi, et al. (2022). Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein. bioRxivdoi: https://doi.org/10.1101/2022.04.18.488614 https://www.biorxiv.org/content/10.1101/2022.04.18.488614v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Angiotensin, Antibodies, Antibody, Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytometry, Enzyme, Flow Cytometry, Kidney, Mortality, Mutation, Omicron, Protein, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Sotrovimab, Spike Protein, Syndrome, Vaccine

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Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.

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