Study: Increased Receptor Affinity and Reduced Recognition by Specific Antibodies Contribute to Immune Escape of SARS-CoV-2 Variant Omicron. ​​​​​​​Image Credit: Orpheus FX / Shutterstock

SARS-CoV-2 Omicron escapes immune response due to high ACE2 affinity and low antibody specificity

In a recent study published in the journal Vaccinesresearchers revealed how severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evades Omicron neutralizing antibodies (nAb).

Two days after it was first reported on November 24, 2021, the World Health Organization (WHO) designated SARS-CoV-2 Omicron as a variant of concern (VOC). The WHO estimated a potentially higher risk of hazard for the Omicron VOC, given the high risk of the COVID-19 pandemic continuing worldwide and a significantly higher R-value of Omicron than Delta VOC.

Preliminary studies revealed an increased risk of reinfection and vaccine breakthrough infections with the Omicron variant. Nevertheless, the disease caused by the Omicron variant is relatively mild and healthcare facilities remain functional despite the huge increase in infections. Therefore, it is possible that the pandemic could end with the global spread of Omicron VOC and consequent broad immunization with significantly reduced disease severity and mortality.

Study: Increased Receptor Affinity And Decreased Recognition By Specific Antibodies Contribute To Immune Escape Of SARS-CoV-2 Variant Omicron† ​​​​​​​Image Credit: Orpheus FX/Shutterstock

About the study

In the present study, researchers reported the mechanisms underlying the increased transmissibility and resistance to infection- or vaccine-induced antibodies of the SARS-CoV-2 Omicron variant. Serum samples were obtained from recovering individuals infected with SARS-CoV-2 Wuhan strain, double vaccinated individuals and boosted individuals. Participants received BNT162b2 or mRNA-1273 messenger ribonucleic acid (mRNA) vaccines.

The binding kinetics of angiotensin-converting enzyme-2 (ACE2): receptor binding domain (RBD) was evaluated. High precision streptavidin (SAX) biosensors were loaded with biotinylated ACE2 and later quenched with biocytin. Serial dilution of RBD in Kinetics Buffer (KB) was performed. Enzyme-linked immunosorbent assays (ELISAs) were performed and a bio-layer interferometry (BLI)-based assay was used to test the ability of serum samples to compete with ACE2 to bind to wild-type (WT), Delta, and Omicron RBDs variants.

Heat-inactivated serum samples were diluted and incubated with 100 median infectious dose of tissue culture (TCID50) of the SARS-CoV-2 WT, Delta, or Omicron variant. Then this mixture (serum + virus) was added to Vero cells, incubated for four days and checked for cytopathic effect (CPE). The authors expressed neutralizing titers as the highest dilution of sera at which CPE was completely inhibited. Statistical significance was measured using paired or unpaired Student’s t-test.

​​​​​​​ACE2 spike interaction and mutations found in RBD of B.1.617.2 (Delta) and B.1.1.529 (Omicron).  (A) S monomer (blue ribbon and surface) bound to ACE2 ectodomain (yellow surface).  (B) Detail of (A), highlighting the mutated residues (orange sticks) in Delta.  (C) Same as in (B) but with emphasis on the mutated residues in Omicron.  From PDB files 6ACG and 2AJF.ACE2 spike interaction and mutations found in RBD of B.1.617.2 (Delta) and B.1.1.529 (Omicron). †A) S-monomer (blue ribbon and surface) bound to ACE2 ectodomain (yellow surface). †B) Detail of (A), with emphasis on the mutated residues (orange sticks) in Delta. †C) Same as in (B) but highlight the mutated residues in Omicron. From PDB files 6ACG and 2AJF.


The researchers observed an approximately two-fold increase in the binding affinity of RBDs from Delta and Omicron variants to ACE2 relative to RBD from SARS-CoV-2 WT. This increased affinity was due to the increased association rate and decreased dissociation rate. In addition, the natural infection-induced immunoglobulin G (IgG) antibodies showed poor recognition of mutant RBDs. In contrast, those elicited after two or three mRNA vaccine doses recognized RBDs of WT and Delta variant equally, but Omicron RBD recognition was poor or impaired.

When the half-maximal optical density (OD50) of the antibody titers was measured, the team observed a significant reduction in the recognition of Omicron and Delta variants RBD relative to WT RBD. Recovering serum samples showed reduced recognition of Omicron RBD, while no changes were noted for WT or Delta RBD. BLI experiments revealed profound differences between binding and inhibitory properties of several RBDs tested. Notably, Omicron RBD binding (to ACE2) was lower than that of Delta RBD. Sera from boosted individuals showed the highest binding, followed by sera from double vaccinated individuals and convalescent individuals.

In addition, sera from convalescent subjects failed to inhibit ACE2 RBD binding at the concentration tested. Serum antibodies from recipients of two vaccine doses showed mean inhibition of 28.5% and 27.3% against RBD of Delta and Omicron VOCs, respectively, without any statistical differences. Nevertheless, the inhibitory potential increased dramatically after receiving the booster dose, although it remained lower against Omicron (45%) than against the Delta variant (66%).

As inferred by CPE, the recovering sera showed poor neutralizing ability against all variants tested. Sera from dual vaccine recipients had similar neutralizing titers against SARS-CoV-2 WT and Delta variant. However, neutralization was significantly lower against the Omicron variant than WT or Delta. This reduced potency was consistent for sera from boosted individuals.


In the present study, researchers assessed the differences exhibited by sera from three different types of subjects: recovering subjects and primary and booster vaccination recipients. The findings showed an enhanced binding affinity of Omicron RBD to the ACE2 receptor, which is a plausible explanation for the high infectivity of SARS-CoV-2 Omicron VOC. In addition, the researchers argue that Omicron VOC may have evolved two mechanisms to circumvent nAbs.

First, the highly mutated RBD may not correspond to antibody responses, as antibodies elicited by natural infection or vaccination are less specific for Omicron RBD, ie ‘specificity escape’. Second, the higher affinity of Omicron RBD for ACE2 may present a challenge for nAbs to compete with it, ie ‘affinity escape’. Finally, although both Delta and Omicron VOCs showed a higher affinity for ACE2, the combination of specificity and affinity escape resulted in a more pronounced reduction in neutralization.

Reference magazine:

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