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 have revealed how the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron evades neutralizing antibodies (nAbs).

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 harm for Omicron’s VOC given the high risk of spreading the COVID-19 pandemic globally and a significantly higher R-value of Omicron than Delta. VOC.

Preliminary studies have revealed a high risk of reinfection and breakthrough infections with the Omicron variant. Nevertheless, the disease caused by the Omicron variant has been relatively mild and health facilities remain functional despite the huge increase in infections. Therefore, it is possible that the pandemic will end with the global spread of Omicron VOC and the resulting widespread immunization with significantly reduced disease severity and mortality.

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

About the study

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

The binding kinetics of angiotensin-converting enzyme-2 (ACE2): receptor binding domain (RBD) were assessed. High precision streptavidin (SAX) biosensors were loaded with biotinylated ACE2 and later quenched with biocytin. Serial dilution of RBD in kinetic buffer (KB) was performed. Enzyme immunoassays (ELISA) were performed and a biolayer interferometry (BLI)-based assay was used to test the ability of serum samples to compete with ACE2 for binding to type RBDs. wild (WT), Delta and Omicron variants.

Heat-inactivated serum samples were diluted and incubated with 100 tissue culture median infectious dose (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 the neutralizing titers as the highest dilution of the sera, completely inhibiting CPE. Statistical significance was measured using the paired or unpaired Student’s t test.

Interaction and ACE2-spike 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 the ACE2 ectodomain (yellow surface).  (B) Detail of (A), highlighting mutated residues (orange bars) in Delta.  (C) Same as (B) but highlighting 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) Monomer S (blue ribbon and surface) bound to the ACE2 ectodomain (yellow surface). (B) Detail of (A), highlighting mutated residues (orange bars) in Delta. (VS) Similar to (B) but highlighting the mutated residues in Omicron. From PDB files 6ACG and 2AJF.


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

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

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

As inferred by the CPE, convalescent sera showed low neutralizing capacity against all variants tested. Sera from double vaccine recipients had comparable neutralizing titers against SARS-CoV-2 WT and the 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, the researchers evaluated the differences shown by the sera of three different types of subjects: convalescent subjects and recipients of the primary and booster vaccination. The findings showed the enhanced binding affinity of Omicron RBD to the ACE2 receptor, plausibly explaining the high infectivity of SARS-CoV-2 Omicron VOC. Additionally, the researchers postulate that Omicron VOC may have evolved two mechanisms to evade the traps.

First, the highly mutated RBD might not match antibody responses, since antibodies elicited by natural infection or vaccination are less specific for Omicron RBD, i.e. ‘specificity escape’. Second, Omicron RBD’s higher affinity for ACE2 could present challenges for catch-ups to compete with it, i.e. “affinity evasion”. Finally, although Delta and Omicron COVs showed greater affinity for ACE2, the combination of specificity and affinity escape resulted in a more pronounced reduction in neutralization.

Journal reference:

  • Increased receptor affinity and reduced recognition by specific antibodies contribute to immune evasion of SARS‐CoV‐2 variant Omicron, Vogt, A.‐C.; Augusto, G.; Martina, B.; Chang, X.; Nasrallah, G.; Speiser, DE; Vogel, M.; Bachmann, MF; Mohsen, MO, Vaccines 2022, 10, 743, DOI:,

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