Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant

BMC Med. 2022 Mar 3;20(1):102. doi: 10.1186/s12916-022-02312-5.


Background: The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and immediately classified as a variant of concern (VOC), since it shows substantially more mutations in the spike protein than any previous variant, especially in the receptor-binding domain (RBD). We analyzed the binding of the Omicron RBD to the human angiotensin-converting enzyme-2 receptor (ACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta, or Delta RBD variants.

Methods: All RBDs were produced in insect cells. RBD binding to ACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 81 vaccinated individuals, and 34 booster recipients were titrated by ELISA on RBDs from the original Wuhan strain, Beta, Delta, and Omicron VOCs. In addition, the neutralization efficacy of authentic SARS-CoV-2 wild type (D614G), Delta, and Omicron by sera from 2× or 3× BNT162b2-vaccinated persons was analyzed.

Results: Surprisingly, the Omicron RBD showed a somewhat weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. A 2.6× reduction in Omicron RBD binding was observed for serum of 2× BNT162b2-vaccinated persons. Neutralization of Omicron SARS-CoV-2 was completely diminished in our setup.

Conclusion: These results indicate an immune escape focused on neutralizing antibodies. Nevertheless, a boost vaccination increased the level of anti-RBD antibodies against Omicron, and neutralization of authentic Omicron SARS-CoV-2 was at least partially restored. This study adds evidence that current vaccination protocols may be less efficient against the Omicron variant.

Keywords: Antibody titer; Beta variant (B.1.351); COVID-19; Delta variant (B.1.617.2); Human angiotensin-converting enzyme-2 receptor (ACE2); Omicron variant (B.1.1.529); Receptor-binding domain (RBD); SARS-CoV-2; Vaccination; Virus neutralization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BNT162 Vaccine
  • COVID-19* / prevention & control
  • Humans
  • Pandemics
  • SARS-CoV-2 / genetics
  • Spike Glycoprotein, Coronavirus / genetics


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • BNT162 Vaccine

Supplementary concepts

  • SARS-CoV-2 variants