The first molecular-level structural analysis of the Omicron variant spike protein in complex with human ACE2 is now available. The near-atomic resolution analysis—using cryo-electron microscopy—yields insights into how the heavily mutated Omicron variant attaches to and infects human cells.

This work is published in Science in the paper, “SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex.

“Understanding the molecular structure of the viral spike protein is important as it will allow us to develop more effective treatments against Omicron and related variants in the future,” said Sriram Subramaniam, PhD, professor of biochemistry and molecular biology at the University of British Columbia. “By analyzing the mechanisms by which the virus infects human cells, we can develop better treatments that disrupt that process and neutralize the virus.”

The spike protein, which is located on the outside of SARS-CoV-2, enables it to enter human cells. The Omicron variant has an unprecedented 37 mutations on its spike protein—three to five times more than previous variants.

The structural analysis revealed that several mutations (R493, S496, and R498) create new salt bridges and hydrogen bonds between the spike protein and the human cell receptor ACE2. The researchers noted that these interactions “appear to compensate for other Omicron mutations such as K417N known to reduce ACE2 binding affinity, resulting in similar biochemical ACE2 binding affinities for Delta and Omicron variants.”

“Overall, the findings show that Omicron has greater binding affinity than the original virus, with levels more comparable to what we see with the Delta variant,” said Subramaniam. “It is remarkable that the Omicron variant evolved to retain its ability to bind with human cells despite such extensive mutations.”

The researchers conducted neutralization assays and showed that pseudoviruses displaying the Omicron spike protein exhibit increased antibody evasion. In contrast to previous variants, Omicron showed measurable evasion from all six monoclonal antibodies tested, with complete escape from five. The variant also displayed increased evasion of antibodies collected from vaccinated individuals and unvaccinated COVID-19 patients.

“Notably, Omicron was less evasive of the immunity created by vaccines, compared to immunity from natural infection in unvaccinated patients. This suggests that vaccination remains our best defense,” said Subramaniam.

The increase in antibody evasion, the authors noted, “together with retention of strong interactions at the ACE2 interface, represent important molecular features that likely contribute to the rapid spread of the Omicron variant.”

Based on the observed increase in binding affinity and antibody evasion, the researchers say that the spike protein mutations are likely contributing factors to the increased transmissibility of the Omicron variant.