Inactivated SARS-CoV-2 Variant Omicron, Lineage B.1.1.529, BA.2 (USA/CO-CDPHE-2102544747/2021)

The SARS-CoV-2 Omicron (B.1.1.529) variant was discovered in South Africa on November 24, 2021, and was declared a variant of concern (VOC) by the World Health Organization on November 26. It has rapidly replaced Delta (B.1.617.2) as the predominant SARS-CoV-2 variant circulating globally. The Omicron spike (S) protein contains 30 mutations and is the most immune-evading VOC discovered to date, surpassing Beta (B.1.351) in its ability to resist neutralization by antibodies. Structural studies have helped reveal conformational changes in the VOC S protein and provide insights into the atomic-level mechanisms driving its enhanced transmissibility and immune evasion.

The prefusion SARS-CoV-2 S protein consists of S1 and S2 subunits, which undergo structural changes to facilitate receptor binding and fusion with host cell membranes. While the S2 subunit maintains a stable conformation prior to receptor binding, the S1 subunit is inherently dynamic due to its mobile N-terminal domain (NTD) and receptor-binding domain (RBD). The RBD transitions between a "closed" ("down") state (where the ACE2 receptor binding site is blocked) and an "open" ("up") state (where the ACE2 binding site is exposed). Following receptor binding and proteolytic processing of the S protein, the S2 subunit undergoes a major conformational change, leading to the release of the fusion peptide (FP), which mediates fusion of the virus with the host cell membrane. RBD dynamics are influenced by interprotomer RBD-to-RBD and RBD-to-NTD contacts, as well as other S protein structural elements, including the SD1 and SD2 subdomains and the "N2R (NTD-to-RBD) linker" connecting the NTD and RBD within the protomer.