Structural Basis for the Enhanced Infectivity and Immune Evasion of Omicron Subvariants

The Omicron variants of SARS-CoV-2 have emerged as the dominant strains worldwide, causing the COVID-19 pandemic. Each Omicron subvariant contains at least 30 mutations on the spike protein (S protein) compared to the original wild-type (WT) strain. Here we report the cryo-EM structures of the trimeric S proteins from the BA.1, BA.2, BA.3, and BA.4/BA.5 subvariants, with BA.4 and BA.5 sharing the same S protein mutations, each in complex with the surface receptor ACE2. All three receptor-binding domains of the S protein from BA.2 and BA.4/BA.5 are up, while the BA.1 S protein has two up and one down. The BA.3 S protein displays increased heterogeneity, with the majority in the all up RBD state. The different conformations preferences of the S protein are consistent with their varied transmissibility. By analyzing the position of the glycan modification on Asn343, which is located at the S309 epitopes, we have uncovered the underlying immune evasion mechanism of the Omicron subvariants. Our findings provide a molecular basis of high infectivity and immune evasion of Omicron subvariants, thereby offering insights into potential therapeutic interventions against SARS-CoV-2 variants.

Automated summary

The Omicron variants of SARS-CoV-2, characterized by numerous spike protein mutations, have become the dominant strains globally. Cryo-EM structures of the trimeric S proteins from different Omicron subvariants (BA.1, BA.2, BA.3, and BA.4/BA.5) in complex with ACE2 receptor were determined. The S protein conformations varied among subvariants, correlating with their transmissibility and immune evasion mechanisms. Understanding the molecular basis of Omicron's infectivity and immune evasion is crucial for developing effective therapeutic interventions against SARS-CoV-2 variants.