Structural Study Reveals How Omicron Affects Antibody Access to Conserved S2′ Site in Spike Protein

SARS-CoV-2 Omicron variants evade antibodies targeting spike residues 815–825 through steric hindrance resulting from S2′-helix shifts and restricted S1–ACE2 distancing in the early fusion intermediate conformation, @Nature reported. The variants also show increased reliance on cathepsin-mediated entry that impairs inhibition of S2′ cleavage.

The H655Y mutation is central to this evasion of antibody 76E1.

The pan-coronavirus epitope consists of spike residues 815–825 centred on the S2′ site. These residues are buried in the prefusion spike but are transiently exposed upon ACE2 binding. Antibody 76E1 targets spike residues 815–825 and specifically recognizes an open early fusion intermediate conformation in which the epitope adopts a helical conformation designated the S2′-helix.

The study demonstrates that Omicron exhibits enhanced steric hindrance to antibodies targeting S815–825. Antibody size directly affects its access to the S2′-helix. Minimization of antibody size reversed Omicron evasion mechanisms.

Size-minimized antibodies enhanced neutralizing activity against authentic Omicron variants. They also enhanced neutralizing activity against SARS-CoV-1 and against HCoV-229E. The research used integrated functional and structural analyses including cryoelectron microscopy.

The H655Y mutation plays a critical role in Omicron evasion of 76E1-FL. Fig. Separate figures detail enhanced cathepsin-mediated entry and molecular mechanisms of partial evasion.

These findings establish small-molecule targeting of the S2′-helix as a strategy for pan-coronavirus therapies. A related paper titled 'Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2' was published on 30 June 2022. The current paper is titled 'Steric hindrance of antibody binding in an Omicron spike fusion intermediate'.