Kavli Affiliate: Robert Edwards
| Authors: Victoria Stalls, Jared Lindenberger, Sophie Gobeil, Rory Henderson, Rob Parks, Maggie Barr, Margaret Deyton, Mitchell Martin, Katarzyna Janowska, Xiao Huang, Aaron May, Micah Speakman, Esther Beaudoin, Robert J Edwards, Amanda Eaton, David Montefiori, Wilton Williams, Kevin O’Neil Saunders, Kevin Wiehe, Barton F Haynes and Priyamvada Acharya
| Summary:
The BA.2 lineage of the SARS-CoV-2 Omicron variant has gained in proportion relative to BA.1. As differences in their spike (S) proteins may underlie differences in their pathobiology, here we determined cryo-EM structures of a BA.2 S protein ectodomain and compared these to previously determined BA.1 S structures. BA.2 Receptor Binding Domain (RBD) mutations induced remodeling of the internal RBD structure resulting in its improved thermostability and tighter packing within the 3-RBD-down spike. In the S2 subunit, the fusion peptide in the BA.2 was less accessible to antibodies than in BA.1. Pseudovirus neutralization and spike binding assays revealed extensive immune evasion while defining epitopes of two RBD-directed antibodies, DH1044 and DH1193, that bound the outer RBD face to neutralize both BA.1 and BA.2. Taken together, our results indicate that stabilization of the 3-RBD-down state through interprotomer RBD-RBD packing is a hallmark of the Omicron lineages, and reveal differences in key functional regions in the BA.1 and BA.2 S proteins.