Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins (preprint)

ABSTRACT

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype and Omicron BA.1 strains. The structure of the BA.2 spike timer reveals that all three receptor-binding domains (RBD) in the spike trimer are in open conformation, ready for high affinity binding to human ACE2, providing the basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to the mouse ACE2 with high potency. In contrast, the wildtype spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.