Determinants of Spike infectivity, processing, and neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

SARS-CoV-2 Omicron rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission and immune evasion are thought to be driven by numerous mutations in the Om-icron Spike protein. Here, we systematically introduced BA.1 and/or BA.2 Omicron Spike mutations into the ancestral Spike protein and examined the impacts on Spike function, processing, and susceptibility to neutralization. Individual mutations of S371F/L, S375F, and T376A in the ACE2-receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes to G339D, D614G, N764K, and L981F moderately enhanced it. Most mutations in the N-terminal region and receptor-binding domain reduced the sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine and by therapeutic antibodies. Our results represent a systematic functional anal-ysis of Omicron Spike adaptations that have allowed this SARS-CoV-2 variant to dominate the current pandemic.

Automated summary

The SARS-CoV-2 Omicron variant has rapidly become the dominant strain in the COVID-19 pandemic, mainly due to its enhanced transmission and immune evasion capabilities resulting from multiple mutations in the Spike protein. Certain mutations impair infectivity, while others moderately enhance it. Moreover, most mutations in the Spike protein reduce its susceptibility to neutralization by sera from vaccinated individuals and therapeutic antibodies.