Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity for host receptor angiotensin-converting enzyme 2 (ACE2) than BA.5 and other variants. Structural analyses of BA.2.75 spike shows its decreased thermostability and increased frequency of the receptor binding domain (RBD) in the up'' conformation under acidic conditions, suggesting enhanced low-pH-endosomal cell entry. Relative to BA.4/BA.5, BA.2.75 exhibits reduced evasion of humoral immunity from BA.1/BA.2 breakthroughinfection convalescent plasma but greater evasion of Delta breakthrough-infection convalescent plasma. BA.5 breakthrough-infection plasma also exhibits weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld and Bebtelovimab remain effective against BA.2.75. These results suggest BA.2.75 may prevail after BA.4/ BA.5, and its increased receptor-binding capability could support further immune-evasive mutations.

Automated summary

The newly emerged SARS-CoV-2 Omicron subvariant, BA.2.75, has shown a growth advantage over other circulating variants in India. This study reveals that BA.2.75 has a higher affinity for the host receptor ACE2 and exhibits increased low-pH-endosomal cell entry. It also demonstrates reduced evasion of humoral immunity from certain convalescent plasma, while showing a distinct neutralizing antibody escape pattern. These findings suggest that BA.2.75 may become the dominant variant following BA.4/BA.5.