Recently emerged SARS-CoV-2 Omicron subvariant,BA.2.75,displayed a local growth advantage over BA.2.38,BA.2.76 and BA.5 in India.The underlying mechanism of BA.2.75's enhanced infectivity, especially compared to BA.5,remains unclear.Herewe show that BA.2.75 exhibits substantially higher ACE2-binding affinity than BA.5.Also,BA.2.75 spike shows decreased thermostability and increased “up’RBD conformation in acidic conditions, suggesting enhanced low-pH-endosomal cell-entry pathway utilizationBA.2.75 is less humoral immune evasive than BA.4/BA.5 in BA.1/BA.2 breakthrough-infection convalescents;however,BA.2.75 shows heavier neutralization evasion in Delta breakthrough-infection convalescents.Importantly, plasma from BA.5 breakthrough infection exhibit significantly weaker neutralization against BA.2.75 than BA.5 mainly due to BA.2.75’s distinct RBD and NTD-targeting antibody escaping pattern from BA.4/BA.5.AdditionallyEvusheld and Bebtelovimab remain effective against BA.2.75,and Sotrovimab recovered RBD-binding affinity.Together our results suggest BA.2.75 may prevail after the global BA.4/BA.5 wave,and its increased receptor-binding capability could allow further incorporation ofimmune-evasive mutations.
