@article {Cao2022.07.18.500332, author = {Yunlong Cao and Weiliang Song and Lei Wang and Pan Liu and Can Yue and Fanchong Jian and Yuanling Yu and Ayijiang Yisimayi and Peng Wang and Yao Wang and Qianhui Zhu and Jie Deng and Wangjun Fu and Lingling Yu and Na Zhang and Jing Wang and Tianhe Xiao and Ran An and Jing Wang and Lu Liu and Sijie Yang and Xiao Niu and Qingqing Gu and Fei Shao and Xiaohua Hao and Ronghua Jin and Youchun Wang and Xiaoliang Sunney Xie and Xiangxi Wang}, title = {Characterizations of enhanced infectivity and antibody evasion of Omicron BA.2.75}, elocation-id = {2022.07.18.500332}, year = {2022}, doi = {10.1101/2022.07.18.500332}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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{\textquoteright}s enhanced infectivity, especially compared to BA.5, remains unclear. Here, we show that BA.2.75 exhibits substantially higher ACE2-binding affinity than BA.5. Also, BA.2.75 spike shows decreased thermostability and increased {\textquotedblleft}up{\textquotedblright} RBD conformation in acidic conditions, suggesting enhanced low-pH-endosomal cell-entry pathway utilization. BA.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{\textquoteright}s distinct RBD and NTD-targeting antibody escaping pattern from BA.4/BA.5. Additionally, Evusheld 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 of immune-evasive mutations.Competing Interest StatementX.S.X. and Y.C. are inventors on the provisional patent applications of BD series antibodies, which includes BD30-604 (DXP-604), BD55-5840 (SA58) and BD55-5514 (SA55). X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals. Other authors declare no competing interests.}, URL = {https://www.biorxiv.org/content/early/2022/08/10/2022.07.18.500332}, eprint = {https://www.biorxiv.org/content/early/2022/08/10/2022.07.18.500332.full.pdf}, journal = {bioRxiv} }