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bioRxiv · 10.1101/2020.07.09.195263

Structures of potent and convergent neutralizing antibodies bound to the SARS-CoV-2 spike unveil a unique epitope responsible for exceptional potency

Shuo Du·Yunlong Cao·Qinyu Zhu·Guopeng Wang·Xiaoxia Du·Runsheng He·Hua Xu·Yinghui Zheng·Bo Wang·Yali Bai·Chenggong Ji·Ayijiang Yisimayi·Qisheng Wang·Ning Gao·X. Sunney Xie·Xiao-dong Su·Junyu Xiao
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Abstract

Understanding the mechanism of neutralizing antibodies (NAbs) against SARS-CoV-2 is critical for effective vaccines and therapeutics development. We recently reported an exceptionally potent NAb, BD-368-2, and revealed the existence of VH3-53/VH3-66 convergent NAbs in COVID-19. Here we report the 3.5-[A] cryo-EM structure of BD-368-2s Fabs in complex with a mutation-induced prefusion-state-stabilized spike trimer. Unlike VH3-53/VH3-66 NAbs, BD-368-2 fully blocks ACE2 binding by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" and "down" positions. BD-368-2 also triggers fusogenic-like structural rearrangements of the spike trimer, which could impede viral entry. Moreover, BD-368-2 completely avoids the common epitope of VH3-53/VH3-66 NAbs, evidenced by multiple crystal structures of their Fabs in tripartite complexes with RBD, suggesting a new way of pairing potent NAbs to prevent neutralization escape. Together, these results rationalize a unique epitope that leads to exceptional neutralization potency, and provide guidance for NAb therapeutics and vaccine designs against SARS-CoV-2.

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Shuo Du, Yunlong Cao, Qinyu Zhu, Guopeng Wang, Xiaoxia Du, Runsheng He, Hua Xu, Yinghui Zheng, Bo Wang, Yali Bai, Chenggong Ji, Ayijiang Yisimayi, Qisheng Wang, Ning Gao, X. Sunney Xie, Xiao-dong Su, Junyu Xiao. 2020-07-09. Structures of potent and convergent neutralizing antibodies bound to the SARS-CoV-2 spike unveil a unique epitope responsible for exceptional potency. https://doi.org/10.1101/2020.07.09.195263

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