Spike mutations in SARS-CoV-2 variants confer resistance to antibody neutralization

 Ruoke Wang, Qi Zhang, Jiwan Ge, Wenlin Ren, Rui Zhang, Jun Lan, Bin Ju, Bin Su, Fengting Yu, Peng Chen, Huiyu Liao, Yingmei Feng, Xuemei Li, Xuanling Shi, Zheng Zhang, Fujie Zhang, Qiang Ding, Tong Zhang, Xinquan Wang,  

View ORCID ProfileLinqi Zhang

doi: https://doi.org/10.1101/2021.03.09.434497

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.03.09.434497v1.full.pdf

Abstract

New SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

Competing Interest Statement

The authors have filed patent applications on some of the antibodies described.

https://www.biorxiv.org/content/10.1101/2021.03.09.434497v1