TY - JOUR
T1 - Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron
AU - Ma, Huan
AU - Zhang, Xinghai
AU - Zheng, Peiyi
AU - Dube, Peter H.
AU - Zeng, Weihong
AU - Chen, Shaohong
AU - Cheng, Qingyu
AU - Yang, Yunru
AU - Wu, Yan
AU - Zhou, Junhui
AU - Hu, Xiaowen
AU - Xiang, Yan
AU - Zhang, Huajun
AU - Chiu, Sandra
AU - Jin, Tengchuan
N1 - Funding Information:
We thank Jia Wu, Jun Liu and Hao Tang from Wuhan Institute of Virology for the management of BSL-3 facility. We thank National Virus Resource Center for providing Omicron variant (CCPM-B-V-049-2112-18). We thank Prof. Wei Chen for providing pseudotyped Omicron BA.1 and BA.2. We thank Ralph S. Baric for providing MA10. We thank Anhui Zhifei Longcom Biopharmaceutical Co., Ltd for providing WT SARS-CoV-2 RBD-tr2. We thank the staff at the BL19U1 and BL02U1 beamline at Shanghai Synchrotron Radiation Facility (SSRF) for the assistance during data collection. We also thank the authors from the original laboratory and the submitting laboratory who generated and shared, via the GISAID EpiCoV database, the amino acid sequence data on which this study is based. We would like to thank staff at the core facility of USTC for their kind suport. This study was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030104), the National Natural Science Foundation of China (31870731, 32100745), the Fundamental Research Funds for the Central Universities (WK9100000019), and a COVID-19 pilot grant from UTHSCSA to Y.X.
Funding Information:
We thank Jia Wu, Jun Liu and Hao Tang from Wuhan Institute of Virology for the management of BSL-3 facility. We thank National Virus Resource Center for providing Omicron variant (CCPM-B-V-049-2112-18). We thank Prof. Wei Chen for providing pseudotyped Omicron BA.1 and BA.2. We thank Ralph S. Baric for providing MA10. We thank Anhui Zhifei Longcom Biopharmaceutical Co., Ltd for providing WT SARS-CoV-2 RBD-tr2. We thank the staff at the BL19U1 and BL02U1 beamline at Shanghai Synchrotron Radiation Facility (SSRF) for the assistance during data collection. We also thank the authors from the original laboratory and the submitting laboratory who generated and shared, via the GISAID EpiCoV database, the amino acid sequence data on which this study is based. We would like to thank staff at the core facility of USTC for their kind suport. This study was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030104), the National Natural Science Foundation of China (31870731, 32100745), the Fundamental Research Funds for the Central Universities (WK9100000019), and a COVID-19 pilot grant from UTHSCSA to Y.X.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9
Y1 - 2022/9
N2 - SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development of broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, with potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 with aRBD-5 and aRBD-7, respectively. Here, we resolved the crystal structures of these Nbs in complex with the receptor-binding domain (RBD) of the spike protein, and found that aRBD-2 contacts with highly-conserved RBD residues and retains binding to the RBD of the Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, and BA.2 variants. In contrast, aRBD-5 and aRBD-7 bind to less-conserved RBD epitopes non-overlapping with the epitope of aRBD-2, and do not show apparent binding to the RBD of some variants. However, when fused with aRBD-2, they effectively enhance the overall binding affinity. Consistently, aRBD-2-5-Fc and aRBD-2-7-Fc potently neutralized all of the tested authentic or pseudotyped viruses, including WT, Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.1.1 and BA.2. Furthermore, aRBD-2-5-Fc provided prophylactic protection against the WT and mouse-adapted SARS-CoV-2 in mice, and conferred protection against the Omicron BA.1 variant in hamsters prophylactically and therapeutically, indicating that aRBD-2-5-Fc could potentially benefit the prevention and treatment of COVID-19 caused by the emerging variants of concern. Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19.
AB - SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development of broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, with potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 with aRBD-5 and aRBD-7, respectively. Here, we resolved the crystal structures of these Nbs in complex with the receptor-binding domain (RBD) of the spike protein, and found that aRBD-2 contacts with highly-conserved RBD residues and retains binding to the RBD of the Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, and BA.2 variants. In contrast, aRBD-5 and aRBD-7 bind to less-conserved RBD epitopes non-overlapping with the epitope of aRBD-2, and do not show apparent binding to the RBD of some variants. However, when fused with aRBD-2, they effectively enhance the overall binding affinity. Consistently, aRBD-2-5-Fc and aRBD-2-7-Fc potently neutralized all of the tested authentic or pseudotyped viruses, including WT, Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.1.1 and BA.2. Furthermore, aRBD-2-5-Fc provided prophylactic protection against the WT and mouse-adapted SARS-CoV-2 in mice, and conferred protection against the Omicron BA.1 variant in hamsters prophylactically and therapeutically, indicating that aRBD-2-5-Fc could potentially benefit the prevention and treatment of COVID-19 caused by the emerging variants of concern. Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19.
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UR - http://www.scopus.com/inward/citedby.url?scp=85137136054&partnerID=8YFLogxK
U2 - 10.1038/s41422-022-00700-3
DO - 10.1038/s41422-022-00700-3
M3 - Article
C2 - 35906408
AN - SCOPUS:85137136054
SN - 1001-0602
VL - 32
SP - 831
EP - 842
JO - Cell Research
JF - Cell Research
IS - 9
ER -