China National Center for Bioinformation; Chinese Academy of Sciences (CAS) - Beijing Institute of Genomics; Chinese Academy of Sciences (CAS) - School of Future Technology; Chinese Academy of Sciences (CAS) - Center for Excellence in Animal Evolution and Genetics
Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology; University of Science and Technology of China (USTC) - School of Life Sciences
With the wide distribution of vaccines against COVID-19, we are witnessing gradually waning neutralizing antibodies and cases of breakthrough infections. This necessitate the development of drugs aside from vaccines, particularly ones that can be administered outside of hospitals. Here, we present two cross-reactive nanobodies, R14 and S43, that maintain potent neutralizing activities against SARS-CoV-2 after aerosolization, and show cross-reactivity against multiple SARS-CoV-2 variants, including the latest Omicron, and several sarbecoviruses. Through intranasal delivery to mice, the two nanobodies significantly reduce the lung viral RNAs at low doses, R14 also displays potent pre- and post-exposure prophylactics. Furthermore, the neutralizing mechanisms of R14 and S43 are revealed by the crystal structure of the RBD of SARS-CoV-2 in complex with either nanobody, inspiring bi-specific mAbs or cocktails against future emerging variants. Our work provides two promising candidates as convenient inhalable therapeutics against SARS-CoV-2 infection, which would contribute to end the COVID-19 pandemic.
Note: Funding: This work was supported by the CAS Project for Young Scientists in Basic Research (YSBR-010), and National Natural Science Foundation of China (81922044, 82041047 and 52091541), the Ministry of Science and Technology of the People’s Republic of China (2021YFC0863300) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29040203). Q.W. is supported by the Youth Innovation Promotion Association CAS (2018119). G.F.G is supported by the foundation of the NSFC Innovative Research Group (81621091).
Declaration of Interests: Q. W., G.F.G., H. L., P. H. and L. W. are listed as inventors and detection on patent applications for R14 and S43 based antiviral treatment. The other authors declare that they have no competing interest.
Ethics Approval Statement: Alpaca immunization was handled according to the alpaca guidelines approved by the Animal Ethics Committee [2017(55)] at Shanxi Agricultural University (Taigu, Shanxi, China). The animal experiments with SARS-CoV-2 challenge were conducted under animal biosafety level 3 (ABSL3) facility in Institute of Microbiology, Chinese Academy of Sciences (IMCAS) or Chinese Center for Disease Control and Prevention (China CDC). This study was approved by the Ethics Committee of Institute of Microbiology, Chinese Academy of Sciences (Ethical approval No. APIMCAS2021091) or the Ethics Committee of National Institution for Viral Disease Control and Prevention, China CDC (Ethical approval No. 20211124088).
Liu, Honghui and Wu, Lili and Liu, Bo and Xu, Ke and Lei, Wenwen and Deng, Jianguo and Du, Pei and Han, Pengcheng and Wang, Lebing and Wang, Dongbin and Zhang, Xiaolong and Su, Chao and Zheng, Anqi and Wang, Xiaoyun and He, Qingwen and Jia, Yunfei and Li, Shihua and Yan, Xinxin and Fan, Zheng and Bi, Yuhai and Chen, Hua and Liu, William J. and Qi, Jianxun and Qi, Shuhui and Cui, Qingwei and Fan, Ruiwen and Jiang, Jingkun and Wu, Gui Zhen and Gao, George F. and Wang, Qihui, Aerosolized Nanobodies Prevent Infections of SARS-CoV-2 in PrEP and PEP Settings in Mice and are Effective to Variants. Available at SSRN: https://ssrn.com/abstract=4001946 or http://dx.doi.org/10.2139/ssrn.4001946
This version of the paper has not been formally peer reviewed.
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