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Aerosolized Nanobodies Prevent Infections of SARS-CoV-2 in PrEP and PEP Settings in Mice and are Effective to Variants

44 Pages Posted: 3 Feb 2022 Publication Status: Review Complete

See all articles by Honghui Liu

Honghui Liu

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Lili Wu

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Bo Liu

affiliation not provided to SSRN

Ke Xu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention

Wenwen Lei

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention

Jianguo Deng

Tsinghua University

Pei Du

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Pengcheng Han

Southeast University; Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Lebing Wang

affiliation not provided to SSRN

Dongbin Wang

Tsinghua University

Xiaolong Zhang

affiliation not provided to SSRN

Chao Su

affiliation not provided to SSRN

Anqi Zheng

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Xiaoyun Wang

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Qingwen He

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Yunfei Jia

Shanxi Agricultural University; Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

Shihua Li

affiliation not provided to SSRN

Xinxin Yan

affiliation not provided to SSRN

Zheng Fan

affiliation not provided to SSRN

Yuhai Bi

affiliation not provided to SSRN

Hua Chen

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

William J. Liu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention

Jianxun Qi

affiliation not provided to SSRN

Shuhui Qi

affiliation not provided to SSRN

Qingwei Cui

affiliation not provided to SSRN

Ruiwen Fan

affiliation not provided to SSRN

Jingkun Jiang

Tsinghua University

Gui Zhen Wu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention

George F. Gao

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

Qihui Wang

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology

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Abstract

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).

Keywords: SARS-CoV-2, SARS-CoV-2 variants, sarbecoviruses, cross-reactive antibody, Nanobody, aerosolization, inhalable therapeutics, crystal structure

Suggested Citation

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.

Honghui Liu

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Lili Wu

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Bo Liu

affiliation not provided to SSRN ( email )

No Address Available

Ke Xu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention ( email )

China

Wenwen Lei

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention ( email )

China

Jianguo Deng

Tsinghua University ( email )

Pei Du

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Pengcheng Han

Southeast University ( email )

Sipailou 2#
Nanjing, Jiangsu Province 210096
China

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Lebing Wang

affiliation not provided to SSRN ( email )

No Address Available

Dongbin Wang

Tsinghua University ( email )

Xiaolong Zhang

affiliation not provided to SSRN ( email )

No Address Available

Chao Su

affiliation not provided to SSRN ( email )

No Address Available

Anqi Zheng

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Xiaoyun Wang

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

Qingwen He

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Yunfei Jia

Shanxi Agricultural University ( email )

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Shihua Li

affiliation not provided to SSRN ( email )

No Address Available

Xinxin Yan

affiliation not provided to SSRN ( email )

No Address Available

Zheng Fan

affiliation not provided to SSRN ( email )

No Address Available

Yuhai Bi

affiliation not provided to SSRN ( email )

No Address Available

Hua Chen

China National Center for Bioinformation ( email )

Beijing
China

Chinese Academy of Sciences (CAS) - Beijing Institute of Genomics

Beijing, 100101
China

Chinese Academy of Sciences (CAS) - School of Future Technology

Beijing, 100049
China

Chinese Academy of Sciences (CAS) - Center for Excellence in Animal Evolution and Genetics

Kunming, 650223
China

William J. Liu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention ( email )

China

Jianxun Qi

affiliation not provided to SSRN ( email )

No Address Available

Shuhui Qi

affiliation not provided to SSRN ( email )

No Address Available

Qingwei Cui

affiliation not provided to SSRN ( email )

No Address Available

Ruiwen Fan

affiliation not provided to SSRN ( email )

No Address Available

Jingkun Jiang

Tsinghua University ( email )

Gui Zhen Wu

Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases - National Institute for Viral Disease Control and Prevention

China

George F. Gao (Contact Author)

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

University of Science and Technology of China (USTC) - School of Life Sciences ( email )

China

Qihui Wang

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Pathogenic Microbiology and Immunology ( email )

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

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