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A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS.
Cell. 2020 Aug 06; 182(3):722-733.e11.Cell

Abstract

Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.

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Authors+Show Affiliations

Dai L
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Hainan 571199, China. Electronic address: dailp@biols.ac.cn.
Zheng T
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
Xu K
Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Hainan 571199, China.
Han Y
Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
Xu L
Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100032, China.
Huang E
Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, Anhui 230088, China.
An Y
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Cheng Y
Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, Anhui 230088, China.
Li S
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Liu M
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Yang M
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Li Y
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Cheng H
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Yuan Y
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Zhang W
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Ke C
Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, China.
Wong G
Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; Department of Microbiology-Infectiology and Immunology, Laval University, Quebec City, QC G1V 4G2, Canada.
Qi J
Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Qin C
Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100032, China. Electronic address: qinchuan@pumc.edu.cn.
Yan J
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: yanjh@im.ac.cn.
Gao GF
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China. Electronic address: gaof@im.ac.cn.

MeSH

Angiotensin-Converting Enzyme 2AnimalsAntibodies, NeutralizingAntibodies, ViralBetacoronavirusCOVID-19COVID-19 VaccinesCell Line, TumorChlorocebus aethiopsCoronavirus InfectionsHEK293 CellsHumansMiceMice, Inbred BALB CMiddle East Respiratory Syndrome CoronavirusPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein BindingProtein Interaction Domains and MotifsReceptors, VirusSevere acute respiratory syndrome-related coronavirusSARS-CoV-2Sf9 CellsSpecific Pathogen-Free OrganismsSpodopteraTransfectionUniversal DesignVaccinationVero CellsViral Vaccines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32645327

Citation

Dai, Lianpan, et al. "A Universal Design of Betacoronavirus Vaccines Against COVID-19, MERS, and SARS." Cell, vol. 182, no. 3, 2020, pp. 722-733.e11.
Dai L, Zheng T, Xu K, et al. A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS. Cell. 2020;182(3):722-733.e11.
Dai, L., Zheng, T., Xu, K., Han, Y., Xu, L., Huang, E., An, Y., Cheng, Y., Li, S., Liu, M., Yang, M., Li, Y., Cheng, H., Yuan, Y., Zhang, W., Ke, C., Wong, G., Qi, J., Qin, C., ... Gao, G. F. (2020). A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS. Cell, 182(3), 722-e11. https://doi.org/10.1016/j.cell.2020.06.035
Dai L, et al. A Universal Design of Betacoronavirus Vaccines Against COVID-19, MERS, and SARS. Cell. 2020 Aug 6;182(3):722-733.e11. PubMed PMID: 32645327.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS. AU - Dai,Lianpan, AU - Zheng,Tianyi, AU - Xu,Kun, AU - Han,Yuxuan, AU - Xu,Lili, AU - Huang,Enqi, AU - An,Yaling, AU - Cheng,Yingjie, AU - Li,Shihua, AU - Liu,Mei, AU - Yang,Mi, AU - Li,Yan, AU - Cheng,Huijun, AU - Yuan,Yuan, AU - Zhang,Wei, AU - Ke,Changwen, AU - Wong,Gary, AU - Qi,Jianxun, AU - Qin,Chuan, AU - Yan,Jinghua, AU - Gao,George F, Y1 - 2020/06/28/ PY - 2020/5/4/received PY - 2020/6/3/revised PY - 2020/6/23/accepted PY - 2020/7/10/pubmed PY - 2020/8/29/medline PY - 2020/7/10/entrez KW - COVID-19 KW - MERS KW - MERS-CoV KW - SARS KW - SARS-CoV KW - SARS-CoV-2 KW - betacoronavirus KW - coronavirus KW - receptor-binding domain (RBD) KW - vaccine SP - 722 EP - 733.e11 JF - Cell JO - Cell VL - 182 IS - 3 N2 - Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32645327/A_Universal_Design_of_Betacoronavirus_Vaccines_against_COVID_19_MERS_and_SARS_ DB - PRIME DP - Unbound Medicine ER -