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A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS.

Lianpan Dai | Tianyi Zheng | Kun Xu | Yuxuan Han | Lili Xu | Enqi Huang | Yaling An | Yingjie Cheng | Shihua Li | Mei Liu | Mi Yang | Yan Li | Huijun Cheng | Yuan Yuan | Wei Zhang | Changwen Ke | Gary Wong | Jianxun Qi | Chuan Qin | Jinghua Yan | George F Gao
Cell | 2020

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.

Pubmed ID: 32645327

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This is a list of tools and resources that we have found mentioned in this publication.


ESPript 2.2 (tool)

RRID:SCR_006587

A utility, whose output is a PostScript file of aligned sequences with graphical enhancements. Its main input is an ascii file of pre-aligned sequences. Optional files allow further rendering. The program calculates a similarity score for each residue of the aligned sequences. The output shows: * Secondary Structures * Aligned sequences * Similarities * Accessibility * Hydropathy * User-supplied markers * Intermolecular contacts In addition, similarity score can be written in the bfactor column of a pdb file, to enable direct display of highly conserved areas. You can run ESPript from this server with the HTML interface. It is configured for a maximum of 1,000 sequences. Links to webESPript * ENDscript: you can upload a PDB file or enter a PDB code such as 1M85. The programs DSSP and CNS are executed via the interface, so as to obtain an ESPript figure with a lot of structural information (secondary structure elements, intermolecular contacts). You can also find homologous sequences with a BLAST search, perform multiple sequence alignments with MULTALIN or CLUSTALW and create an image with BOBSCRIPT or MOLSCRIPT to show similarities on your 3D structure. * ProDom: you can enter a sequence identifier to find homologous domains, perform multiple sequence alignments with MULTALIN and click on the link to ESPript. * Predict Protein: you can receive a mail in text (do not use the HTML option when you submit your request in Predict Protein) with aligned sequences and numerous information including secondary structure prediction. Click on a special html link to upload your mail in ESPript. * NPS(at): you can execute the programs BLAST and CLUSTALW to obtain multiple alignments. You can predict secondary structure elements and click on the link to ESPript. This program started in the laboratory of Dr Richard Wade at the Institut de Biologie Structurale, Grenoble. It moved later to the Laboratory of Molecular Biophysics in Oxford, then to the Institut de Pharmacologie et de Biologie Structurale in Toulouse. It is now developed in the Laboratoire de BioCristallographie of Dr Richard Haser, Institut de Biologie et de Chimie des Prot��������ines, Lyon and in the Laboratoire de Biologie Mol��������culaire et de Relations Plantes-Organismes, group of Dr Daniel Kahn, Institut National de la Recherche Agronomique de Toulouse.

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CCP4 (tool)

RRID:SCR_007255

Portal for Macromolecular X-Ray Crystallography to produce and support an integrated suite of programs that allows researchers to determine macromolecular structures by X-ray crystallography, and other biophysical techniques. Used in the education and training of scientists in experimental structural biology for determination and analysis of protein structure.

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Phenix (tool)

RRID:SCR_014224

A Python-based software suite for the automated determination of molecular structures using X-ray crystallography and other methods. Phenix includes programs for assessing data quality, experimental phasing, molecular replacement, model building, structure refinement, and validation. It also includes tools for reflection data and creating maps and models. Phenix can also be used for neutron crystallography. Tutorials and examples are available in the documentation tab.

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CHO-K1 (tool)

RRID:CVCL_0214

Cell line CHO-K1 is a Spontaneously immortalized cell line with a species of origin Cricetulus griseus (Chinese hamster)

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BALB/cAnNCrl (tool)

RRID:MGI:2683685

laboratory mouse with name BALB/cAnNCrl from MGI.

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Goat Anti-Mouse IgG - H&L Polyclonal Antibody, HRP Conjugated (antibody)

RRID:AB_955439

This polyclonal targets Mouse Mouse IgG secondary - H&L

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CD4 (antibody)

RRID:AB_394331

This monoclonal targets CD4

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FITC anti-mouse CD3 (antibody)

RRID:AB_312661

This monoclonal targets CD3

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PE anti-mouse IL-4 (antibody)

RRID:AB_315318

This monoclonal targets IL-4

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PE/Cyanine7 anti-mouse TNF-alpha (antibody)

RRID:AB_2256076

This monoclonal targets TNF-alpha

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Vero (cell line)

RRID:CVCL_0059

Cell line Vero is a Spontaneously immortalized cell line with a species of origin Chlorocebus sabaeus

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HEK293T (cell line)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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Huh-7 (cell line)

RRID:CVCL_0336

Cell line Huh-7 is a Cancer cell line with a species of origin Homo sapiens (Human)

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