A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS.
Lianpan Dai1, Lianpan Dai2, Tianyi Zheng2, Kun Xu1, Yuxuan Han2, Lili Xu3, Enqi Huang, Yaling An2, Cheng Yingjie, Shihua Li2, Liu Mei2, Mi Yang2, Yan Li2, Huijun Cheng2, Yuan Yuan2, Wei Zhang2, Changwen Ke4, Gary Wong2, Jianxun Qi2, Chuan Qin3, Jinghua Yan2, George F. Gao •
TL;DR: A dimeric form of MERS-CoV RBD is described that overcomes limited immunogenicity and significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MSPV infection.
About: This article is published in Cell.The article was published on 2020-08-06 and is currently open access. It has received 368 citations till now.
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TL;DR: In this article, the authors discuss which viral elements are used in COVID-19 vaccine candidates, why they might act as good targets for the immune system and the implications for protective immunity.
Abstract: Vaccines are urgently needed to control the coronavirus disease 2019 (COVID-19) pandemic and to help the return to pre-pandemic normalcy. A great many vaccine candidates are being developed, several of which have completed late-stage clinical trials and are reporting positive results. In this Progress article, we discuss which viral elements are used in COVID-19 vaccine candidates, why they might act as good targets for the immune system and the implications for protective immunity.
726 citations
Jingyun Yang1, Wei Wang1, Zimin Chen1, Shuaiyao Lu2, Fanli Yang1, Zhenfei Bi1, Linlin Bao2, Fei Mo1, Xue Li1, Yong Huang1, Weiqi Hong1, Yun Yang2, Yuan Zhao2, Fei Ye1, Sheng Lin1, Wei Deng2, Hua Chen1, Hong Lei1, Ziqi Zhang1, Min Luo1, Hong Gao2, Yue Zheng1, Yanqiu Gong1, Xiaohua Jiang1, Yanfeng Xu2, Qi Lv2, Dan Li1, Manni Wang1, Fengdi Li2, Shunyi Wang2, Guanpeng Wang2, Pin Yu2, Yajin Qu2, Li Yang1, Hongxin Deng1, Aiping Tong1, Jiong Li1, Z. H. Wang1, Jinliang Yang1, Guobo Shen1, Zhiwei Zhao1, Yuhua Li, Jingwen Luo1, Hongqi Liu2, Wenhai Yu2, Mengli Yang2, Jingwen Xu2, Junbin Wang2, Haiyan Li2, Haixuan Wang2, Dexuan Kuang2, Panpan Lin1, Zhengtao Hu1, Wei Guo1, Wei Cheng1, Yanlin He1, Xiangrong Song1, Chong Chen1, Zhihong Xue1, Shaohua Yao1, Lu Chen1, Xuelei Ma1, Siyuan Chen1, Maling Gou1, Weijin Huang, Youchun Wang, Changfa Fan, Zhixin Tian3, Ming Shi4, Fu-Sheng Wang4, Lunzhi Dai1, Min Wu1, Gen Li5, Guangyu Wang6, Yong Peng1, Zhiyong Qian1, Canhua Huang1, Johnson Y.N. Lau7, Zhenglin Yang8, Yuquan Wei1, Xiaobo Cen1, Xiaozhong Peng2, Chuan Qin2, Kang Zhang5, Guangwen Lu1, Xiawei Wei1 •
TL;DR: It is shown that a recombinant vaccine that comprises residues 319–545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates as early as 7 or 14 days after the injection of a single vaccine dose.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
573 citations
Wilfredo F. Garcia-Beltran1, Evan C. Lam2, Michael G Astudillo1, Diane Yang1, Tyler E. Miller1, Jared Feldman2, Blake M. Hauser2, Timothy M. Caradonna2, Kiera L. Clayton2, Adam Nitido2, Mandakolathur R. Murali1, Galit Alter2, Richelle C. Charles1, Anand S. Dighe1, John A. Branda1, Jochen K. Lennerz1, Daniel Lingwood2, Aaron G. Schmidt2, A. John Iafrate1, Alejandro B. Balazs2 •
TL;DR: It is found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels, highlighting the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
516 citations
TL;DR: This review briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19, and introduced the protein structures and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines.
Abstract: The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.
464 citations
TL;DR: An overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials are provided, and certain potential safety issues that require consideration when developing vaccines are highlighted.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named coronavirus disease (COVID-19). Currently, considerable efforts have been put into developing effective and safe drugs and vaccines against SARS-CoV-2. Vaccines, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, have already entered clinical trials. In this review, we provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Furthermore, we summarize several strategies utilized in the development of vaccines against other infectious viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the aim of aiding in the design of effective therapeutic approaches against SARS-CoV-2.
408 citations
References
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TL;DR: The methods presented in the chapter have been applied to solve a large variety of problems, from inorganic molecules with 5 A unit cell to rotavirus of 700 A diameters crystallized in 700 × 1000 × 1400 A cell.
Abstract: Publisher Summary X-ray data can be collected with zero-, one-, and two-dimensional detectors, zero-dimensional (single counter) being the simplest and two-dimensional the most efficient in terms of measuring diffracted X-rays in all directions. To analyze the single-crystal diffraction data collected with these detectors, several computer programs have been developed. Two-dimensional detectors and related software are now predominantly used to measure and integrate diffraction from single crystals of biological macromolecules. Macromolecular crystallography is an iterative process. To monitor the progress, the HKL package provides two tools: (1) statistics, both weighted (χ2) and unweighted (R-merge), where the Bayesian reasoning and multicomponent error model helps obtain proper error estimates and (2) visualization of the process, which helps an operator to confirm that the process of data reduction, including the resulting statistics, is correct and allows the evaluation of the problems for which there are no good statistical criteria. Visualization also provides confidence that the point of diminishing returns in data collection and reduction has been reached. At that point, the effort should be directed to solving the structure. The methods presented in the chapter have been applied to solve a large variety of problems, from inorganic molecules with 5 A unit cell to rotavirus of 700 A diameters crystallized in 700 × 1000 × 1400 A cell.
31,667 citations
TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Abstract: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as `Coot'.
27,505 citations
"A Universal Design of Betacoronavir..." refers methods in this paper
...REAGENT or RESOURCE SOURCE IDENTIFIER pCAGGS-SARS-CoV-2-RBD-sc-dimer-His, residues 319-537, two copies in tandem, accession number: YP_009724390 This paper N/A pCAGGS-SARS-CoV-RBD-His, residues 306-527, accession number: NP_828851 This paper N/A pCAGGS-SARS-RBD-sc-dimer-His, residues 306-523, two copies in tandem, accession number: NP_828851 This paper N/A pCAGGS-MERS-CoV-S, accession number: JX869059 This paper N/A pCAGGS-SARS-CoV-2-S, accession number: YP_009724390 This paper N/A pCAGGS-SARS-CoV-S, accession number: NP_828851 This paper N/A Software and Algorithms PyMOL software The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC. https://pymol.org/2/ BIAevaluation Version 4.1 GE Healthcare N/A ESPript 3 Robert and Gouet, 2014 http://espript.ibcp.fr/ESPript/ESPript/ GraphPad Prism 8.0 GraphPad Software https://www.graphpad.com/ HKL2000 Otwinowski and Minor, 1997 N/A Phaser Read, 2001 N/A Coot Emsley and Cowtan, 2004 http://www2.mrclmb.cam.ac.uk/personal/ peemsley/coot/ CCP4 Collaborative Computational Project, Number 4, 1994 http://www.ccp4.ac.uk/ Phenix Adams et al., 2010 http://www.phenix-online.org/ MolProbity Williams et al., 2018 N/A OriginPro 2018 OriginLab Corporation https://www.OriginLab.com ll Article...
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...Restrained rigidbody refinement with REFMAC5 (CCP4 suite) andmanual model building with Coot (Emsley andCowtan, 2004) were then performed....
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...REFMAC5 (CCP4 suite) and manual model building with Coot (Emsley and Cowtan, 2004) 725...
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Na Zhu1, Dingyu Zhang, Wenling Wang1, Xingwang Li2, Bo Yang1, Jingdong Song1, Xiang Zhao1, Baoying Huang1, Weifeng Shi, Roujian Lu1, Peihua Niu1, Faxian Zhan1, Xuejun Ma1, Dayan Wang1, Wenbo Xu1, Wenbo Xu3, Guizhen Wu1, George F. Gao, Wenjie Tan1 •
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
21,455 citations
Paul D. Adams1, Paul D. Adams2, Pavel V. Afonine1, Gábor Bunkóczi3, Vincent B. Chen4, Ian W. Davis4, Nathaniel Echols1, Jeffrey J. Headd4, Li-Wei Hung5, Gary J. Kapral4, Ralf W. Grosse-Kunstleve1, Airlie J. McCoy3, Nigel W. Moriarty1, Robert D. Oeffner3, Randy J. Read3, David S. Richardson4, Jane S. Richardson4, Thomas C. Terwilliger5, Peter H. Zwart1 •
TL;DR: The PHENIX software for macromolecular structure determination is described and its uses and benefits are described.
Abstract: Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
18,531 citations
TL;DR: The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography.
Abstract: The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims and so there may be more than one program to cover each function. The programs are written mainly in standard Fortran77. They are from a wide variety of sources but are connected by standard data file formats. The package has been ported to all the major platforms under both Unix and VMS. The suite is distributed by anonymous ftp from Daresbury Laboratory and is widely used throughout the world.
17,220 citations
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