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Project 4: Computational panbetaCoV immunogen design

项目4：计算panbetaCoV免疫原设计

基本信息

批准号：
10842505
负责人：
Rory Henderson
金额：
$ 96.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10842505
关键词：
2019-nCoV Adenovirus Vector Alphavirus Animal Model Animals Antibody Response Antigens B-Lymphocytes Bioinformatics CD8-Positive T-Lymphocytes COVID-19 pandemic COVID-19 vaccine Cattle Cavia Cells Cessation of life Chiroptera Clinical Clinical Trials Conserved Sequence Coronavirus Coronavirus Infections Coronavirus spike protein Cross Reactions DNA Development Disease Disease Outbreaks Ebola virus Epidemic Epitopes Escape Mutant Evolution Exercise Family suidae Filovirus Foundations Future Goals HIV Infections HIV Vaccine Trials Network HIV vaccine HIV-1 Hand Human Immune response Infection Influenza Hemagglutinin Knowledge Literature Macaca Macaca mulatta Marburgvirus Mediating Merbecovirus Messenger RNA Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Molecular Molecular Conformation Morbidity - disease rate Mus Mutation Pathogenicity Persons Phase Phase III Clinical Trials Polysaccharides Polyvalent Vaccine Population Proteins Proteome Replicon Reporting Resistance Rodent Role SARS coronavirus SARS-CoV-2 spike protein Sarbecovirus Structure Symptoms T cell response T-Lymphocyte Testing Vaccine Antigen Vaccine Design Vaccines Variant Viral Virus Work Zoonoses animal coronavirus betacoronavirus betacoronavirus vaccine combat coronavirus pandemic cost design disorder control efficacy clinical trial expectation experience fitness future outbreak glycoprotein structure immunogenic member mindfulness molecular dynamics mosaic nanoparticle neutralizing antibody novel coronavirus novel virus pandemic disease pandemic preparedness protein structure research clinical testing response simulation swine influenza transmission process vaccine candidate vaccine delivery vaccine strategy vaccine-induced antibodies zoonotic coronavirus

项目摘要

Abstract - Project 4 SARS-CoV-2, a member of the genus Betacoronavirus (betaCoV), is the third major zoonotic outbreak of a highly pathogenic betaCoV in the last two decades. We propose to design vaccines to contribute to the global effort to counter the COVID-19 pandemic as swiftly as possible, and then to build on these designs to create panbetaCoV vaccines that could be used to rapidly contain outbreaks of future coronavirus zoonoses. To these ends, we will design both 1) Spike-targeted antibody vaccines, mindful of SARS-CoV-2 evolution as the pandemic progresses, and 2) conserved-region T-cell vaccine designs, to refocus CD8 T-cell response to regions in the proteome that cannot escape without a high fitness cost. These efforts toward pandemic vaccines will then be used as a foundation to extend our vaccine design strategies to counter the variability found among BetaCoVs, the highly diverse genus of CoVs that are found in bat populations. Based on our preliminary explorations of BetaCoV sequence diversity, we expect the design of a trivalent Spike-based vaccine using computational/bioinformatic and structure-based strategies to provide protection against the known range of diversity found in the subgenus Sarbecovirus. This includes both SARS-CoV-1, SARS-CoV-2, and the many related viruses isolated from bats and pangolins. If successful, these designs will be extended to cover Merbecovirus the subgenus that includes the MERS virus and other related viruses found in wild bats, rodents and cattle. Our Specific Aims are: Aim 1. Track the evolution of the SARS-CoV-2 during the COVID-19 pandemic. Aim 2. Design Spike vaccine antigens that optimize epitope exposure and betaCoV diversity coverage. Aim 3. Design T cell vaccines utilizing the most conserved regions in betaCoV. Our Spike-based computational vaccine designs will be based on our structural B cell mosaics strategy, and will be informed by Spike glycoprotein structures and molecular dynamic modeling, and will incorporate alignments of diverse Spike proteins. Using this approach we will design a trivalent set of complementary of proteins that optimally covers the natural diversity found among Sarbecoviruses in the bat reservoir. As we cannot predict with certainty the antigenic profile of viruses that may give rise to future zoonoses, we propose a two-pronged approach, and will simultaneously explore a conserved-region T-cell strategy that, although it might not block infection, could substantially mitigate disease, reducing both morbidity and transmission. Our T-cell vaccine designs will optimize the coverage of linear epitopes among BetaCoVs with a trivalent vaccine mix using our computational design strategy called Epigraphs. By focusing on the most conserved regions in the betaCoV proteome, we can more readily cover the broad spectrum of BetaCoVs diversity than in the more diverse Spike.

摘要-项目4