PanCorVac (Center for Pan-Coronavirus Vaccine Development)

PanCorVac（泛冠状病毒疫苗开发中心）

基本信息

批准号：
10327846
负责人：
YOSHIHIRO KAWAOKA
金额：
$ 700.03万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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/10327846
关键词：
2019-nCoV Affinity Animal Model Animals Antibodies Antibody Response Antigens B-Lymphocytes Bacteriophages CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 pandemic COVID-19 vaccine Capsid Proteins Cellular Immunity Cohort Studies Complement Coronavirus Data Development Epitopes Evaluation Face Funding Generations Genes Goals Head Human Immune Immune response Immunization Immunize Immunodominant Epitopes Immunoglobulins Immunology Individual Infection Influenza Japanese Population Knowledge Longitudinal cohort study Maintenance Memory B-Lymphocyte Mesocricetus auratus Messenger RNA Methods Mission Modification Molecular Virology Monoclonal Antibodies Mus Mutate National Institute of Allergy and Infectious Disease Phenotype Plasma Cells Population Prevention Preventive vaccine Property Proteins Public Health Research Research Personnel Research Project Grants SARS coronavirus SARS-CoV-2 antigen SARS-CoV-2 infection SARS-CoV-2 spike protein Sampling Sequence Homology Serum Specificity Structure of germinal center of lymph node T cell response T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Transgenic Mice United States National Institutes of Health Vaccinated Vaccination Vaccines Viral Proteins Virus Virus-like particle Wild Type Mouse base combat coronavirus receptor coronavirus vaccine cross reactivity design high throughput analysis human coronavirus immunogenic immunogenicity innovation lipid nanoparticle long term memory nanobiotechnology neutralizing antibody novel novel strategies novel vaccines pandemic disease protective efficacy receptor response single cell technology stem structural biology universal coronavirus vaccine vaccine candidate vaccine development viral transmission zoonotic coronavirus

项目摘要

SUMMARY Most of the vaccines currently approved or in development against the pandemic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus target immunodominant, strain-specific epitopes in the SARS-CoV-2 spike (S) protein and are therefore not expected to confer protection against other coronaviruses. Accordingly, the NIAID announced NOT-AI-21-002, which calls for the “development of prophylactic vaccines to provide broad and durable protection against coronaviruses, especially SARS-CoV-2 and others with pandemic potential”. In response to this call, we assembled the Pan-Coronavirus Vaccine (PanCoVac) consortium to develop and test novel pan-coronavirus vaccines. Research Project 1 (RP1; Design and evaluation of pan- CoV vaccines) uses two strategies to develop broadly protective coronavirus vaccines: (i) Focus immune responses away from the immunodominant epitopes in the head region of S and towards the more conserved, immune-subdominant epitopes in the stem region of S; and (ii) Refocus immune responses from the variable immunodominant epitopes towards more conserved epitopes in the head region of S. For each strategy, several innovative approaches will be used. Novel antigens will be presented by virus-like particles based on a self- assembling bacteriophage coat protein (a highly immunogenic platform). The candidate vaccines will be tested for their immunogenicity and protective efficacy against different coronaviruses in an animal model. Selected candidates will be tested in a second animal model, and with an mRNA lipid nanoparticle platform. Additional studies will test the durability of immune responses and the effect of vaccination on virus transmission. Samples from vaccinated animals will be provided to Research Project 2 (RP2; Immunological responses to pan-CoV vaccines) for a detailed assessment of B- and T-cell responses. First, RP2 will continue its ongoing efforts to generate and characterize panels of SARS-CoV S-specific mAbs, which will be used in RP1 to help characterize and prioritize vaccine candidates. Moreover, “Ig-omics”, which involves single-cell technologies allowing high- throughput analysis of B-cell responses, phenotypes, immunoglobulin (Ig) repertoires and mAbs that react to several coronaviruses (a technology developed by one of the RP2 investigators), will be used to characterize B cell-mediated immunity and mAb specificity induced by the candidate vaccines. RP2 will also test (and compare with data from a human cohort study) the ability of the candidate vaccines to elicit responses to cross-reactive CD4 and CD8 T cell epitopes. In particular, recently developed novel methods will be used to characterize and compare the T-cell repertoires upon infection and vaccination. An Administrative Core will oversee and manage all financial and administrative aspects of the consortium. Our proposed research draws strength from a multi- institutional team of experts in molecular virology, structural biology, nanobiotechnology, and B- and T-cell immunology.

概括目前已批准或正在开发的大多数针对大流行 SARS-CoV-2（严重急性呼吸综合征冠状病毒 2) 病毒靶向 SARS-CoV-2 中免疫显性的毒株特异性表位刺突 (S) 蛋白，因此预计不会提供针对其他冠状病毒的保护作用。 NIAID 宣布了 NOT-AI-21-002，呼吁“开发预防性疫苗以提供针对冠状病毒，特别是 SARS-CoV-2 和其他大流行病提供广泛而持久的保护为了响应这一号召，我们组建了泛冠状病毒疫苗 (PanCoVac) 联盟开发和测试新型泛冠状病毒疫苗研究项目1（RP1；泛冠状病毒疫苗的设计和评估）。冠状病毒疫苗）使用两种策略来开发具有广泛保护性的冠状病毒疫苗：（i）焦点免疫反应远离 S 头部区域的免疫显性表位，转向更保守的表位， S 茎区的免疫亚显性表位；以及 (ii) 重新聚焦变量的免疫反应；免疫显性表位朝向 S 头部区域更保守的表位。对于每种策略，有几个将使用基于自身的病毒样颗粒呈现新型抗原。组装噬菌体外壳蛋白（高免疫原性平台）将进行测试。因其在动物模型中对不同冠状病毒的免疫原性和保护功效。候选者将在第二种动物模型中进行测试，并使用 mRNA 纳米脂质颗粒平台。研究将测试免疫反应的持久性以及疫苗接种对病毒传播的影响。来自肺炎动物的样本将提供给研究项目 2（RP2；对泛冠状病毒的免疫反应）首先，RP2 将继续努力，以对 B 细胞和 T 细胞反应进行详细评估。生成并表征 SARS-CoV S 特异性单克隆抗体组，这些抗体将在 RP1 中用于帮助表征此外，“Ig组学”涉及单细胞技术，可以实现高水平的疫苗接种。 B 细胞反应、表型、免疫球蛋白 (Ig) 库和单克隆抗体的通量分析几种冠状病毒（由 RP2 一名研究人员开发的技术）将用于表征 B 候选疫苗诱导的细胞介导的免疫和单克隆抗体特异性也将进行测试（并进行比较）。根据人类队列研究的数据）候选疫苗引发交叉反应的能力特别是，最近开发的新方法将用于表征和 CD8 T 细胞表位。管理核心将监督和管理感染和疫苗接种后的 T 细胞库。我们提出的研究从多方面汲取力量。分子病毒学、结构生物学、纳米生物技术以及 B 和 T 细胞专家组成的机构团队免疫学。