Core 3: Non-human Primate Core

核心3：非人类灵长类核心

• 批准号: 10327522
• 负责人: Barton F. Haynes
• 金额: $ 448.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10327522
• 关键词: 2019-nCoV; Accreditation; Adjuvant; African Green Monkey; Alphavirus; Anatomy; Animal Model; Animals; Antibody titer measurement; B-Lymphocytes; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 pandemic; Cells; Centers for Disease Control and Prevention (U.S.); Chiroptera; Collaborations; Data; Development; Disease; Disease Outbreaks; Disease Progression; Epitopes; Evaluation; Exposure to; Flow Cytometry; Future; Genomics; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immunity; Immunization; Immunologic Monitoring; Immunologics; Interferon Type II; International; Leadership; Letters; Lung; Macaca; Macaca fascicularis; Macaca mulatta; Messenger RNA; Middle East Respiratory Syndrome; Modeling; Monitor; Pathogenicity; Physiological; Preclinical Testing; Program Research Project Grants; Proteins; Pulmonary Pathology; Replicon; Rhesus; SARS coronavirus; Sampling; T cell response; T-Lymphocyte; TLR7 gene; Testing; Time; United States National Institutes of Health; Vaccinated; Vaccine Design; Vaccines; Virus; Virus Diseases; aluminum sulfate; base; betacoronavirus; betacoronavirus vaccine; cytokine; design; expectation; immunogenicity; immunopathology; improved; lipid nanoparticle; nanoparticle; neutralizing antibody; nonhuman primate; pleiotropism; pre-clinical; prototype; response; success; transcriptome; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine-induced antibodies; 2019-nCoV; Accreditation; Adjuvant; African Green Monkey; Alphavirus; Anatomy; Animal Model; Animals; Antibody titer measurement; B-Lymphocytes; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 pandemic; Cells; Centers for Disease Control and Prevention (U.S.); Chiroptera; Collaborations; Data; Development; Disease; Disease Outbreaks; Disease Progression; Epitopes; Evaluation; Exposure to; Flow Cytometry; Future; Genomics; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immunity; Immunization; Immunologic Monitoring; Immunologics; Interferon Type II; International; Leadership; Letters; Lung; Macaca; Macaca fascicularis; Macaca mulatta; Messenger RNA; Middle East Respiratory Syndrome; Modeling; Monitor; Pathogenicity; Physiological; Preclinical Testing; Program Research Project Grants; Proteins; Pulmonary Pathology; Replicon; Rhesus; SARS coronavirus; Sampling; T cell response; T-Lymphocyte; TLR7 gene; Testing; Time; United States National Institutes of Health; Vaccinated; Vaccine Design; Vaccines; Virus; Virus Diseases; aluminum sulfate; base; betacoronavirus; betacoronavirus vaccine; cytokine; design; expectation; immunogenicity; immunopathology; improved; lipid nanoparticle; nanoparticle; neutralizing antibody; nonhuman primate; pleiotropism; pre-clinical; prototype; response; success; transcriptome; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine-induced antibodies

Abstract - Core 3 The current SARS-CoV-2 pandemic is the third major pathogenic outbreak caused by a betaCoV in the last two decades. Development of panbetacoronavirus (panbetaCoV) vaccines for group 2b and group 2c beta CoVs is a major priority of this P01. In addition, this P01 will evaluate alphavirus replicons, modified mRNA-lipid nanoparticles and protein nanoparticles as panbetaCoV vaccine platforms. Nonhuman primates (NHPs) such as cynomolgus or rhesus macaques have been shown by the NHP Core 3 team to be excellent models of SARS- CoV-2 acquisition. NHPs are important components of vaccine design and testing as they have anatomical, physiological and immunological similarities to humans. The NHP Core 3 will support the P01 by achieving the following Specific Aims: Aim 1. Test the protectivecapacityof panbetaCoVneutralizing antibodyvaccines using cynomolgus or rhesus monkeys as animal models. Down-selected B cell vaccines derived from Projects 1, 2, 3 or 4 will be tested in NHP models. We hypothesize that macaques will be as excellent models of bat or pangolin CoV acquisition as they are for human prototype group 2b CoVs (SARS-CoV-1 and 2) and group 2c human virus, MERS. Aim 2. Test the protective capacity of panbetaCoV T cell basedvaccines using cynomolgus or rhesus monkeys as animal models. CD8 T cell responses have been shown to be a component of immune correlates of protection from SARS-CoV-2 in rhesus macaques. The hypothesis here is that a T cell-targeted vaccine can synergize with B cell vaccines to improve protection with low neutralizing antibody titers. Down-selected T cell vaccines derived from Project 4 will be tested in NHP models, whereT cell responses will be assessed through a step-wise epitope-based approach using assays including IFN-γ-based ELISpot, multi-parameter flow cytometry-based assays, and 10X genomics transcriptome analysis. Aim 3. Monitor Vaccine Associated Enhancement of Disease (VAED) in macaques by panbetaCoV vaccines. We will monitor vaccinated macaques for lung pathology and enhancedBAL cytokines and lung CoV PFU. Thus, NHP Core 3 will be an integral component of this P01 and key to P01 success.

摘要 - 核心3 当前的SARS-COV-2大流行是最后两个Betacov引起的第三次主要致病性暴发 几十年。用于2B组和2C组βCOVS的Panbetacoronavirus（Panbetacov）疫苗的开发为 该P01的主要优先级。此外，该P01将评估α病毒复制品，修饰的mRNA-lipid 纳米颗粒和蛋白质纳米颗粒作为Panbetacov疫苗平台。非人类灵长类动物（NHP）这样 由于NHP Core 3团队已经表明了Cynomolgus或Rhesus猕猴，这是SARS的出色模型 - COV-2采集。 NHP是疫苗设计和测试的重要组成部分，因为它们具有解剖学， 与人类的生理和免疫学相似。 NHP Core 3将通过实现P01支持P01 以下特定目的：目标1。测试panbetacovneutalization antibodyVaccines的保护效果 使用cynomolgus或恒河猴作为动物模型。源自衍生的下选择的B细胞疫苗 项目1、2、3或4将在NHP模型中进行测试。我们假设猕猴将是出色的模型 对人类原型2B COV（SARS-COV-1和2）的BAT或PANGOLIN COV采集的获取 2C组人类病毒，MERS。 AIM 2。测试基于Panbetacov T细胞的保护能力 使用cynomolgus或恒河猴作为动物模型。 CD8 T细胞反应已显示为 免疫相关性的颗粒猕猴中免受SARS-COV-2保护的组成部分。这里的假设是 T细胞靶向的疫苗可以与B细胞疫苗协同作用，以改善防护 抗体滴度。从项目4得出的下选择的T细胞疫苗将在NHP模型中测试 响应将通过包括基于IFN-γ在内的测定法进行基于逐步的表位方法评估 ELISPOT，基于多参数流式细胞仪的测定和10倍基因组学转录组分析。目标3。 Panbetacov疫苗猕猴中疾病的增强（VAED）相关的疫苗。 我们将监测接种的猕猴，用于肺部病理学和增强的细胞因子和肺COV PFU。那， NHP Core 3将是该P01的组成部分，并且是P01成功的关键。