Core 3: Non-human Primate Core

核心3：非人类灵长类核心

• 批准号: 10842501
• 负责人: Barton F. Haynes
• 金额: $ 279.88万
• 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/10842501
• 关键词: Accreditation; Adjuvant; African Green Monkey; Alphavirus; Anatomy; Animal Model; Animals; Antibodies; Antibody titer measurement; B-Lymphocytes; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID test; Cells; 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; animal coronavirus; betacoronavirus; betacoronavirus vaccine; cytokine; design; expectation; immunogenicity; immunopathology; improved; lipid nanoparticle; nanoparticle; neutralizing antibody; nonhuman primate; pandemic disease; pleiotropism; pre-clinical; prototype; response; success; synergism; transcriptome; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine platform; 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 大流行是过去两年中第三次由 betaCoV 引起的重大病原体爆发 针对 2b 组和 2c 组 β 冠状病毒的泛β冠状病毒 (panbetaCoV) 疫苗的开发已持续了数十年。 该 P01 的一个主要优先事项此外，该 P01 将评估甲病毒复制子、修饰的 mRNA-脂质。 纳米颗粒和蛋白质纳米颗粒作为 panbetaCoV 疫苗平台。 NHP Core 3 团队已证明食蟹猴或恒河猴是 SARS 的优秀模型 - NHP 的采集是疫苗设计和测试的重要组成部分，因为它们具有解剖学、 NHP Core 3 与人类的生理学和免疫学相似性将通过实现以下目标来支持 P01。 具体目标如下： 目标 1. 测试泛β冠状病毒中和抗体疫苗的保护能力 使用食蟹猴或恒河猴作为动物模型，衍生自下调选择的 B 细胞疫苗。 项目 1、2、3 或 4 将在 NHP 模型中进行测试。 蝙蝠或穿山甲 CoV 的获取与人类原型 2b 组 CoV（SARS-CoV-1 和 2）一样，并且 2c 组人类病毒，MERS 目标 2. 测试基于 panbetaCoV T 细胞的疫苗的保护能力。 使用食蟹猴或恒河猴作为动物模型已证明 CD8 T 细胞反应是一种。 恒河猴免受 SARS-CoV-2 影响的免疫相关成分 这里的假设是。 T 细胞靶向疫苗可以与 B 细胞疫苗协同作用，以低中和性提高保护作用 项目 4 衍生的下调 T 细胞疫苗将在 NHP 模型中进行测试，其中 T 细胞 将通过基于表位的逐步方法，使用包括基于 IFN-γ 在内的检测来评估反应 ELISpot、基于多参数流式细胞术的测定和 1​​0X 基因组转录组分析。 通过 panbetaCoV 疫苗监测猕猴的疫苗相关疾病增强 (VAED)。 我们将监测肺炎猕猴的肺部病理学和增强的 BAL 细胞因子和肺 CoV PFU。 NHP Core 3 将成为 P01 不可或缺的组成部分，也是 P01 成功的关键。