Project 3: Mechanistic studies and comparisons of vaccines in preclinical models

项目3：临床前模型中疫苗的机理研究和比较

• 批准号: 10425032
• 负责人: BALI PULENDRAN
• 金额: $ 137.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425032
• 关键词: Adjuvant; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Binding; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Collaborations; Data; Dendritic Cells; Development; Emulsions; Ensure; Epitopes; Evaluation; Evolution; Frequencies; Goals; Heterophile Antigens; Human; Immune response; Immunization; Immunize; Immunologics; Innate Immune Response; Innate Immune System; Lead; Ligands; Monoclonal Antibodies; Mosaicism; Mus; Mutation; Oils; Patients; Performance; Phase I Clinical Trials; Phylogeny; Plasma Cells; Plasmablast; Play; Pre-Clinical Model; Proteins; Resistance; Role; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Sarbecovirus; Science; Solid; Specificity; Squalene; Structure; Surface; Systems Biology; T cell response; T-Lymphocyte; TLR7 gene; Toll-like receptors; Vaccination; Vaccine Design; Vaccines; Viral; Viral Vaccines; Water; Work; aluminum sulfate; base; betacoronavirus; betacoronavirus vaccine; candidate selection; clinical development; clinically relevant; coronavirus vaccine; cross reactivity; cytokine; design; immunogenic; immunogenicity; insight; lead candidate; lymph nodes; nanoparticle; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; preclinical development; programs; response; scaffold; translation to humans; vaccine candidate; variants of concern; virology

PROJECT SUMMARY– PROJECT 3: Mechanistic studies and comparisons of vaccines in preclinical models The two primary goals of the Project are to: (i) define the immunological parameters (i.e., CD4+ T cell help; innate immune response) that regulate the breadth of the antibody response in mechanistic studies in mice, and (ii) evaluate pan-sarbecovirus and pan-betacoronavirus vaccine candidates aimed at inducing broadly protective immune responses in nonhuman primates (NHPs) (with Core D, Nonhuman Primates, Villinger). In Aim 1, we will determine the mechanisms by which the innate immune system and T follicular cells regulate the breadth of antibody responses induced by broadly protective coronavirus vaccines designed in Project 2 (King). We will perform mechanistic studies in mice to determine the impact of CD4+ T cell help and specific DC subsets in regulating the breadth of vaccine-elicited Ab responses. This will yield insights about critical immunological parameters that determine antibody breadth and, looking ahead, provide a rational basis for the development of adjuvants that stimulate broad Ab responses. In Aim 2 we will conduct two studies in NHPs to evaluate pan-sarbecovirus and pan-betacoronavirus vaccine candidates from Project 2 and select lead candidates for further preclinical and clinical development. These studies will use clinically relevant adjuvants to ensure optimal translation to humans. We will assess the magnitude, breadth and durability of nAb responses induced by immunization with nanoparticle immunogens formulated with AS03 and 3M-052/alum, both of which have demonstrated superior adjuvant effects in terms of their capacity to promote high-magnitude and durable neutralizing antibody responses in NHPs. We will thus directly compare AS03 with 3M-052/alum for their capacity to enhance the breadth of nAb responses. We will work with Project 1 (Veesler) and Cores B (Virology, Baric), C (Viral Evolution, Bloom) and D to evaluate the immunogenicity and protective breadth of the responses elicited by each nanoparticle vaccine candidate and define the epitope specificities of cross-reactive responses. We will characterize the dynamics of the antigen-specific B cell response, assess plasmablast and plasma cell frequencies, and sort antigen-specific single B cells and isolate monoclonal antibodies from immunized NHPs. These mAbs will be produced by Core A (Protein Sciences, King) and analyzed in Project 1 and Cores B and C for their binding and neutralizing breadth, epitope specificity, and resistance to escape mutations.

项目总结-项目3：临床前疫苗的机制研究和比较 模型 该项目的两个主要目标是：（i）定义免疫学参数（即，CD 4 + T细胞辅助; 先天免疫应答），其在小鼠的机制研究中调节抗体应答的宽度， 和（ii）评估泛沙贝病毒和泛β冠状病毒候选疫苗，旨在广泛诱导 非人灵长类动物（NHP）的保护性免疫应答（核心D，非人灵长类动物，Villinger）。 在目标1中，我们将确定先天免疫系统和T滤泡细胞调节的机制， 项目2中设计的具有广泛保护性的冠状病毒疫苗诱导的抗体应答的广度 （国王）。我们将在小鼠中进行机制研究，以确定CD 4 + T细胞辅助和特异性免疫应答的影响。 DC亚群在调节疫苗引起的Ab应答的宽度中的作用这将产生关于关键的见解 确定抗体宽度的免疫学参数，并展望未来，为免疫学提供合理的基础。 开发刺激广泛Ab应答的佐剂。在目标2中，我们将在非健康中心进行两项研究， 评估项目2中的泛肉瘤病毒和泛β冠状病毒候选疫苗，并选择牵头疫苗 用于进一步临床前和临床开发的候选物。这些研究将使用临床相关的佐剂 以确保最佳的翻译给人类。我们将评估nAb的强度、广度和持久性， 用AS 03和3 M-052/明矾配制的纳米颗粒免疫原免疫诱导的应答， 这两种化合物在其促进免疫应答的能力方面都显示出上级佐剂作用 高强度和持久的中和抗体反应。因此，我们将直接比较AS 03与 3 M-052/alum，因为它们能够增强nAb应答的广度。我们将与项目1合作 （Veesler）和核心B（病毒学，Baric）、C（病毒进化，Bloom）和D，以评价免疫原性 和由每种纳米颗粒疫苗候选物引发的应答的保护宽度，并定义表位 交叉反应的特异性。我们将描述抗原特异性B细胞的动力学特征 反应，评估浆母细胞和浆细胞频率，分选抗原特异性单个B细胞并分离 来自免疫的NHP的单克隆抗体。这些mAb将由Core A（Protein Sciences， King），并在项目1和核心B和C中分析它们的结合和中和宽度、表位 特异性和对逃逸突变的抗性。