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.

项目摘要 - 项目3：临床前疫苗的机理研究和比较 型号 该项目的两个主要目标是：（i）定义免疫学参数（即CD4+ T细胞帮助； 天生的免疫反应）调节小鼠机械研究中抗体反应的广度， （ii）评估旨在广泛诱导的候选pan-sarbecovirus和pan-betacoronavirus疫苗 非人类灵长类动物（NHP）（核心D，非人类灵长类动物，维林格）中的保护性免疫调查。 在AIM 1中，我们将确定先天免疫系统和T卵泡细胞调节的机制 项目2中设计的广泛保护的冠状病毒疫苗引起的抗体反应的广度 （国王）。我们将在小鼠中进行机械研究，以确定CD4+ T细胞帮助和特定的影响 DC子集在确定疫苗吸收的AB反应的广度时。这将产生有关关键的见解 免疫学参数决定抗体广度并展望未来，为抗体宽度提供了合理的基础 开发刺激广泛AB反应的调节器。在AIM 2中，我们将在NHP中进行两项研究 评估PAN-SARBECOVIRUS和PAN​​-BETACORONAVIRUS疫苗候选项目2，然后选择铅 候选人进行进一步的临床前和临床发展。这些研究将使用临床相关的调节器 确保最佳翻译为人类。我们将评估NAB的大小，宽度和耐用性 用AS03和3M-052/校友配方的纳米颗粒免疫原化引起的反应， 这两者都证明了其促进能力的卓越调整效果 NHP中的高磁性和耐用的中和抗体反应。因此，我们将直接将AS03与 3M-052/明矾的能力增强了NAB响应的广度。我们将与项目1合作 （Veesler）和核B（病毒学，Baric），C（病毒进化，开花）和D，以评估免疫原性 并保护每种纳米颗粒疫苗引起的反应的广度，并定义表位 交叉反应的特异性。我们将表征抗原特异性B细胞的动力学 响应，评估浆液和浆细胞频率，以及对抗原特异性单B细胞和分离 免疫NHP的单克隆抗体。这些mAb将由核心A（蛋白质科学， 国王）并在项目1和核心B和C中进行了分析 特异性和逃避突变的抵抗力。