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

基本信息

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
项目类别：
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

项目摘要

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；先天免疫反应）调节小鼠机制研究中抗体反应的广度， (ii) 评估泛 sarbecovirus 和泛 betacoronavirus 候选疫苗，旨在广泛诱导非人类灵长类动物 (NHP) 的保护性免疫反应（使用 Core D、非人类灵长类动物、Villinger）。在目标 1 中，我们将确定先天免疫系统和滤泡 T 细胞的调节机制项目 2 中设计的广泛保护性冠状病毒疫苗诱导的抗体反应的广度（King）。我们将在小鼠中进行机制研究，以确定 CD4+ T 细胞帮助和特异性的影响。 DC 子集在调节疫苗引起的抗体反应的广度方面这将产生关于关键的见解。免疫学参数决定了抗体的广度，并展望未来，为抗体的研究提供了合理的基础。开发刺激广泛抗体反应的佐剂在目标 2 中，我们将在 NHP 中进行两项研究评估项目 2 中的泛 sarbecovirus 和泛 betacoronavirus 候选疫苗并选择先导疫苗这些研究将使用临床相关的佐剂进行进一步的临床前和临床开发。为了确保对人类的最佳转化，我们将评估 nAb 的规模、广度和持久性。使用由 AS03 和 3M-052/明矾配制的纳米颗粒免疫原进行免疫诱导的反应，就其促进能力而言，两者均表现出卓越的佐剂作用。因此，我们将直接将 AS03 与 NHP 中的高强度和持久的中和抗体反应进行比较。 3M-052/明矾有能力增强 nAb 反应的广度，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 用于评估免疫原性和每种纳米颗粒候选疫苗引起的反应的保护范围，并定义表位我们将描述抗原特异性 B 细胞的动态特征。响应，评估浆母细胞和浆细胞频率，并对抗原特异性单个 B 细胞进行分类并分离来自免疫 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 中分析了它们的结合和中和宽度、表位特异性和对逃避突变的抵抗力。