Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines

疫苗中针对 B 细胞的组合佐剂的机理研究

• 批准号: 10599324
• 负责人: Luc Teyton
• 金额: $ 67.81万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-23 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599324
• 关键词: Adjuvant; Adjuvanticity; Affinity; Agonist; Animal Model; Anti-Bacterial Agents; Antibodies; Antibody Response; Antigens; Attenuated; B-Lymphocytes; B-cell receptor repertoire sequencing; Biological; Biological Models; CD4 Positive T Lymphocytes; Categories; Cells; Cervarix; Child; Childhood; Complex; Conjugate Vaccines; Consensus; Coupled; Dose; Endosomes; Europe; FDA approved; False Allegation; Formulation; Fright; Genetic Transcription; Goals; Guillain Barré Syndrome; Helper-Inducer T-Lymphocyte; Hepatitis B Vaccines; Hygiene; Immune response; Immunity; Immunology; Industry; Influenza A Virus, H1N1 Subtype; Injections; Knowledge; Ligands; MF59; Measures; Memory; Microbe; Molecular; Narcolepsy; Papillomavirus; Perception; Pertussis; Pertussis Vaccine; Phase; Polysaccharides; Preventive treatment; Reaction; Receptor Activation; Research; Safety; Saponins; Serotyping; Squalene; Streptococcus pneumoniae; Subunit Vaccines; Synthesis Chemistry; TLR7 gene; Toll-like receptors; Toxic effect; Toxin; Tween 80; Vaccination; Vaccine Design; Vaccines; alpha Tocopherol; aluminum sulfate; autism spectrum disorder; cell type; combinatorial; design; dosage; improved; infectious disease treatment; influenza infection; influenza virus vaccine; nanomolar; neglect; pathogen; pathogenic microbe; prevent; protein expression; prototype; receptor; response; side effect; single cell technology; social stigma; synergism; uptake; vaccine formulation

In full response to RFA-AI-20-004, we propose to study the mechanisms of cooperativity between NKT cell and TLR adjuvants. We have previously shown that we could use a combination of NKT cell and TLR7 adjuvants to produce high affinity protective anti-bacterial glycan vaccines. Our goal is now to understand the mechanisms of this cooperative effects between the two adjuvants to optimize it and produce a vaccine formulation that promotes protection after a single administration. In addition, we contend that mechanistic studies will also allow the limitation of the potential side effects of adjuvants. To this end, our proposal is built on two separate and complementary specific aims: Aim 1: Evaluate endosomal TLR ligands for their ability to enhance NKT cell responses and their B cell helper activities. We have produced nanomolar affinity anti-glycan antibodies by combining NKT cell and TLR7 agonists. This response was dependent on NKT and CD4 T cell help. We hypothesize that each endosomal TLR ligand may have a different enhancing effect in a combinatorial usage. We will investigate NKT, T follicular helper, dendritic, and B cell responses by single cell technologies for RNA and protein expression in animal models of vaccination for each TLR/NKT cell pair that we will study. B cell receptor sequencing and pathogen challenges will be used to measure the efficacy of each combination. Aim 2: Evaluate the importance of the co-delivery of the two adjuvants to particular cell types and endosomal/lysosomal compartments. We hypothesize that the physical aspects of adjuvanticity with respect to antigen uptake and delivery to processing compartments are critical. By co-delivering antigen and adjuvants to particular cells and within chosen compartments, using synthetic chemistry to control their pairing and separation, mechanisms of adjuvant activity will be examined. The biological consequences of this molecular based design of adjuvant combinations will be evaluated with respect to dosage, toxicity, and efficacy. We expect to develop robust formulations that induce protection after a single vaccine administration. Our entire proposal is focused exclusively on vaccines aimed at developing protective B cell immunity, and our model system is a conjugate vaccine against Streptococcus pneumoniae.

在对RFA-AI-20-004的全面响应中，我们建议研究NKT细胞和 TLR佐剂。我们以前已经表明，我们可以将NKT细胞和TLR7佐剂的组合使用 产生高亲和力保护性抗菌聚糖疫苗。我们的目标是了解 两种佐剂之间的这种合作作用，以优化它并产生促进的疫苗配方 单个管理后的保护。此外，我们认为机械研究还将允许 佐剂潜在副作用的限制。为此，我们的建议建立在两个单独的基础上， 补充特定目的：目标1：评估内体TLR配体增强NKT细胞的能力 响应及其B细胞帮手活动。我们通过 结合NKT细胞和TLR7激动剂。该反应取决于NKT和CD4 T细胞帮助。我们 假设每个内体TLR配体在组合使用中可能具有不同的增强作用。 我们将通过单细胞技术研究NKT，T卵泡辅助器，树突状和B细胞反应 我们将研究每个TLR/NKT细胞对的动物疫苗接种模型中的蛋白质表达。 B单元 受体测序和病原体挑战将用于测量每种组合的功效。 目标2：评估两个佐剂对特定细胞类型的共同交付的重要性 内体/溶酶体室。我们假设辅助性的物理方面尊重 对于抗原吸收并将其交付到加工室是至关重要的。通过共同交付抗原和佐剂 到特定细胞和所选隔室内，使用合成化学来控制其配对和 将检查分离，辅助活性的机制。该分子的生物学后果 基于剂量，毒性和功效的辅助组合设计将进行评估。我们期望 开发稳健的配方，在一次疫苗给药后诱导保护。 我们的整个建议仅专注于旨在发展保护性B细胞免疫的疫苗，我们 模型系统是针对肺炎链球菌的结合疫苗。