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

基本信息

批准号：
10218993
负责人：
Luc Teyton
金额：
$ 69.98万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
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/10218993
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 Dendritic Cells Dose 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 Lead 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 base cell type combinatorial design dosage infectious disease treatment influenza infection influenza virus vaccine nanomolar neglect pathogen pathogenic microbe prevent protein expression receptor response side effect single cell technology social stigma synergism uptake vaccine development

项目摘要

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.

为了充分回应 RFA-AI-20-004，我们建议研究 NKT 细胞和 TLR 佐剂。我们之前已经证明，我们可以使用 NKT 细胞和 TLR7 佐剂的组合来生产高亲和力保护性抗菌聚糖疫苗。我们现在的目标是了解两种佐剂之间的这种协同作用对其进行优化并生产出促进单次给药后的保护。此外，我们认为机制研究也将允许限制佐剂的潜在副作用。为此，我们的建议建立在两个独立的和互补的具体目标：目标 1：评估内体 TLR 配体增强 NKT 细胞的能力反应及其 B 细胞辅助活动。我们通过以下方法生产了纳摩尔亲和力抗聚糖抗体结合 NKT 细胞和 TLR7 激动剂。这种反应依赖于 NKT 和 CD4 T 细胞的帮助。我们假设每种内体 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 RNA 技术研究 NKT、滤泡辅助性 T、树突状细胞和 B 细胞反应以及我们将研究的每个 TLR/NKT 细胞对在疫苗接种动物模型中的蛋白质表达。 B细胞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：评估两种佐剂共同递送至特定细胞类型的重要性以及内体/溶酶体区室。我们假设辅助性的物理方面与尊重抗原的摄取和递送至处理室是至关重要的。通过共同递送抗原和佐剂针对特定的细胞和选定的隔室，使用合成化学来控制它们的配对和将检查佐剂活性的分离、机制。该分子的生物学后果佐剂组合的基于设计将在剂量、毒性和功效方面进行评估。我们期望开发强大的配方，在单次疫苗接种后即可产生保护作用。我们的整个提案仅专注于旨在发展保护性 B 细胞免疫的疫苗，并且我们的模型系统是针对肺炎链球菌的结合疫苗。