Co-Presentation and Delivery of TLR Agonist Combinations with Subunit Antigens to Pathogen-Match the Immune Response

TLR 激动剂与亚单位抗原组合的共提呈和递送，以匹配病原体的免疫反应

• 批准号: 9580295
• 负责人: DAVID A PUTNAM
• 金额: $ 58.04万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9580295
• 关键词: Adaptive Immune System; Adjuvant; Adjuvant Study; Agonist; Aluminum; Anti-Bacterial Agents; Antigens; Antiviral Agents; Area; B-Lymphocytes; Bacteria; Binding; Cell Maturation; Cells; Cessation of life; Communicable Diseases; Dendritic Cells; Dendritic cell activation; Engineering; Future; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Receptors; Individual; Infection; Influenza; Influenza A virus; Innate Immune System; Listeria; Membrane; Memory; Modeling; Molecular; Nucleotides; Outcome; Pathway interactions; Production; Reagent; Recombinant Vaccines; Recombinants; Reporter; Research; Research Personnel; Signal Pathway; Signal Transduction; Sodium Chloride; Specificity; Subunit Vaccines; System; T-Lymphocyte; TLR2 gene; Technology; Toll-like receptors; Vaccine Antigen; Vaccine Design; Vaccines; Vesicle; Viral; Virus; Work; adaptive immune response; aluminum sulfate; design; extracellular; falls; flexibility; improved; innovation; innovative technologies; novel vaccines; nucleotide receptor; pathogen; prevent; receptor; response; tool; vaccine development; vaccine efficacy

Project Summary/Abstract Subunit vaccines are a key strategy for preventing infectious disease and related deaths.. However, the use of subunit antigens, which elicit a weaker immune response than intact pathogen, has coincided with a need for safe and effective adjuvants to improve vaccine efficacy, increase immune response, and reduce the size and quantity of vaccine necessary to impart immunity. However, we lack a detailed picture of how engaging multiple innate immune receptors simultaneously or sequentially, on the same cell, or different cells, alters the outcome of the immune response. Our research team has engineered a new, flexible, pathogen-mimicking recombinant outer membrane vesicle (rOMV) platform capable of presenting functional antigen together with desired combinations of adjuvants. We intend to use this innovative technology to investigate how different adjuvant combinations of TLR and NOD agonists engage the innate immune system and help direct the immune response against viral and bacterial pathogens. Our hypothesis, to be evaluated through the Specific Aims, is that rOMVs can co-present antigen with specific combinations of adjuvants to induce pathogen-matched and protective immune responses (e.g., anti-viral and anti-bacterial). The specific aims are to: Aim 1: Identify the molecular pathways elicited by individual or combinations of adjuvants on rOMVs. rOMVs will be decorated with TLR and NOD agonists to understand how the resulting innate immune receptor agonists activate and influence cell signaling pathways using established reporter cells, and determine how those pathways are altered by co-presentation of TLR and NOD agonists. We will compare the response to soluble combinations of the same adjuvants on both signaling and dendritic cell activation and maturation. Aim 2: Determine how rOMV-adjuvant combinations direct the adaptive immune response to immunization using OVA as a model antigen. We will use OVA antigen to characterize the adaptive immune response induced by rOMV expressing single or combinations of adjuvants and compare them to single or combinations of soluble adjuvants. We will identify the combination(s) that promote strong and directive T cell, B cell and/or memory responses. Aim 3: Determine whether tailored rOMV adjuvant combinations can direct specific anti-viral and anti-bacterial protective immunity. We will use OVA-presenting rOMVs, as well as pathogen-specific antigens presented on rOMVs, decorated with different single or combined adjuvants in challenge models for both a viral (influenza) and a bacterial pathogen (Listeria) modified to express OVA as well as the native pathogens (i.e., no OVA). We will examine how innate signaling pathway activation and immune response correlate to protective immunity. The anticipated outcome of the proposed studies is a mechanistic understanding of how adjuvant combinations work at the molecular, cellular and organismal level to protect against viral and bacterial pathogens. The outcome will help to define a set of guiding principles that we and other investigators in the field can use to more robustly design adjuvant systems to maximize the efficacy of subunit vaccines.

项目摘要/摘要 亚基疫苗是预防传染病和相关死亡的关键策略。但是，使用 与完整病原体相比，引起免疫反应弱的亚基抗原与需要 安全有效的佐剂以提高疫苗功效，增加免疫反应并减少大小和 赋予免疫力所需的疫苗数量。但是，我们缺乏详细的描述 同时或依次在同一细胞或不同细胞上同时或依次地改变了结果，改变了结果 免疫反应。我们的研究团队设计了一种新的，灵活的，病原体的模仿 重组外膜囊泡（ROMV）平台，能够将功能性抗原一起呈现 佐剂的所需组合。我们打算使用这项创新技术来研究 TLR和点头激动剂的不同辅助组合参与先天免疫系统，并帮助指导 对病毒和细菌病原体的免疫反应。我们的假设，可以通过 具体目的是，ROMV可以与佐剂的特定组合共同抗原以诱导 病原体匹配和保护性免疫反应（例如抗病毒和抗菌）。具体目标 为：目标1：确定由ROMV上的个体或佐剂组合引起的分子途径。 ROMV将装饰有TLR和点头激动剂，以了解产生的先天免疫受体如何 激动剂使用已建立的报告基细胞激活并影响细胞信号通路，并确定这些细胞 TLR和点头激动剂的共阳性改变了途径。我们将比较对可溶的响应 同一佐剂在信号传导和树突状细胞激活和成熟方面的组合。目标2： 确定如何使用OVA指导对免疫的适应性免疫反应 作为模型抗原。我们将使用OVA抗原来表征ROMV诱导的自适应免疫反应 表达佐剂的单一或组合，并将其与可溶性佐剂的单个或组合进行比较。 我们将确定促进强和指令T细胞，B细胞和/或内存响应的组合。 AIM 3：确定量身定制的ROMV辅助组合是否可以指导特定的抗病毒和抗细菌 保护性免疫。我们将使用OVA呈现的ROMV，以及介绍的病原体特异性抗原 ROMV，在病毒式挑战模型中装饰有不同的单一或组合佐剂（流感） 和细菌病原体（李斯特菌）修饰以表达OVA以及天然病原体（即无OVA）。我们 将检查先天信号通路的激活和免疫反应如何与保护性免疫相关。 拟议的研究的预期结果是对辅助组合的机械理解 在分子，细胞和生物水平上工作，以防止病毒和细菌病原体。结果 将有助于定义我们和该领域的其他调查人员可以更强大的指导原则 设计辅助系统以最大化亚基疫苗的功效。