Using parenteral combination adjuvants to induce pan-mucosal cellular and humoral immunity

使用肠外组合佐剂诱导全粘膜细胞和体液免疫

• 批准号: 10525805
• 负责人: LISA A MORICI
• 金额: $ 68.55万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525805
• 关键词: Address; Adjuvant; Affect; Antibodies; Antibody Formation; Antibody-mediated protection; Antigens; B-Lymphocytes; Bacterial Infections; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cells; Cellular Immunity; Chlamydia; Citrobacter; Communicable Diseases; Data; Enterotoxins; Escherichia coli; Female; Future; Gastrointestinal tract structure; Goals; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunoglobulin Class Switching; Individual; Infection; Influenza; Injections; Intervention; Intestinal Mucosa; Intramuscular; Investigation; Knowledge; Lead; Lung; Lymphoid Tissue; Major Histocompatibility Complex; Medical; Membrane; Memory; Memory B-Lymphocyte; Mission; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Parabiosis; Persons; Phenotype; Play; Program Development; Publishing; Recording of previous events; Research; Role; Site; Structure of parenchyma of lung; Surface; T-Cell Activation; T-Lymphocyte; Testing; Tissues; United States National Institutes of Health; Vaccine Adjuvant; Vaccine Antigen; Vaccine Design; Vaccines; Vesicle; Virus Diseases; Work; aluminum sulfate; combat; draining lymph node; experimental study; human disease; innovation; insight; migration; mucosal site; mutant; novel; parenteral administration; pathogen; pathogenic bacteria; pathogenic virus; protective efficacy; reproductive tract; response; tool; trafficking; vaccine development

PROJECT SUMMARY Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always induce the required mucosal immune responses. This highlights a gap in our understanding of how non-mucosal immunization might be manipulated to elicit mucosal immune responses and how such knowledge could be exploited to create better vaccines against mucosal pathogens. Defining the role that adjuvants play in this response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal antibody and cellular immune responses are not well understood. Our published work and preliminary experiments using major histocompatibility complex class I (MHCI) and II (MHCII) and B cell tetramers to examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP- ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous T and B cell immune responses to the lung, intestinal mucosa, and female reproductive tract (FRT). When dmLT is combined with a safe, bacterial-derived outer membrane vesicle (OMV) adjuvant, CD4 T cell numbers and vaccine-specific antibodies and B cells are even further increased. Simultaneously, OMV adjuvant induces significant expansion of vaccine-specific CD8 T cells. Furthermore, immunization with dmLT- or OMV-adjuvanted vaccines elicits protection against bacterial infections in the lung and gut. These results lead us to hypothesize that intradermal immunization with combined dmLT plus OMVs will drive antigen-specific B cells and T cells to the mucosa and enhance vaccine protection against mucosal pathogens. We propose to: 1) determine how intradermal immunization with dmLT combined with OMV adjuvant directs 1) T cells and 2) B cells to mucosal tissue and whether these cells are bona fide tissue resident memory cells. In parallel, we will 3) examine if immunization with dmLT-OMV adjuvanted vaccines is protective against mucosal viral and bacterial infections in the lung, gut and FRT. This investigation will provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.

项目概要 大多数病原体通过粘膜表面进入体内，但迄今为止，大多数许可的疫苗都是注射的 胃肠外注射，主要是肌内注射。虽然它们在引发全身免疫力方面表现出色，但并不总是 诱导所需的粘膜免疫反应。这凸显了我们对非粘膜如何 可以操纵免疫来引发粘膜免疫反应，以及如何利用这些知识 用于制造更好的针对粘膜病原体的疫苗。定义佐剂在此发挥的作用 反应是开发此类疫苗的关键；然而，决定佐剂驱动的粘膜的机制 抗体和细胞免疫反应尚不清楚。我们已发表的工作和初步 使用主要组织相容性复合物 I 类 (MHCI) 和 II 类 (MHCII) 以及 B 细胞四聚体进行实验 使用新型解毒细菌 ADP- 进行皮内免疫后检查粘膜免疫反应 核糖基化肠毒素（称为 dmLT）证明我们可以重新定位内源性 T 和 B 细胞免疫 对肺、肠粘膜和女性生殖道（FRT）的反应。当 dmLT 与 安全、细菌来源的外膜囊泡 (OMV) 佐剂、CD4 T 细胞数量和疫苗特异性 抗体和B细胞甚至进一步增加。同时，OMV 佐剂诱导显着扩增 疫苗特异性 CD8 T 细胞。此外，使用 dmLT 或 OMV 佐剂疫苗进行免疫可引发 防止肺部和肠道细菌感染。这些结果使我们推测皮内注射 dmLT 联合 OMV 的免疫将驱动抗原特异性 B 细胞和 T 细胞到达粘膜并 增强疫苗对粘膜病原体的保护。我们建议：1）确定如何皮内注射 dmLT 联合 OMV 佐剂免疫将 1) T 细胞和 2) B 细胞引导至粘膜组织， 这些细胞是否是真正的组织驻留记忆细胞。同时，我们将 3) 检查是否进行了免疫接种 含有 dmLT-OMV 佐剂的疫苗可预防肺部、肠道的粘膜病毒和细菌感染 和 FRT。这项研究将为佐剂如何调节粘膜和免疫系统提供新的见解。 让我们能够指导有利于消除病原体的反应。