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.

项目摘要 大多数病原体以粘膜表面进入身体，但迄今为止，大多数持牌疫苗被注入 育儿，主要是肌肉内。虽然擅长引起全身免疫，但并不总是 诱导所需的粘膜免疫反应。这突出了我们对非粘膜的理解的差距 可以操纵免疫以引起粘膜免疫反应以及这种知识如何 利用以对粘膜病原体产生更好的疫苗。定义佐剂在此中扮演的角色 反应是开发此类疫苗的关键。但是，决定佐剂驱动粘膜的机制 抗体和细胞免疫反应尚不清楚。我们发表的作品和初步 使用主要的组织相容性复合物I类（MHCI）和II（MHCII）和B细胞四聚体进行实验 用新的排毒细菌ADP-检查粘膜免疫反应后的粘膜免疫反应 核糖蛋白肠毒素称为DMLT，证明我们可以重新定位内源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，细菌衍生的外膜囊泡（OMV）佐剂，CD4 T细胞数量和疫苗特异性 抗体和B细胞进一步增加。同时，OMV辅助诱导显着膨胀 疫苗特异性CD8 T细胞的此外，用DMLT或OMV辅助疫苗免疫引起的 防止肺和肠道细菌感染。这些结果使我们假设皮内 与联合DMLT Plus OMV进行免疫接种将使抗原特异性B细胞和T细胞驱动到粘膜，并将 增强针对粘膜病原体的疫苗保护。我们建议：1）确定皮内 与OMV辅助结合使用DMLT免疫可导致1）T细胞和2）B细胞到粘膜组织和 这些细胞是否是真正的组织驻留记忆细胞。同时，我们将3）检查是否免疫 DMLT-OMV辅助疫苗可防止粘膜病毒和肺中的细菌感染 和frt。这项调查将提供有关佐剂如何调节粘膜免疫力和 允许我们指导反应，有利于消除病原体。