Motorized delivery of bacterial antigens to mucosal barriers to enhance immunity against infection

将细菌抗原机动递送至粘膜屏障以增强抗感染免疫力

• 批准号: 10370989
• 负责人: Ronnie H Fang
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370989
• 关键词: Address; Affinity; Anti-Bacterial Agents; Antibiotics; Antibodies; Antigens; B-Lymphocytes; Bacteria; Bacterial Antigens; Bacterial Infections; Bacterial Toxins; Binding; Biological; Biological Assay; Biomimetics; Cell membrane; Cessation of life; Characteristics; Chitosan; Clostridium Infections; Clostridium difficile; Collaborations; Communicable Diseases; Consumption; Data; Development; Disease; Dose; Enteral; Environment; Evaluation; Formulation; Future; Gastrointestinal tract structure; Goals; Histologic; Hospitals; Immobilization; Immune; Immune response; Immune system; Immunity; In Vitro; Incidence; Infection; Intestines; Long-Term Care; Magnesium; Malignant Neoplasms; Measures; Membrane; Molecular Conformation; Motor; Motor Activity; Mucous Membrane; Mus; Oral; Oral Administration; Pathogenesis; Penetration; Population; Proliferating; Proteins; Public Health; Recording of previous events; Regimen; Research; Research Personnel; Safety; Scheme; Stomach; Technology; Tissue Sample; Toxin; Toxoids; Training; United States; Vaccination; Vaccine Design; Vaccines; Virulence Factors; Virus; antitoxin; authority; base; design; draining lymph node; experience; in vivo; macrophage; mouse model; nanovaccine; novel; oral vaccine; parenteral administration; pathogen; primary endpoint; priority pathogen; prophylactic; response; success; uptake; vaccine distribution; weapons

PROJECT SUMMARY/ABSTRACT Clostridium difficile is a highly threatening pathogen that has risen to prominence as a result of antibiotic overuse and misuse. The bacteria are particularly rampant in long-term care and hospital settings, where it is responsible for a significant number of infections. In response to this challenge, researchers are looking into different ways of managing C. difficile infections. One such strategy that holds significant potential is antivirulence vaccination, where the body is trained to recognize and neutralize the “weapons” employed by bacteria to colonize their hosts and proliferate. Despite their promise, these vaccines oftentimes suffer from a lack of efficacy, and their deployment can also be encumbered by the need for parenteral administration. In this exploratory project, our goal is to develop an entirely new biomimetic micromotor vaccine that can be orally administered to effectively protect against C. difficile infection. The platform consists of two key components: (1) a self-propelled magnesium (Mg)-based micromotor and (2) a macrophage membrane coating that detains bacterial virulence factors. When combined together, we hypothesize that these motor toxoids will be capable of delivering C. difficile toxins to the gut’s immune system, where it can elicit potent antibacterial immune responses that protect against subsequent challenge by the pathogen. By leveraging the natural affinity of toxins for cell membranes, this approach can be used to immobilize multiple antigens in a nonreversible manner. The Mg core enables the motor toxoids to propel upon entry into the intestines, and this will promote the active delivery of the antigenic payloads towards the mucosal barrier, enabling better antigen retention and therefore more efficient immune processing and activation. To achieve our goals, we will first develop a motor toxoid formulation loaded with C. difficile toxins and evaluate its characteristics both in vitro and in vivo (Aim 1). Then, in vivo prophylactic efficacy will be evaluated in a murine model of live C. difficile infection (Aim 2). If successful, this approach for the active delivery of oral vaccines can be readily applied to other high-priority pathogens by modulating the membrane coating and bacterial antigens used for synthesis.

项目概要/摘要 艰难梭菌是一种高度威胁的病原体，由于抗生素的过度使用而变得日益突出 细菌在长期护理和医院环境中尤其猖獗，这是其造成的。 为了应对这一挑战，研究人员正在寻找不同的方法。 控制艰难梭菌感染的一种具有巨大潜力的策略是抗毒力疫苗接种， 身体被训练来识别和消灭细菌用来殖民宿主的“武器” 尽管它们有希望，但这些疫苗常常缺乏功效，而且它们的效果也很差。 在这个探索性项目中，注射给药的需要也会阻碍部署。 目标是开发一种全新的仿生微电机疫苗，可以口服有效地 防止艰难梭菌感染 该平台由两个关键组件组成：(1) 自走式镁。 (Mg) 基微电机和 (2) 保留细菌毒力因子的巨噬细胞膜涂层。 综合起来，我们认为这些运动类毒素将能够将艰难梭菌毒素输送到 肠道的免疫系统，它可以引发有效的抗菌免疫反应，从而防止随后的感染 通过利用毒素对细胞膜的天然亲和力，这种方法可以 用于以不可逆的方式固定多种抗原 镁核心使运动类毒素能够推动。 一旦进入肠道，这将促进抗原有效负载向肠道的主动递送 粘膜屏障，能够更好地保留抗原，从而更有效地进行免疫处理和激活。 为了实现我们的目标，我们将首先开发一种含有艰难梭菌毒素的运动类毒素制剂，并评估 其体外和体内特性（目标 1）然后，将在小鼠体内评估其体内预防功效。 活艰难梭菌感染模型（目标 2）如果成功，这种主动递送口服疫苗的方法可以实现。 通过调节膜涂层和细菌抗原，可以轻松应用于其他高优先级病原体 用于合成。