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: 10605209
• 负责人: Ronnie H Fang
• 金额: $ 23.7万
• 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/10605209
• 关键词: Address; Affinity; Anti-Bacterial Agents; Antibiotics; Antibodies; Antigens; Authorization documentation; 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; Macrophage; 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; Virulence Factors; Virus; antitoxin; authority; design; draining lymph node; experience; fabrication; in vivo; mouse model; nanovaccine; novel; oral vaccine; parenteral administration; pathogen; primary endpoint; priority pathogen; prophylactic; response; success; uptake; vaccine development; 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.

项目总结/摘要 艰难梭菌是一种高度威胁性的病原体，由于抗生素的过度使用而变得突出 和滥用。这种细菌在长期护理和医院环境中特别猖獗， 大量的感染。为了应对这一挑战，研究人员正在寻找不同的方法 管理C。艰难感染。其中一个具有巨大潜力的策略是抗病毒疫苗接种， 在那里，身体被训练来识别和中和细菌用来殖民宿主的“武器”， 并扩散。尽管它们有希望，但这些疫苗通常缺乏功效，并且它们的免疫力和免疫力都很差。 由于需要肠胃外给药，也会妨碍展开。在这个探索性的项目中，我们 目标是开发一种全新的仿生微马达疫苗，可以口服， 防止C。艰难感染该平台由两个关键部件组成：（1）一个自走式镁 （2）巨噬细胞膜涂层，其滞留细菌毒力因子。当 结合在一起，我们假设这些运动类毒素将能够递送C.艰难梭菌毒素 肠道的免疫系统，在那里它可以引发有效的抗菌免疫反应，保护免受随后的 病原体的挑战。通过利用毒素对细胞膜的天然亲和性，这种方法可以被 用于以不可逆的方式抑制多种抗原。镁核心使运动类毒素能够 这将促进抗原有效载荷主动递送到肠内， 粘膜屏障，能够更好地保留抗原，因此更有效的免疫加工和激活。 为了实现我们的目标，我们将首先开发一种载有C.艰难梭菌毒素和评估 其在体外和体内的特性（目的1）。然后，将在小鼠中评价体内预防功效。 live C.艰难梭菌感染（目的2）。如果成功，这种主动递送口服疫苗的方法可以 通过调节膜包被和细菌抗原， 用于合成。