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.

项目总结/文摘