Bioemulsifying Vaccine Delivery System for Immunomodulation

用于免疫调节的生物乳化疫苗输送系统

• 批准号: 7279235
• 负责人: DAVID L. KAPLAN
• 金额: $ 38.02万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279235
• 关键词: Acinetobacter; Address; Adjuvant; Anabolism; Animals; Antibodies; Antigens; Area; Behavior; Biological; Biological Assay; Biological Process; Biopolymers; Breathing; Cellular Structures; Chemistry; Clinical; Clinical Trials; Collaborations; Collection; Colony-forming units; Data; Dendritic Cells; Disease model; Dose; Drug Formulations; Engineering; Family; Fatty Acids; Foundations; Future; Genetic; Genetic Engineering; Goals; Group Structure; Haptens; Hydroxylation; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunology; In Vitro; Individual; Infection; Japan; Kinetics; Knock-out; Label; Lead; Length; Lung; Macrophage Activation; Mediating; Methods; Modeling; Molecular Weight; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mouse Strains; Mucosal Immunity; Mus; Nature; Needles; Numbers; Oral; Outcome; Pasteurella pseudotuberculosis; Phase; Physiological; Polymers; Polysaccharides; Positioning Attribute; Preparation; Production; Property; Proteins; Reaction; Recombinants; Relative (related person); Reporting; Role; Route; Scientist; Score; Series; Side; Site; Solid; Solutions; Structure; Subgroup; Surface Tension; System; TNF gene; Testing; Tissues; Toxic effect; Vaccine Adjuvant; Vaccines; Variant; Vertebral column; Virulent; Weight; Work; Yersinia; analog; analytical tool; base; biological preparation; clinical application; cytokine; design; emulsan; established cell line; feeding; immunoregulation; improved; in vivo; insight; macrophage; member; microbial; microorganism; mucosal site; novel; novel vaccines; receptor; research study; response; subcutaneous; vaccine delivery; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): In our recent studies we have demonstrated that the biopolymeric emulsifier, emulsan, possesses exciting potential with regard to dual function (direct emulsification and immunomodulation). In particular, a compelling set of features including structural tailorability, innate ability to carry proteins, easy and large scale synthesis, lack of toxicity (to the extent tested thus far), and strong indication of vaccine efficacy and immunomodulation prompt the plans in the present proposal. The structural features of these novel biopolymeric systems can be 'tailored' through a combination of physiological control and/or genetic engineering and we have demonstrated that alteration in structure of these bioemulsifiers directly relates to changes in solution properties (e.g., emulsification, surface tension) and biological function (e.g., macrophage activation such as TNF.). In vivo, vaccine efficacy has been demonstrated in a number of animal studies including with a DNP-hapten carrier, Lyme and Yersinia. Based on these prior data, the hypothesis in this proposal is that structural variants of these microbial exopolysaccharides can provide new insight into our understanding of mechanistic features of the polymer interactions with the innate immune system and lead to the identification of promising candidate vaccine adjuvants. These data would lead to new and more effective vaccine adjuvants, an area of strong clinical need. The unique and powerful dual function of emulsification properties of these polymers combined with strong structural tailorability, suggests that new and useful functional adjuvants can be obtained. The studies planned will focus on biological preparation and assessment of these bioemulsifiers. An interdisciplinary team of scientists with expertise in biopolymer engineering, immunology and disease models, will conduct the proposed studies and has also been involved in the collection of the Preliminary Data. The specific aims include: (#1) synthesis and characterization of emulsan structural variants, (#2) assessments of innate immune recognition of the structural variants, (#3) assessment of the variants in an in vivo vaccine disease model based on the utilization of emulsan with a recombinant Yersinia pseudotuberculosis vaccine to induce protective immunity in a murine disease model (Aim #3), and the efficacy of emulsans in intranasal delivery of the vaccine formulation (Aim #4). The proposed studies will provide a solid foundation upon which to correlate emulsan structure and cellular responses leading to specific levels and types of immunological activities. Furthermore, lead adjuvant candidates will result from the study in preparation for formulation studies and clinical trials in future work.

描述(申请人提供)：在我们最近的研究中，我们已经证明了生物聚合物乳化剂在双重功能(直接乳化和免疫调节)方面具有令人兴奋的潜力。特别是，一系列令人信服的特征，包括结构可裁剪、天生携带蛋白质的能力、容易和大规模合成、无毒性(迄今测试的程度)以及对疫苗效力和免疫调节的强烈指示，促使本提案中的计划。这些新型生物聚合物体系的结构特征可以通过生理控制和/或基因工程的组合来“定制”，我们已经证明，这些生物乳化剂结构的变化与溶液性质(例如乳化、表面张力)和生物功能(例如巨噬细胞激活，如肿瘤坏死因子)的变化直接相关。在体内，疫苗的有效性已在许多动物研究中得到证明，包括DNP半抗原载体莱姆和耶尔森氏菌。基于这些先前的数据，本建议中的假设是，这些微生物胞外多糖的结构变体可以为我们提供新的见解，了解聚合物与天然免疫系统相互作用的机制特征，并导致识别有前景的候选疫苗佐剂。这些数据将导致新的、更有效的疫苗佐剂，这是一个临床上非常需要的领域。这些聚合物独特而强大的乳化性能和强大的结构可调性相结合，表明可以获得新的有用的功能助剂。计划中的研究将集中在这些生物乳化剂的生物制备和评估上。一个由具有生物聚合物工程、免疫学和疾病模型专业知识的科学家组成的跨学科团队将进行拟议的研究，并参与初步数据的收集。具体目标包括：(1)乳胶结构变异体的合成和表征，(2)对结构变异体的天然免疫识别的评估，(#3)在体内疫苗疾病模型中对乳胶变异体与重组耶尔森菌假结核疫苗一起使用来诱导小鼠疾病模型保护性免疫的评估(目标#3)，以及乳胶体在疫苗制剂鼻内给药中的有效性(目标#4)。拟议的研究将提供一个坚实的基础，在此基础上将乳胶结构和细胞反应联系起来，从而导致特定水平和类型的免疫活动。此外，这项研究将产生候选的主要佐剂，为今后的制剂研究和临床试验做准备。