Bioemulsifying Vaccine Delivery System for Immunomodulation

描述（由申请人提供）：在我们最近的研究中，我们已经证明生物聚合物乳化剂emulsan具有令人兴奋的双重功能（直接乳化和免疫调节）潜力。特别是，一组令人信服的特征，包括结构可剪裁性，携带蛋白质的先天能力，容易和大规模合成，缺乏毒性（到目前为止测试的程度），以及疫苗功效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”，并且我们已经证明这些生物乳化剂的结构改变直接与溶液性质的变化（例如，乳化，表面张力）和生物功能（例如，巨噬细胞活化，例如TNF）。在体内，疫苗效力已在许多动物研究中得到证实，包括使用DNP-半抗原载体、莱姆和耶尔森氏菌。基于这些先前的数据，本提案中的假设是，这些微生物胞外多糖的结构变体可以为我们理解聚合物与先天免疫系统相互作用的机制特征提供新的见解，并导致有希望的候选疫苗佐剂的鉴定。这些数据将导致新的和更有效的疫苗佐剂，一个强烈的临床需求领域。这些聚合物的独特和强大的乳化性能的双重功能与强大的结构可定制性相结合，表明可以获得新的和有用的功能助剂。计划的研究将集中在生物制剂和评估这些生物乳化剂。一个跨学科的科学家团队，在生物聚合物工程，免疫学和疾病模型方面具有专业知识，将进行拟议的研究，并参与收集初步数据。具体目标包括：（#1）emulsan结构变体的合成和表征，（#2）结构变体的先天免疫识别的评估，（#3）基于emulsan与重组假结核耶尔森氏菌疫苗一起用于在鼠疾病模型中诱导保护性免疫的体内疫苗疾病模型中的变体的评估（目的#3），以及乳剂在疫苗制剂鼻内递送中的功效（目标#4）。拟议的研究将提供一个坚实的基础上，相关emulsan结构和细胞反应，导致特定的水平和类型的免疫活性。此外，主要佐剂候选物将从该研究中产生，为未来工作中的制剂研究和临床试验做准备。

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.