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 i nclude: (#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. ? ?
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