A sustained vaccine-vehicle for cattle pathogens

牛的传染病在世界范围内具有巨大的经济和福利影响。通过牛疾病（伴随生产力的损失）或潜在的人畜共患病而具有重要性的高发病率病原体包括沙门氏菌、大肠杆菌O 157、结核病和弯曲杆菌，仅举几例。全世界牛的数量超过13亿，牛疫苗产品的潜在市场是巨大的（目前估计为10亿美元）。大多数牛都携带非致病性寄生虫泰氏锥虫。这种原生动物维持在低水平，而不影响肉牛和奶牛群的生产力。通过利用锥虫寄生虫的遗传易处理性，我们已经开发了T。作为牛中抗原的潜在递送系统。重要的是，预计溶媒在牛中可长期保持低水平，从而实现持续的抗原递送。我们先前的工作已经克服了开发载体的主要障碍：即，长期体外培养、稳定工程化载体的生产和异源蛋白的表达。通过优化和验证输送系统，我们现在希望将该技术扩展到适合评估其生物可行性的阶段。值得注意的是，与现有的疫苗策略相比，拟议的疫苗载体的工艺和生产成本可能较低。通过提供重组蛋白的延长释放，T. theileri具有为来自牛病原体的免疫原提供新的和灵活的表达载体的潜力。我们在该开发阶段的目标是：-优化工程寄生虫外源蛋白的表达; -开发和验证疫苗载体的生物遏制策略，以及-检查疫苗载体在牛中的维持和蛋白表达，并测定产生的抗原特异性免疫应答。该申请代表了英国学术界（位于爱丁堡大学和莫雷顿研究所）和工业界（英特威）之间的合作伙伴关系。这提供了一个独特的技能基础，以最大限度地发挥最终的专业化潜力。工业合作伙伴英特威是世界上三家最著名的动物保健公司之一，也是动物疫苗的领先公司。因此，他们的参与使该项目的工业应用成为重点，提供疫苗学，疾病知识和试剂方面的专业知识，以证明该系统的实用性。除了对该提案的直接财务承诺外，工业合作伙伴还将为持续的知识产权保护和广泛提供动物试验的专业设施做出贡献。合并后，这代表了超过10万英镑的“实物”贡献，这相当于超过工业合作伙伴关系申请所需的10%直接现金贡献的约20%的财务贡献。

Infectious diseases of cattle have an enormous financial and welfare impact world-wide. High incidence pathogens with importance either through cattle disease (with associated loss of productivity) or the potential for human zoonosis include salmonella, E.coli O157, tuberculosis and Campylobacter, to name but a few. With a world cattle population in excess of 1.3 billion, the potential market for bovine vaccine products is enormous (currently estimated at 1 billion US$). Most cattle harbour the non-pathogenic parasite Trypanosoma theileri. This protozoan is sustained at low-levels without affecting productivity in beef and dairy herds. By utilising the genetic tractability of trypanosomatid parasites, we have developed T. theileri as a potential delivery system for antigens in cattle. Importantly, the vehicle is expected to persist at a low-level in cattle for long periods enabling sustained antigen delivery. Our prior work has overcome the major hurdles to development of the vehicle: namely, long-term in vitro culture, production of the stably-engineered vehicle and the expression of heterologous proteins. By optimisation and validation of the delivery system, we now wish to widen the technology to a stage suitable for evaluation of its commerical viability. Significantly, the process and production costs of the proposed vaccine-vehicle are likely to be low in comparison to existing vaccine strategies. By providing prolonged release of recombinant protein, T. theileri has the potential to afford a novel and flexible expression vehicle for immunogens from cattle pathogens. Our aims in this development phase are to: -optimise expression of exogenous proteins by the engineered parasite; -develop and validate a biological containment strategy for the vaccine-vehicle, and -examine maintenance and protein expression of the vaccine-vehicle in cattle and to assay the resulting antigen-specific immune responses. This application represents a partnership between UK academics (based at the University of Edinburgh and Moredun Research Institute) and Industry (Intervet). This provides a unique skills base to maximise the potential for ultimate commericalisation. The Industrial Partner, Intervet, is among the three most prominent animal health companies in the world and the leading company for animal vaccines. As such, their involvement brings a strong focus to the industrial applications of the project providing expertise in vaccinology, disease knowledge, and reagents to prove practicality of the system. In addition to their direct financial commitment to the proposal, the Industrial Partner also will contribute to ongoing IP protection and extensive provision of specialist contained facilities for animal trials. Combined, this represents an 'in-kind' contribution in excess of £100,000, this equating to an approximately 20% financial contribution over-and above the 10% direct cash contribution required for an Industrial Partnership Application.