A sustained vaccine-vehicle for cattle pathogens

牛的传染病对全世界的经济和福利造成巨大影响。具有重要意义的高发病率病原体包括沙门氏菌、大肠杆菌O157、结核病和弯曲杆菌，这些病原体要么通过牛病（伴随生产力损失），要么可能导致人类人畜共患病。由于世界牛的数量超过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）。大多数牛体内都有非致病性的锥虫。这种原生动物维持在低水平，不影响牛肉和奶牛群的生产力。通过利用锥虫寄生虫的遗传易感性，我们开发了T. theileri作为牛抗原的潜在递送系统。重要的是，该载体有望在牛体内长期保持低水平，从而实现持续的抗原递送。我们之前的工作已经克服了载体发展的主要障碍：即长期体外培养，稳定工程载体的生产和异种蛋白的表达。通过优化和验证输送系统，我们现在希望将技术扩大到适合评估其商业可行性的阶段。重要的是，与现有疫苗战略相比，拟议疫苗载体的工艺和生产成本可能较低。通过延长重组蛋白的释放时间，牛肠杆菌有可能为牛病原体的免疫原提供一种新颖而灵活的表达载体。我们在这个开发阶段的目标是：优化外源蛋白的表达工程寄生虫；-开发和验证疫苗载体的生物控制策略，并检查疫苗载体在牛体内的维持和蛋白质表达，并测定由此产生的抗原特异性免疫反应。该应用程序代表了英国学术界（基于爱丁堡大学和莫尔顿研究所）和工业界（Intervet）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商业化的潜力。工业合作伙伴Intervet是世界上最著名的三家动物保健公司之一，也是动物疫苗的领先公司。因此，他们的参与将重点放在项目的工业应用上，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政承诺外，工业合作伙伴还将为持续的知识产权保护和广泛提供专门的动物试验设施作出贡献。综合起来，这代表了超过10万英镑的“实物”贡献，这相当于大约20%的财务贡献，超过了工业伙伴申请所需的10%的直接现金贡献。

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.