Development of next generation vaccine technology inducing rapid and strong immunity through targeted delivery of antigens to chicken immune cells

安全和无疾病的家禽生产系统对于维持粮食供应、养活日益增长的人口和改善农业社区的生计至关重要。然而，养殖业生产可持续增长的最大威胁是多种传染性动物病原体的出现、重新出现和持续流行，如禽流感。对这些病原体的控制主要是通过接种疫苗来实现的。然而，目前大多数疫苗的效果并不理想，它们可能只会减少临床疾病的表现和死亡率，但受感染的动物继续释放病毒，导致易感幼稚和接种疫苗的动物持续感染链。例如，尽管向一只禽类大规模部署了多剂流感疫苗，但疾病的表现仍以地方性流行的形式出现，农民继续承受着令人衰弱的损失，高达100%的鸡群死亡或鸡蛋产量损失以及人畜共患感染的威胁。因此，需要改进现有的疫苗，以产生更强的免疫力和对疾病的全面保护，同时减少受感染动物的传染性病毒排放，防止这些病毒在养殖动物中流行。在这项提案中，我们计划开发强大而有效的疫苗，以激发针对病毒病原体的强大和持久的体液和细胞免疫反应，这些病原体会给家禽业造成严重的经济损失。作为一项原则证明，我们已经证明，与非靶向对应物或传统的灭活病毒疫苗相比，靶向向鸡免疫细胞递送抗原可以增强接种鸡的抗原特异性免疫反应。靶向疫苗表现出明显更快的免疫反应和明显更高的免疫反应。因此，这些研究为将这项新的疫苗技术从实验室推向农场提供了强有力的数据。为了实现这一目标，我们与商业家禽疫苗生产商MSD Animal Health建立了合作伙伴关系。通过这次合作，我们将研究如何进一步优化我们开发的靶向抗原递送疫苗(TADV)配方，以i)诱导更快速的免疫，并针对感染不同地理区域的家禽的抗原性AIV变体提供更有效和更广泛的免疫反应；ii)利用我们成熟的昆虫细胞培养和重组病毒载体(火鸡疱疹病毒)系统，改进鸡的生产和递送方法。这一研究成果将为下一代改良禽流感疫苗的研制提供新的平台，并为其他重要的畜禽和人类病原体疫苗技术的改进提供平台。这些新的高度保护性和成本效益高的疾病控制工具和战略的提供应该会将传染病对农场动物的影响降至最低，并为英国和世界其他地区提供大量间接的经济、公共卫生、环境和社会效益。

Safe and disease-free poultry production systems are crucial for maintaining food supplies to feed the increasing human population and to improve the livelihoods of farming communities. However, the biggest threat in the sustainable growth of farmed animal production is the emergence, re-emergence and continual prevalence of a multitude of infectious animal pathogens, such as avian influenza. Primarily, the control against these pathogens is achieved through vaccination. However, the effectiveness of most of the current vaccines is suboptimal, where they may only reduce manifestation of clinical disease and mortality, but infected animals continue to shed viruses resulting in a continual chain of infections to susceptible naïve and vaccinated animals. For example, despite the large-scale deployment of multiple doses of influenza vaccine to an individual bird, manifestation of disease continues in the form of endemic prevalence and farmers continue to bear debilitating losses with up to 100 percent flock mortality or loss of egg production along with the threat of zoonotic infections. Therefore, improvement of the current vaccines are required that produce stronger immunity and full protection against disease, together with a reduction in shedding of infectious virus from infected animals, preventing the endemic prevalence of these viruses in farmed animals. In this proposal, we plan to develop robust and effective vaccines that elicit strong and durable humoral and cellular immune responses against viral pathogens which cause severe economic losses in poultry industries. As a proof-of-principle, we have demonstrated that targeted delivery of antigens to chicken immune cells potentiate the antigen-specific immune responses in vaccinated chickens compared to the untargeted counterpart or the conventional killed virus vaccines. The targeted vaccines demonstrated a significantly faster and a significantly higher immune response. These studies therefore provided strong data to take this new vaccine technology from laboratory to the farm. To achieve this goal, we have established partnership with a commercial poultry vaccine producer "MSD Animal Health". Through this collaboration, we will investigate how our developed targeted antigen delivery vaccine (TADV) formulation can further be optimised to i) induce even more rapid immunity and provide more potent and broader immune responses against antigenic AIV variants infecting poultry in different geographic regions; ii) enhance the production and delivery methods in chickens using our well-established insect cell cultures and recombinant viral vector (herpesvirus of turkey) system. The result obtained from this proposed research would provide a novel next generation improved AIV vaccine and a platform for improvement of vaccine technology against other important livestock and human pathogens. Availability of these novel highly protective and cost-effective disease control tools and strategies should minimise the impact of infectious diseases on farm animals, and offer substantial indirect economic, public health, environmental and social benefits to the UK and rest of the world.