Protecting poultry from avian influenza, Newcastle disease, infectious bronchitis, and Gumboro disease with a single dose of a multivalent vaccine

家禽是增长最快的部门之一，在提供粮食安全、经济发展和减贫方面发挥着重要作用。近年来，对禽肉和禽蛋的需求呈指数级增长，目前每年家禽数量超过500亿只。该报告估计，家禽产量在未来十年将继续增长24%。然而，家禽生产可持续性的最大威胁是多种传染性病原体的高度流行，例如禽流感病毒（AIV）、纽卡斯尔病病毒（NDV）和传染性支气管炎病毒（IBV）以及传染性法氏囊病病毒（IBDV）的不同亚型（H5、H7和H9）。在地球仪的许多地区，这些病原体造成的产量损失估计至少占20%。首先，通过接种疫苗来控制这些疾病。然而，目前大多数疫苗的有效性并不理想，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传播病毒，导致易感的未接种疫苗和接种疫苗的动物连续感染链，导致体重减少。肉禽的增重以及产蛋和种禽群的产蛋量和质量下降。例如，尽管针对每种目标疾病的每种疫苗的多个重复剂量的过度部署，病原体的表现仍以地方流行的形式继续，并且农民继续承受使人衰弱的损失，有时高达100%的鸡群死亡率或产蛋量的损失以及在AIV的情况下的人畜共患感染威胁。目前的疫苗具有几个固有的缺点，包括（i）每种疾病一种疫苗，这需要多次接种疫苗和多次处理禽类，导致昂贵的疫苗接种计划;（ii）在前三周龄期间给鸡接种疫苗，在这段时间期间，禽类携带母源抗体（MDA），其干扰疫苗性能，并且疫苗的效力显著降低;（iii）疫苗是在不理想的蛋中生产的，需要用细胞培养系统替代;（iv）疫苗不相容，不易区分受感染的动物和接种疫苗的动物（DIVA），因此，在地方病地区不能轻易恢复无病状态。因此，需要新的创新疫苗，可以克服这些挑战。本提案计划解决这些挑战，并开发一种多价疫苗制剂，为鸡提供保护，使其免受多达六种主要病原体（AIV-H5，AIV-H7，AIV-H9，NDV，IBV，IBDV）的侵害。该项目将建立在我们的新型靶向抗原递送疫苗（TADV）平台上，该平台选择性地将疫苗抗原递送到鸡免疫细胞并增强抗原特异性免疫应答。我们的研究提供了证据，与非靶向对应物或常规灭活病毒疫苗相比，含有与特异性结合鸡抗原呈递细胞（APC）的抗体融合的修饰的血凝素（HA）抗原的单剂量TADV疫苗在MDA阳性鸡中诱导显著更快、更高和更持久的免疫应答。在这里，我们将使用我们的TADV技术并开发多价TADV制剂，其中单剂量将含有来自不同病毒的多达六种免疫原性抗原，包括（AIV-H5、AIV-H7、AIV-H9、NDV、IBV、IBDV）。该多价疫苗可在孵化场递送至日龄鸡，克服MDA干扰并在接种疫苗的禽类中诱导高度保护性免疫。这种新型的保护性和具有成本效益的疾病控制工具和策略的可用性应最大限度地减少传染病对农场动物的影响，并在全球范围内提供巨大的间接经济，公共卫生，环境和社会效益。

Poultry is one of the fastest-growing sectors that is playing a major role in the provision of food security, economic development and poverty reduction. The demand for poultry meat and eggs has been increasing exponentially in recent years with the current annual population of poultry reaching over 50,000 million. This estimates that poultry production continues to grow by 24% in the next decade. However, the biggest threat in the sustainability of poultry production is the hyper prevalence of a multitude of infectious pathogens, such as different subtypes (H5, H7 and H9) of avian influenza viruses (AIV), Newcastle disease virus (NDV) and infectious bronchitis virus (IBV) and infectious bursal disease virus (IBDV). An estimated production loss from these pathogens account for at least 20% in many regions around the globe. Primarily, the control against these diseases is achieved through vaccination. However, the effectiveness of most of the current vaccines is suboptimal, where they may only reduce the 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 resulting in reduced weight gain in meat birds and reduced egg production and quality in layers and breeder flocks. For example, despite the hyper deployment of multiple repeated doses of each vaccine for each target disease, the manifestation of pathogens continues in the form of endemic prevalence and farmers continue to bear debilitating losses with sometimes up to 100% flock mortality or loss of egg production and zoonotic infection threats in the case of AIV. Current vaccines carry several inherent drawbacks including (i) one vaccine per disease which require multiple vaccinations and multiple bird handling resulting in expensive vaccination programmes; (ii) vaccines are given to chickens during the first three weeks of age, during this time period, birds carry maternally derived antibodies (MDA) which interferes with the vaccine performance and the efficacy of vaccines is reduced significantly; (iii) vaccines are produced in the eggs that are not ideal and requires replacement with cell culture systems; (iv) vaccines are not compatible for easy differentiation of infected from vaccinated animals (DIVA), therefore, disease-free status cannot be reclaimed easily in endemic disease regions. Therefore, new innovative vaccines are needed that could overcome these challenges.This proposal plans to address these challenges and to develop a multivalent vaccine formulation that offers protection to chickens from up to six major pathogens (AIV-H5, AIV-H7, AIV-H9, NDV, IBV, IBDV). This project will be built on our novel Target Antigen Delivery Vaccine (TADV) platform which selectively delivers vaccine antigens to chicken immune cells and potentiate antigen-specific immune response. Our studies have provided evidence that a single dose of our TADV vaccine containing modified haemagglutinin (HA) antigen fused to the antibody that specifically binds to chicken antigen-presenting cells (APCs) induced significantly faster, higher and more durable immune response in MDA positive chickens compared to the untargeted counterpart or the conventional killed virus vaccines. Here, we will use our TADV technology and develop a multivalent TADV formulation in which a single dose will contain up to six immunogenic antigens from different viruses including (AIV-H5, AIV-H7, AIV-H9, NDV, IBV, IBDV). This multivalent vaccine can be delivered to day-old chickens at the hatchery overcoming MDA inference and inducing highly protective immunity in vaccinated birds. Availability of such novel 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 globally.