Development of live attenuated vaccine candidates for Newcastle Disease Virus

新城疫病毒候选减毒活疫苗的开发

• 批准号: BB/R012792/1
• 负责人: Steve Goodbourn
• 金额: $ 50.51万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR012792%2F1
• 关键词: Development; live; attenuated; vaccine; candidates

The farming of poultry and production of eggs is of growing economic importance to Thailand, as well as other countries in the region, but like all livestock industries, animal production is susceptible to disruption by outbreaks of infectious disease. Newcastle Disease Virus is a major pathogen of birds and causes significant economic losses in first world and developing countries, requiring widespread slaughter policies for control. Although Thailand has remained free from NDV since 2014, neighbouring countries have suffered NDV outbreaks; Thai exports of poultry have correspondingly increased. Keeping flocks free from NDV is thus of paramount importance. Available vaccines are not very effective at protecting birds against genotype VII NDV currently circulating in regions of Asia and elsewhere. In this proposal we aim to use our knowledge of the avian innate immune response to engineer a genotype VII virus to be incapable of evading host innate immunity (specifically the interferon system) and therefore generate a lead candidate for a live attenuated vaccine. Our approach has several interdependent phases: We will initially analyse the properties of the "V" protein of a highly pathogenic ("velogenic") genotype VII NDV as an antagonist of interferon induction or the interferon response and compare this with the "V" protein of an apathogenic ("lentogenic") strain. We will identify key host target proteins that are signalling molecules involved in the interferon system and which interact with the V proteins, and we will validate the importance of these proteins in avian innate immunity using in vitro assays. We will characterise the V/host interactions at the molecular level and will identify V determinants that are essential for interactions. We will then engineer both lentogenic and velogenic (genotype VII) strains of NDV to express altered V proteins that cannot interact with the key host target proteins and by extension which render the virus unable to evade host innate immunity. We will test for attenuation of these viruses by experimental infections in chickens, and we will determine whether this correlates with a failure to block interferon induction or enhanced interferon sensitivity in vivo.

家禽养殖和鸡蛋生产对泰国以及该地区其他国家的经济重要性日益增加，但与所有畜牧业一样，动物生产容易受到传染病爆发的影响。纽卡斯尔病病毒是鸟类的主要病原体，在第一世界和发展中国家造成重大的经济损失，需要广泛的屠宰政策来控制。虽然泰国自2014年以来一直没有NDV，但邻国却遭受了NDV的爆发;泰国的家禽出口也相应增加。因此，保持鸡群免受NDV感染至关重要。现有的疫苗在保护鸟类免受目前在亚洲和其他地区流行的基因型VII NDV方面不是非常有效。在本提案中，我们的目标是利用我们对禽类先天免疫应答的了解来设计基因型VII病毒，使其不能逃避宿主先天免疫（特别是干扰素系统），从而产生活减毒疫苗的主要候选物。我们的方法有几个相互依赖的阶段：我们将首先分析的“V”蛋白的高致病性（“velogenic”）基因型VII NDV作为干扰素诱导或干扰素反应的拮抗剂的属性，并比较这与“V”蛋白的无致病性（“lentogenic”）菌株。我们将确定关键的宿主靶蛋白，参与干扰素系统的信号分子，并与V蛋白相互作用，我们将验证这些蛋白质在禽先天免疫中的重要性，使用体外试验。我们将在分子水平上研究V/宿主相互作用，并确定相互作用所必需的V决定簇。然后，我们将工程化NDV的慢生和速生（基因型VII）毒株以表达改变的V蛋白，所述改变的V蛋白不能与关键宿主靶蛋白相互作用，并且通过延伸使病毒不能逃避宿主先天免疫。我们将通过鸡的实验性感染来测试这些病毒的减毒，并且我们将确定这是否与未能阻断干扰素诱导或增强体内干扰素敏感性相关。