Improving existing vaccine platforms to minimise the economic impact of emerging Bluetongue virus (BTV) serotypes

蓝舌病是家畜(主要是羊和牛)的一种主要传染病，由一种名为蓝舌病病毒(BTV)的病毒引起。BTV通过叮咬的蚊子从受感染的动物传播给未受感染的动物。从历史上看，蓝舌病几乎只在世界温带和热带地区被描述，那里温暖的温度既有利于易感昆虫媒介种群的传播，也有利于媒介内的病毒复制周期。然而，在过去的十年中，BTV在南欧广泛传播，出人意料地也在北欧(包括英国)传播，远远超出了其已知的地理上限，给动物健康和经济造成了严重问题。有趣的是，全世界有24种不同的BTV‘型’(称为‘血清型’)。基本上，这些不同的血清型拥有形成病毒颗粒外壳的略有不同的蛋白质。从本质上讲，蓝舌病可以被认为是由24种不同病毒引起的单一疾病！这是因为，如果一只动物接种了针对BTV-1血清类型(BTV-1)的疫苗，那么它将只受到BTV-1感染的保护，而不是针对其他23种BTV血清型的感染。自1998年以来，已有9种不同血清型的13例BTV侵入欧洲。安全有效的灭活疫苗的发展在预防和限制BTV疫情方面产生了巨大的有利影响。然而，任何对新血清型的重大入侵都迫使选择相关的新病毒用于疫苗生产。因为BTV是通过昆虫媒介传播的，所以它有季节性模式。大多数蓝舌病暴发在传入后的第一个媒介季节传播有限，但将在第二年大量传播并造成广泛破坏。因此，疫苗生产的时间表对于阻止新引入的血清型的传播可能是绝对关键的。目前，疫苗制造商从现场获得新的BTV毒株大约需要1到6个月的时间，另外需要14到20个月的时间来开发、测试和生产新的疫苗。快速生产疫苗将确保控制蓝舌病。例如，据估计，英国对BTV-8疫情的控制挽救了英国经济4.85亿GB和1万个工作岗位。那次成功的疫苗接种活动将英国从第二个BTV-8“赛季”中拯救了出来。然而，前一年没有BTV-8疫苗准备好阻止这种疾病在几个中欧国家第二年的毁灭性爆发。这项建议的主要目标是：(I)减少将一种新引入的BTV血清型的适当疫苗推向市场所需的时间；(Ii)收集必要的数据，以确定(并优化)BTV疫苗制备中使用的菌株选择标准；(Iii)设计能够引起免疫反应的病毒，使其能够抵御多种BTV血清型。通过使用新的基因工程技术，我们将开发和表征BTV“合成”病毒，这些病毒可以作为疫苗开发的“现成”毒株。该系统有可能减少制造商从田间获得新菌株所需的时间。我们将研究这些合成病毒如何在组织培养中发挥作用，以及它们在接种疫苗的绵羊中诱导保护性免疫的能力。此外，我们将确定BTV疫苗的哪些部分在接种动物中诱导免疫反应，我们将尝试设计可用作疫苗的病毒，以保护动物免受多种血清型的影响。这项提议的完成提供了开发工具的可能性，以避免未来由新引入的BTV血清型造成的大部分经济损害。

Bluetongue is a major infectious disease of livestock (sheep and cattle mainly) caused by a virus known as Bluetongue virus (BTV). BTV is transmitted from infected to uninfected animals by the biting midges. Historically, bluetongue has been described almost exclusively in temperate and tropical areas of the world where the warm temperatures favoured both the spread of the susceptible insect vector population and also the viral replication cycle within the vector. However, in the last decade BTV has spread extensively in Southern Europe and, unexpectedly, also in Northern Europe (including the United Kingdom) reaching well beyond its known geographical upper limits and causing serious problems to both animal health and the economy. Interestingly there are worldwide 24 different 'types' (known as 'serotypes') of BTV. Basically, these different serotypes possess slightly different proteins that form the outside shell of the viral particle. In essence bluetongue can be considered a single disease caused by 24 different viruses! This is because if an animal is vaccinated against serotype 1 of BTV for example(BTV-1), it will then be protected only against infection by BTV-1 but not against the other 23 BTV serotypes. Since 1998 there have been 13 BTV incursions into Europe of 9 different serotypes. The development of safe and effective inactivated vaccines has had an enormous beneficial impact in preventing and limiting the BTV epidemic. However, any significant incursion of a new serotype forces the selection of the relevant new virus for vaccine production. Because BTV is transmitted by an insect vector it has a seasonal pattern. Most bluetongue outbreaks will have a limited diffusion in the first vector season after introduction, but will spread considerably and cause extensive damage in the following year. Thus, the timeline of vaccine production can be absolutely critical to halting the spread of a newly introduced serotype. At present it takes approximately 1 to 6 months for a vaccine manufacturer to acquire a new BTV strain from the field and a further 14-20 months to develop, test and produce a new vaccine. Rapid production of vaccines will assure containment of bluetongue. For example, it has been estimated that the control of the BTV-8 outbreak in the UK saved the UK economy £ 485M and 10,000 jobs. That successful vaccination campaign saved the UK from its second BTV-8 'season'. However, the previous year there was no BTV-8 vaccine ready to halt the devastating outbreak of the disease in its second year in several Central European countries. The overarching objectives of this proposal are to: (i) reduce the time needed to bring to market an appropriate vaccine for a newly introduced BTV serotype; (ii) collect the data necessary to determine (and optimize) the criteria of strain selection used in BTV vaccine preparations; (iii) engineer viruses that elicit an immune response able to protect against multiple BTV serotypes. By using new genetic engineering techniques, we will develop and characterize BTV 'synthetic' viruses that can function as 'off-the-shelf' strains for vaccine development. This system has the potential to reduce the time required by manufacturers to obtain a new strain from the field. We will study how these synthetic viruses function in tissue culture and their ability to induce a protective immunity in vaccinated sheep. In addition we will determine which portions of the BTV vaccines induce an immune response in the vaccinated animal and we will attempt to engineer viruses that can be used as vaccines to protect the animals against multiple seroptypes. The completion of this proposal offers the possibility to develop the tools to avoid in the future most of the economical damages induced by newly introduced BTV serotypes.