Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs

非洲猪瘟是一种家猪病毒性出血性疾病，在受感染的猪群中造成高达100%的死亡率。非洲猪瘟在撒哈拉以南的非洲大部分地区流行，2007年在格鲁吉亚的波季港爆发过一次疫情。这种疾病从这里向西传播，经过东欧和中欧，向东传播到东亚和东南亚，造成数百万动物死亡，并威胁到全球粮食安全。该病毒威胁着濒危物种巴比熊和侏儒猪，以及亚洲和大洋洲的原生猪种。欧洲流行病学形势的特点是在自由漫游的野猪和生物安全性较低的后院农场中发生大量疫情。尽管实施了行动限制，但这种疾病仍在继续传播，如果没有疫苗，非洲猪瘟不太可能从欧洲根除。经典猪瘟，一种由不同病毒引起的类似疾病，通过有针对性的疫苗接种运动从欧洲野猪中根除，但是非洲猪瘟没有获得许可的疫苗，控制完全依赖于快速诊断和屠宰。在英国，非洲猪瘟阳性病例将导致农场周围10公里范围内的行动限制和受感染畜群的扑杀。除了对动物福利的严重影响和对农民造成的痛苦外，英国2022年的猪和猪肉出口价值为623,154,225英镑，这可能会在非洲猪瘟爆发时损失。对国内猪肉消费的影响难以评估，但消费者信心下降可能带来负面影响。生产疫苗的传统方法还没有成功地保护猪免受非洲猪瘟的侵害。即使与现代佐剂结合使用，灭活病毒也不能提供任何保护。通过组织培养反复传代产生的病毒（非洲猪瘟病毒）减毒株于20世纪60年代初在伊比利亚半岛部署，但有许多不可接受的副作用，包括慢性形式的疾病。最近，对病毒进行有针对性的基因修饰，以删除与免疫逃避相关的基因，这导致了第二代减毒活疫苗的开发。与第一代疫苗相比，这些疫苗具有更有希望的安全性，目前正在越南进行此类疫苗的广泛现场试验，但是这种疫苗在现场传播，并且不可能将接种疫苗的动物与自然感染的动物区分开来。此外，毒力恢复背后的机制尚不清楚，因此仍然迫切需要更安全的替代疫苗。在开发非洲猪瘟亚单位疫苗方面取得了进展，这将消除在实地部署通常致命的病毒的减毒株的安全问题。我们已经证明，八种非洲猪瘟病毒抗原的组合可以预防对非洲猪瘟病毒历史分离株的严重疾病。然而，亚单位疫苗的进一步发展受到我们对保护性免疫反应，特别是局部免疫作用的了解不足的限制。我们建议确定感染当前欧亚株非洲猪瘟病毒的家猪的早期病毒复制位点以及感染对局部免疫反应的影响。牛疱疹病毒4是开发非洲猪瘟亚单位疫苗的一个有吸引力的疫苗平台，因为疱疹病毒可在其他哺乳动物中诱导一种特定类型的免疫反应。因此，我们将评估表达模型非洲猪瘟病毒基因的牛疱疹病毒4，以测试其在猪体内诱导特异性免疫反应的能力以及保护动物免受疾病侵害的能力。

African swine fever is a viral haemorrhagic disease of domestic swine that causes mortality rates of up to 100% in affected herds. African swine fever is endemic in much of Africa south of the Sahara and there was an outbreak in the Georgian port of Poti in 2007. From here the disease spread west through eastern and central Europe and east into eastern and south-eastern Asia killing millions of animals and threatening global food security. The virus threatens endangered species babirusa and pygmy hogs, as well as species of pigs native to Asia and Oceania. The epidemiological situation in Europe is characterised by a substantial number of outbreaks in free-roaming wild boar and backyard farms with low biosecurity. The disease is continuing to spread despite the imposition of movement restrictions and African swine fever is unlikely to be eradicated from Europe without a vaccine. Classical swine fever, a similar disease caused by a different virus, was eradicated from European wild boar through a targeted vaccination campaign, however there is no licensed vaccine to African swine fever and control is entirely dependent on rapid diagnosis and slaughter. A positive case of African swine fever in the UK would lead to movement restrictions in a 10 km zone around the farm and the culling of infected herds. As well as the serious effects on animal welfare and distress caused to farmers, the value of UK pig and pork exports was £623,154,225 in 2022 which would likely be lost in the advent of an outbreak of African swine fever. The effect on domestic consumption of pork is difficult to assess, but a negative impact due to a drop in consumer confidence is possible.Traditional methods of generating vaccines have not been successful at protecting pigs against African swine fever. Inactivated virus provides no protection whatsoever, even in combination with modern adjuvants. Attenuated strains of the virus (African swine fever virus), generated by repeated passage through tissue culture, were deployed in the Iberian Peninsula during the early 1960s but had a number of unacceptable side effects including a chronic form of the disease. More recently, targeted genetic modification of the virus to delete genes associated with immune evasion has led to the development of a second generation of live attenuated virus vaccines. These have a much more promising safety profile than the first generation vaccines and extensive field trials with such a vaccine are currently underway in Vietnam, however this vaccine transmits in the field and it is not possible to distinguish vaccinated animals from those that have been naturally infected. Furthermore, mechanisms behind reversion to virulence are not understood and therefore, alternative, safer vaccines are still desperately needed.Progress has been made in the development of an African swine fever subunit vaccine which would eliminate the safety concerns around deploying an attenuated strain of a normally lethal virus in the field. We have shown that a combination of eight African swine fever virus antigens can prevent severe disease against historical isolates of African swine fever virus. However, further development of subunit vaccines is limited by our poor understanding of the protective immune response and in particular the role of local immunity. We propose to determine sites of early virus replication in domestic pigs infected with the current Eurasian strain of African swine fever virus as well as the effect of infection on local immune responses. Bovine herpesvirus 4 represents an attractive vaccine platform for the development of an African swine fever subunit vaccine due to the induction of a particular type of immune response by herpesviruses in other mammals. Therefore, we will evaluate bovine herpesvirus 4 expressing model African swine fever virus genes to test their ability to induce specific immune responses in pigs as well as their ability to protect animals from disease.