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

非洲猪瘟是家猪的病毒性出血性疾病，在受影响的猪群中导致死亡率高达100%。非洲猪瘟是撒哈拉以南非洲大部分地区的地方病，2007年在格鲁吉亚港口波蒂爆发。该疾病从这里向西传播，穿过东欧和中欧，向东进入东亚和东南亚，杀死了数百万头牲畜，威胁到全球粮食安全。这种病毒威胁到濒危物种Babirusa和侏儒猪，以及亚洲和大洋洲的猪种。欧洲的流行病学情况的特点是，在自由活动的野猪和生物安全性低的后院农场爆发了大量疫情。尽管实施了行动限制，但该疾病仍在继续蔓延，如果没有疫苗，非洲猪瘟不太可能从欧洲根除。经典猪瘟是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，但没有非洲猪瘟的许可疫苗，控制完全依赖于快速诊断和屠宰。如果英国出现非洲猪瘟阳性病例，将导致农场周围10公里范围内的行动限制，并扑杀受感染的猪群。除了对动物福利的严重影响和对农民造成的痛苦外，2022年英国生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很难评估，但由于消费者信心下降而产生的负面影响是可能的。传统的疫苗生产方法在保护猪免受非洲猪瘟感染方面并不成功。灭活病毒不提供任何保护，即使与现代佐剂结合。通过组织培养反复传代产生的减毒病毒株（非洲猪瘟病毒）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，包括慢性疾病。最近，对病毒进行靶向遗传修饰以删除与免疫逃避相关的基因，导致了第二代减毒活病毒疫苗的开发。这些疫苗的安全性比第一代疫苗更有希望，目前越南正在进行广泛的田间试验，但这种疫苗在田间传播，无法区分接种疫苗的动物和自然感染的动物。此外，毒力返强背后的机制尚不清楚，因此，仍然迫切需要替代的、更安全的疫苗。非洲猪瘟亚单位疫苗的开发取得了进展，这将消除在实地部署通常致命病毒的减毒株的安全性问题。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应答，特别是局部免疫作用的认识不足的限制。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型代表了一个有吸引力的疫苗平台，用于开发非洲猪瘟亚单位疫苗，因为疱疹病毒在其他哺乳动物中诱导了一种特定类型的免疫应答。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型，以测试它们在猪中诱导特异性免疫应答的能力以及它们保护动物免于疾病的能力。

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.