African swine fever outbreak containment strategy using small-molecule antiviral drugs

非洲猪瘟（ASF）是一种常见的猪的致命性疾病，具有非常高的社会经济影响。该疾病对英国、欧盟和全球养猪业的风险越来越大，因为它在外高加索、俄罗斯联邦和东欧的一些国家（包括欧盟成员国和最近的中国）迅速蔓延。英国养猪业每年价值约10亿英镑，占红肉市场的40%（Defra，2008-2009; AHDB，2014）。如果ASF进入英国，目前价值约3亿英镑的出口将停止。ASF控制依赖于快速诊断和实施检疫、流动限制和淘汰政策。这些措施对农民和猪肉行业其他相关人员的生计产生了重大影响，并对动物福利产生了严重影响。几个因素导致难以控制ASF。在这个项目中，我们将通过优化小分子抗病毒先导化合物来解决这种新出现的野猪和家猪传染病，这些化合物可以特异性地抑制ASF病毒（ASFV）的复制。我们已经鉴定了一类具有有效抗ASFV活性的分子。除了阐明其确切的作用机制外，还将对已鉴定的先导分子进行优化，以增加（i）使用来自14种基因型的ASFV分离株的参考组的泛基因型活性，（ii）选择性和（iii）在猪中进行安全性和有效性测试之前的口服生物利用度。一旦优化，此类抗病毒药物可以迅速部署（例如在储存之后）在ASF侵入先前无区域的情况下，通过对受感染场所周围的保护区中的猪施用药物作为预防性和过敏性措施。先前对另一种猪流行病--经典猪瘟（CSF）的研究，已经证明，从流行病学和经济角度来看，抗病毒药物是紧急疫苗接种和淘汰/先发制人的扑杀的有效补充和/或替代品。事实上，已经显示，给予CSF感染的猪的抗病毒药物（i）将病毒滴度降低1000倍，（ii）将在血液中检测到病毒的时间缩短74%，和（iii）将从感染/治疗的猪到未治疗的哨兵猪的传播降低85%（Vrancken et al.，2009 a; 2009 b）。使用在欧盟两个猪密集地区进行的流行病学建模研究进一步验证了所提出的CSF抗病毒遏制策略（Ribbens et al.，2012; Backer等人，2013年）。使用抗病毒药物至少可以有效地控制CSF疫情，这与使用更传统的策略（如先发制人的扑杀和紧急疫苗接种）一样有效。尽管尚未注册用于牲畜，但小分子抗病毒药物的优点已在人类医学中得到充分证实，用于治疗艾滋病和丙型肝炎等传染病，这些疾病目前尚无疫苗。这是第一个将高质量的研究机构和生物技术公司结合在一起的项目，这些公司结合了技术技能，专业知识和专业知识，成功地将抗病毒药物的使用作为控制ASF的有效方法。学术界和工业界的合作将通过阐明病毒抑制机制，促进我们对ASFV如何复制的理解，包括某些病毒和/或细胞蛋白的作用。这些见解将有助于促进互补ASFV候选疫苗的合理开发，并将有助于了解如何有效地将抗病毒药物遏制策略与使用减毒活疫苗的疫苗接种结合联合收割机。

African swine fever (ASF) is a frequently fatal disease of pigs with a very high socio-economic impact. The disease represents an increasing risk to the UK, EU and global pig industries due to its dramatic and increasing spread in a number of countries in the Trans Caucasus, Russian Federation and Eastern Europe, including EU member states and most recently China. The UK pig industry is valued at around £1 billion per year and represents 40% of the red meat market (Defra, 2008-2009; AHDB, 2014). Exports, currently valued at about £300 million, would be halted if ASF entered the UK.ASF control relies on rapid diagnosis and implementation of quarantine, movement restrictions and stamping out policies. These measures have a high impact on the livelihoods of farmers and others involved in the pork industry and a severe effect on animal welfare. Several factors contribute to the difficulty in controlling ASF. Amongst these is the lack of a vaccine and presence of wild pig reservoirs of infection.In this project we will tackle this emerging infectious disease of wild and domestic pigs by optimising small-molecule, antiviral lead compounds that specifically inhibit the replication the ASF virus (ASFV). We have already identified a class of molecules with potent anti-ASFV activity. Apart from elucidating their exact mechanism of action, the identified lead molecules will be optimised to increase (i) pan-genotype activity using a reference panel of ASFV isolates from 14 genotypes, (ii) selectivity and (iii) oral bio-availability prior to safety and efficacy testing in pigs. Once optimised, such antiviral drugs can be deployed quickly (e.g. following stockpiling) in case of an ASF incursion into a previously-free area by administering the drug as a prophylactic and metaphylactic measure to pigs in protection zones around infected premises.Previous research on classical swine fever (CSF), another epizootic disease of pigs, has demonstrated that antiviral drugs are a valid supplement and/or alternative to emergency vaccination and stamping-out/pre-emptive culling from an epidemiological and economic point of view. Indeed, it has been shown that an antiviral drug administered to CSF-infected pigs (i) reduces the viral titre by a 1000-fold, (ii) shortens the period virus is detected in blood by 74% and (iii) reduces transmission from infected/treated pigs to untreated sentinel pigs by 85% (Vrancken et al., 2009a; 2009b). The proposed antiviral containment strategy for CSF was further validated using epidemiological modelling studies conducted in two pig-dense areas in the EU (Ribbens et al., 2012; Backer et al., 2013). CSF outbreaks were controlled at least as effectively with antiviral drugs as with more conventional strategies such as pre-emptive culling and emergency vaccination.Although none have been registered for use in livestock, the merits of small-molecule, antiviral drugs are well established in human medicine against infectious diseases such as AIDS and hepatitis C, for which no vaccines are available. This is the first project to bring together a high-quality research organisation and a biotech company that combined have the technical skills, know-how and expertise to successfully introduce the use of antiviral drugs as an effective approach to ASF control. The academic-industry partnership will advance our understanding of how ASFV replicates including the role(s) of certain virus and/or cellular proteins by elucidating the mechanism of virus inhibition. These insights will help advance the rational development of complementary ASFV vaccine candidates and will help understand how to effectively combine an antiviral drug containment strategy with vaccination using a live-attenuated vaccine.