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

使用小分子抗病毒药物遏制非洲猪瘟疫情的策略

• 批准号: BB/S015256/1
• 负责人: Linda Dixon
• 金额: $ 41.1万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS015256%2F1
• 关键词: African; swine; fever; outbreak; containment

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.

非洲猪瘟（ASF）是一种常见的猪致死性疾病，具有非常高的社会经济影响。这种疾病对英国、欧盟和全球养猪业构成越来越大的风险，因为它在跨高加索地区、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）的传播急剧增加。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）。如果非洲猪瘟进入英国，目前价值约3亿英镑的出口将停止。非洲猪瘟控制依赖于快速诊断和实施隔离、行动限制和消灭政策。这些措施对农民和其他参与猪肉产业的人的生计产生很大影响，并对动物福利产生严重影响。有几个因素导致非洲猪瘟难以控制。其中包括缺乏疫苗和存在野猪感染宿主。在这个项目中，我们将通过优化小分子抗病毒先导化合物，专门抑制非洲猪瘟病毒（ASFV）的复制，来解决这种新出现的野猪和家猪传染病。我们已经确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，将对鉴定出的铅分子进行优化，以提高(i)来自14种ASFV基因型分离株的泛基因型活性，（ii）选择性和（iii）在猪的安全性和有效性测试之前的口服生物利用度。一旦优化，这种抗病毒药物可以快速部署（例如，在储存之后），以防非洲猪瘟入侵到以前没有感染的地区，通过将药物作为预防和变态反应措施给予受感染场所周围保护区内的猪。以往对猪的另一种动物流行病经典猪瘟（CSF）的研究表明，从流行病学和经济学的角度来看，抗病毒药物是紧急疫苗接种和消灭/先发制人扑杀的有效补充和/或替代方法。事实上，研究表明，对感染猪瘟的猪使用抗病毒药物(i)将病毒滴度降低1000倍，（ii）将病毒在血液中检测到的时间缩短74%，（iii）将感染/治疗猪向未治疗哨岗猪的传播减少85% （Vrancken等人，2009a; 2009b）。通过在欧盟两个猪密集区进行的流行病学建模研究，进一步验证了拟议的脑脊液抗病毒控制策略（Ribbens等人，2012；Backer等人，2013）。使用抗病毒药物控制脑脊液爆发的效果至少与采用更传统的策略（如先发制人的扑杀和紧急疫苗接种）一样有效。虽然没有一种药物被登记用于牲畜，但小分子抗病毒药物的优点已经在人类医学中得到了很好的证实，可以用来治疗艾滋病和丙型肝炎等传染病，而目前还没有疫苗。这是第一个将一个高质量的研究机构和一家生物技术公司结合在一起的项目，它们拥有技术技能、知识和专业知识，可以成功地将抗病毒药物的使用作为控制非洲猪瘟的有效方法。通过阐明病毒抑制机制，学术界和产业界的合作伙伴关系将促进我们对非洲猪瘟如何复制的理解，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补充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相结合。

项目成果

O-2-Alkylated Cytosine Acyclic Nucleoside Phosphonamidate Prodrugs Display Pan-Genotype Antiviral Activity against African Swine Fever Virus.

• DOI: 10.1128/msphere.00378-22
• 发表时间: 2022-12-21
• 期刊: mSphere
• 影响因子: 4.8