Vaccine strain selection for FMD serotype O and A viruses in South East Asia and

口蹄疫（Foot and mouth disease，FMD）是由口蹄疫病毒（FMD virus，FMDV）引起的一种具有高度传染性和经济破坏性的病毒性疾病，主要危害偶蹄类动物，包括牛、绵羊、山羊和猪。该病在亚洲（包括东南亚（SEA））、非洲、中东和南美洲部分地区流行，而澳大利亚、北美和欧洲没有口蹄疫。FMDV是一种RNA病毒，由于缺乏病毒RNA聚合酶的证明阅读活性和病毒的准种性质，新的抗原变体可以迅速进化，导致在一个血清型内存在7种血清型和许多亚型。针对一种血清型的疫苗接种不提供针对其他血清型的交叉保护，有时一种血清型中的一种亚型对另一种亚型不提供交叉保护。目前，口蹄疫在东南亚和东亚（EA）国家高度流行，有三种流行血清型（血清型O是最主要的血清型，其次是血清型A和Asia1），对澳大利亚和其他自由国家造成威胁。虽然接种疫苗是预防口蹄疫爆发的最重要控制措施之一，但由于在一个血清型中出现了新的谱系和亚谱系，现有疫苗可能无法对这些国家的流行口蹄疫病毒提供足够的交叉保护。2010年期间，韩国经历了这种情况，当时一种新的血清型O型FMDV传播到该国，现有的O1 Manisa疫苗无法提供全面保护。因此，需要对流行病毒与现有疫苗进行定期疫苗匹配试验，如有必要，应选择广泛交叉反应的疫苗株，进行调整并纳入现有疫苗储备。因此，本项目的主要目的是将流行的病毒株与现有疫苗和新的推定疫苗株相匹配，以找到一种合适的疫苗，对该地区流行的新出现的病毒提供最大的交叉保护。目前的疫苗匹配和毒株选择方法主要依赖于血清学试验，该试验使用针对疫苗产生的多克隆抗血清，并比较这些抗血清与疫苗毒株和田间分离株的反应性。然而，这些血清学测试是耗时的，并且由于测试、细胞类型和操作者的日常变化而不完全可靠，因此非常需要开发这种血清学测试的替代方法。由于口蹄疫病毒的抗原决定簇与病毒衣壳相关，疫苗株和流行病毒的衣壳序列可以为选择合适的交叉反应疫苗提供替代数据集。通过使用血清学和衣壳序列数据，可以鉴定特别涉及交叉保护的氨基酸残基，其将对病毒的抗原性具有直接影响。然后，可以通过使用反向遗传学技术突变现有cDNA克隆中的残基来研究这些氨基酸残基的变化对病毒抗原性质的影响。这可以帮助设计一种新的疫苗，它可以提供更好的交叉保护，以对抗正在传播的病毒。该项目解决了开发简化疫苗选择技术的更广泛需求，这将主要有利于科学界。为了实现BBSRC的优先事项，该项目将与“农业和粮食安全”保持一致。

Foot and mouth disease (FMD), caused by FMD virus (FMDV) is a highly contagious and economically devastating viral disease affecting cloven hoofed animals including cattle, sheep, goats and pigs. The disease is endemic in Asia including South East Asia (SEA), Africa, Middle East and some part of South America whereas Australia, North America and Europe are free from FMD. FMDV is a RNA virus, and due to lack of proof reading activity of the viral RNA polymerase and quasi-species nature of the virus, new antigenic variants can evolve rapidly resulting in existence of 7 serotypes and many subtypes within a serotype. Vaccination against one serotype does not provide cross protection against other serotypes and sometimes one subtype to other subtype within a serotype. Currently FMD is highly endemic in SEA and East Asia (EA) countries with three circulating serotypes (serotype O is the most predominant serotype followed by Serotype A and Asia1) causing a threat to Australia and other free countries. Although vaccination is one of the most important control measures to prevent FMD outbreaks, the available vaccines may not be able to provide enough cross protection against the circulating FMDV in these countries due to emergence of new lineages and sub lineages within a serotype. This has been experienced in South Korea during 2010, a FMD free country, when a new lineage of serotype O FMDV spread in to the country and the existing O1Manisa vaccine could not provide full protection. So a regular vaccine matching test of circulating viruses with the existing vaccines is required and if necessary a broad cross reacting vaccine strain should be selected, adapted and incorporated to the existing vaccine reserves. Therefore the main aim of this project is to match circulating virus strains with existing vaccines and new putative vaccine strains to find out a suitable vaccine that provide maximum cross protection against the newly emerging viruses circulating in this region. The current methods of vaccine matching and strain selection mainly rely on serological tests that use polyclonal anti-sera raised against vaccines and comparing the reactivity of these antisera with the vaccine strains and the field isolates. However, these serological tests are time consuming and not fully reliable due to day to day variation of the tests, cell types, and operators, so there is a great need for the development of an alternative approach to this serological test. Since the antigenic determinants of FMDV are associated with the viral capsid, capsid sequences of vaccine strains and circulating viruses may provide an alternative dataset for selection of an appropriate cross reacting vaccine. By using serological and capsid sequence data, amino acid residues specially involved in cross protection which would have a direct impact on the antigenicity of the virus, can be identified. Then the effect of a change in these amino acid residues on the antigenic nature of the virus can be studied by mutating the residues in an existing cDNA clone using reverse genetics technique. This can help to design a new vaccine, which can give better cross protection against the circulating viruses. This project addresses the wider need to develop simplified vaccine selection techniques that would be mainly beneficial for the scientific community. In order to BBSRC priorities, this project will align with 'Agriculture and Food Security'.AfS, ENWW