Attenuation of FMDV Serotypes/Strains to Develop Stable and Effective Live, Attenuated, Vaccines

口蹄疫病毒(FMDV)是一种动物病原体，可感染家养动物(牛、猪、羊)，也可感染许多野生动物。例如，在印度，野生动物体内的口蹄疫病毒可以不断地再次感染家畜。口蹄疫病毒可能是人类已知的最具传染性的哺乳动物病毒，疾病可以非常迅速地传播。感染不会杀死动物，但当它们康复时，它们的农业生产力要低得多。该病毒还可引起长期(“持续”)感染，这些感染是看不见的：它们很难在现场诊断，使疾病控制复杂化。口蹄疫病毒在全球范围内引起疾病，并通过进口受污染的动物产品持续威胁英国农业。疫苗是可用的，但目前只在紧急情况下使用。2001年英国的疫情造成了巨大的经济损失(数十亿英镑)，因为阻止疾病传播的方法是大规模宰杀动物：无论感染与否。数以百万计的健康动物被摧毁。目前的疫苗生产速度很快，而且由于它只能在相对较短的时间内诱导保护性免疫反应，动物需要在其一生中接种疫苗--并重新接种。常规的、反复的接种疫苗是昂贵的。在欧洲，控制口蹄疫病毒的主要方法是大规模吸食受感染的病毒和周围的吸毒者(健康！)动物：在印度，这一政策在社会和政治上都是不可接受的。未来的食品供应安全是一个主要问题。随着印度经济的发展，对肉类产品的需求将不可避免地上升。英国进口的动物产品和动物饲料的价格将会上涨。为了满足这种日益增长的需求，世界各地的农业生产率必须提高，特别是在像英国这样人口密度较高的国家。通过建立非常大的设施，容纳数千只动物，可以提高生产率：这是一种在美国被证明有效的方法。大型动物生产的集约化创造了口蹄疫病毒等病毒造成毁灭性经济损失的机会。国际旅行和贸易的增加意味着，这不是英国可以孤立解决的问题：病毒跨越国界传播。在口蹄疫方面，英国采取了“活疫苗接种”的政策。我们认为，这必须与新疫苗的开发或新的疫苗生产方法相结合，才能使这项政策有效。这就是我们研究的目的。口蹄疫病毒与脊髓灰质炎是同一类型的病毒。有两种类型的疫苗可用于脊髓灰质炎：减毒活疫苗，疫苗使用的病毒株确实会引起感染(并引发终生保护性免疫反应)，但不会导致麻痹性脊髓灰质炎：萨宾疫苗。第二种类型是“被杀”。在这里，脊髓灰质炎病毒(可能导致脊髓灰质炎)在细胞中大量生长，然后用化学方法灭活，使其根本无法生长--但死亡的颗粒确实会引发保护性免疫反应：“Salk”疫苗。用于控制口蹄疫病毒的是后一种“灭活疫苗”。这意味着在生产过程中必须培养大量的病毒(可导致疾病的病毒)。不可避免的是，病毒的逃逸可能会从设施中发生，并导致周围完全可食用的动物爆发--被认为发生在英国2007年口蹄疫疫情。我们提议的研究计划是生产新的活的、减毒的疫苗，以带来口蹄疫疾病控制的变革。我们的战略是利用现代分子生物学来改变病毒，制造能够保护动物而不会导致衰弱疾病的新毒株--活的、减毒的病毒，就像脊髓灰质炎：生产成本低得多，也安全得多。

Foot-and-mouth disease virus (FMDV) is an animal pathogen which infects domesticated animals (cattle, pigs, sheep) but also many wild animals. In India, for example, FMDV in wild animals can continually re-infect domestic animals. FMDV is probably the most contagious mammalian virus known to man and disease can spread very rapidly. Infection does not kill animals, but when they recover, their agricultural productivity is much lower. The virus can also cause long-term ('persistent') infections that are inapparent: they are difficult to diagnose in the field, complicating disease control. FMDV causes disease around the globe and is a continual threat to UK agriculture by the import of contaminated animal products. Vaccines are available, but presently they are only used in emergency situations. The 2001 UK outbreak caused massive economic damage (billions of pounds), as the method of stopping disease spreading was mass animal slaughter: infected or not. Millions of healthy animals were destroyed.The present vaccine is expesive to produce and since it only induces a protective immune response for relatively short periods, animals need to be vaccinated - and re-vaccinated - throughout their lives. Routine, repeated, vaccination is expensive. The primary method of FMDV control in Europe is mass-slaugter of both infected and surrounding sucesptible (healthy!) animals: this policy is socially and politically unacceptible in India.The security of food supply in the future is a major issue. As the Indian economy develops, the demand for meat products will inexorably rise. Prices of animal products imported into the UK and animal feedstuffs will rise. To meet this increasing demand agricultural productivity must rise around the world, especially in countries with high population densities like the UK. Productivity can be increased by creating very large facilities, housing thousands of animals: a method shown to be effective in the US. The intensification of large-animal production creates opportunities of viruses such as FMDV to cause devastating economic damage. Increased international travel and trade means that this cannot be a problem the UK can solve in isolation: viruses move across national boundaries. With regards FMDV, the UK has adopted a 'vaccinate-to-live' policy. We argue this must be coupled with the development of new vaccines, or new methods of producing vaccines, to make this policy effective. This is the purpose of our research.FMDV is the same type of virus as polio. There are two types of vaccine available for polio: live, 'attenuated', vaccines use virus strains that do cause an infection (and raise a life-long protective immune response), but do not cause paralytic poliomyelitis: the 'Sabin' vaccine. The second type is 'killed'. Here, poliovirus (which could cause poliomyelitis) is grown in cells in large quantities, then chemically inactivated so that it cannot grow at all - but the dead particles do raise a protective immune response: the 'Salk' vaccine. It is the latter type of 'killed' vaccine that is used to control FMDV. This means huge amounts of virus have to be grown (virus which can cause disease) in the production process. Inevitably, escapes of virus can occur from facilities and cause an outbreak in the surrounding completely sucestible animals - thought to have occurred in the UK 2007 FMDV outbreak.The program of research we propose is to produce new live, attenuated,vaccines to bring about a transformation in FMDV disease control. Our strategy is to use modern molecular biology to change the virus, to make new strains that can protect animals without causing the debilitating disease - live, attenuated viruses, just like polio: much cheaper and safe to produce.