Epidemiological and evolutionary investigations of pandemic H1N1 influenza virus in pigs and associated occupational risks

40多年来的第一次人类流感大流行正在进行中，致病病毒是由两种不同的猪流感病毒结合而产生的，一种来自美国，另一种来自欧洲。分析表明，这两种祖病毒可能在猪中传播了约9年而未被检测到。流感病毒相互联合收割机以产生新病毒的能力以及快速突变的能力是它们在新的哺乳动物物种（包括人类）中突变和传播的能力的重要特征。猪比大多数其他动物更容易感染流感病毒，这使得它们成为可能发生这种病毒混合的重要动物。猪流感感染在欧洲的猪中很常见，至少每年在许多农场传播。VLA的实验研究表明，猪可以感染人类大流行病毒，重要的是，可以将病毒传播给与它们共同饲养的其他猪。由人类大流行病毒引起的猪流感在至少三个国家爆发，可能是养猪户将病毒传染给猪后感染的。在英国，一些猪群被大量密集地饲养，如果这些农场感染了大流行性流感病毒，就会产生大量的病毒，给饲养猪的农民带来不可预测的后果。人类大流行性病毒的起源来自猪流感病毒，猪对大流行性病毒的易感性以及世界各地养猪场的感染，在其潜在的“混合容器”作用的背景下，对人类和猪的健康提出了几个直接和重要的问题和挑战。这项赠款，沿着平行的实验性赠款申请，旨在回答其中一些问题，并在这样做的过程中，提供一个直接的科学证据基础，为旨在最大限度地减少大流行病对人类和动物的影响的政策提供信息。我们将确定大流行性病毒传播给猪的后果，考虑到个体临床疾病，包括导致疾病体征的宿主或“患者”机制，以及在群体水平上的传播。这些研究将考虑到一些猪可能通过先前的“正常”猪流感感染而自然地部分免疫。我们将利用这项工作来估计猪感染大流行病毒对公共卫生可能构成的挑战。我们的详细调查将包括对存档的猪流感疫情的遗传研究，对英国猪中发生的任何猪流感疫情的临床和病毒学研究，以及通过职业暴露于这些疫情的养猪户的健康。我们将大量增加关于猪流感的可用数据，以便我们能够正确估计这种感染造成的未来风险。通过分析欧洲疫情的数据和样本，以及对猪和与猪接触的农场工人的疫情进行仔细调查，我们将更好地解释大流行病毒是如何产生和传播的，包括最初的病毒组合发生在哪里，以便预测类似事件再次发生的可能性，并提出将持续风险降至最低的建议。通过分析来自猪疫情的样本和平行实验拨款中进行的传播研究，我们将研究病毒突变率，并确定与猪和与猪一起工作的人之间传播相关的流感病毒的特定突变，以便更好地预测大流行病毒突变的直接威胁，从而在人和猪中变得更具毒性，特别是如果人类大流行性病毒在猪群中流行。

The first human influenza pandemic in more than 40 years is ongoing, with the causative virus having arisen from the combination of two different swine influenza viruses, one originating in the USA and the other in Europe. Analyses have demonstrated that the two progenitor viruses were circulating undetected, probably in pigs, for around 9 years. The ability of influenza viruses to both combine with each other to produce new viruses and also to mutate rapidly are important features in their ability to mutate and transmit in novel mammalian species, including humans. Pigs are susceptible to a larger range of influenza viruses than most other animals and this makes them of importance as animals in which such viral mixing can happen. Swine flu infection is common in pigs in Europe and circulates through many farms on at least an annual basis. Experimental studies at VLA have demonstrated that pigs can be infected with the pandemic human virus and, importantly, can spread the virus to other pigs that they are co-housed with. Outbreaks of swine flu in pigs, caused by the human pandemic virus, have occurred in at least three countries, probably following infection of pig farmers who have transmitted the virus to pigs. In Britain, some pigs are farmed in large, very dense populations and, should these farms become infected with the pandemic flu virus, large amounts of virus would be produced with unpredictable consequences for the farmers caring for the pigs. The origin of the human pandemic virus from swine flu viruses, the susceptibility of pigs to the pandemic virus and the infection of pig farms around the world, against the background of their potential 'mixing vessel' role, raises several immediate and important questions and challenges for both human and swine health. This grant, along with the parallel experimental grant application, aims to answer some of them and, in doing so, to provide an immediate scientific evidence base to inform policies aimed at minimising the impact of the pandemic in both humans and animals. We will define the consequences of spread of the pandemic virus to pigs, considering the individual clinical disease, including the host or 'patient' mechanisms that result in disease signs, and the transmission at the population level. These studies will take into account that some pigs may be naturally partially immune through prior 'normal' swine flu infection. We will use this work to estimate the likely challenge posed to public health by pig infection with the pandemic virus. Our detailed investigations will include genetic studies of archived swine influenza outbreaks, clinical and virological studies of any swine flu outbreaks that occur in British pigs and the health of pig farmers who are exposed through their occupation to these outbreaks. We will substantially add to the amount of data available on swine influenza so we can properly estimate how much future risk is posed by this infection. Analysing data and samples from outbreaks in Europe and careful investigations of outbreaks in pigs and farm workers in contact with them, we will explain better how the pandemic virus arose and spread, including where the initial virus combination took place, so that the likelihood of similar events reoccurring can be predicted and recommendations for minimising the ongoing risk can be made. Using analysis of samples from pig outbreaks and transmission studies undertaken in the parallel experimental grant, we will study the rates of viral mutation and identify the specific mutations in influenza viruses that are associated with spread between pigs and people working with pigs in order to predict better the immediate threats from the pandemic virus mutating to become more virulent in people and pigs, particularly if the human pandemic virus becomes endemic in the pig population.