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，致病病毒由两种不同的猪流感病毒组合而成，一种起源于美国，另一种起源于欧洲。分析表明，这两种祖病毒在未被发现的情况下，可能在猪中传播了大约9年。流感病毒相互结合产生新病毒和迅速变异的能力，是它们在包括人类在内的新型哺乳动物物种中变异和传播能力的重要特征。与大多数其他动物相比，猪对流感病毒的易感范围更大，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群中很常见，每年至少在许多农场传播一次。VLA的实验研究表明，猪可以感染大流行性人类病毒，而且重要的是，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猪中爆发，至少在三个国家发生，可能是在猪农将病毒传染给猪之后发生的。在英国，一些猪被大量密集地饲养，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，对养猪的农民造成不可预测的后果。人类大流行病毒来自猪流感病毒，猪对大流行病毒的易感性以及世界各地养猪场的感染，在它们潜在的“混合容器”角色的背景下，对人类和猪的健康提出了几个紧迫而重要的问题和挑战。这笔赠款以及平行的实验赠款申请旨在回答其中的一些问题，并在此过程中提供一个即时的科学证据基础，为旨在尽量减少大流行对人类和动物的影响的政策提供信息。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，以及群体层面的传播，我们将定义大流行病毒在猪群中传播的后果。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可能对公共卫生构成的挑战。我们的详细调查将包括对存档的猪流感爆发的基因研究，对发生在英国猪身上的任何猪流感爆发的临床和病毒学研究，以及通过他们的职业暴露于这些爆发的养猪户的健康。我们将大大增加关于猪流感的可用数据量，以便我们能够适当地估计这种感染在未来会造成多大的风险。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。通过对来自猪暴发和传播研究的样本进行分析，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性病毒突变对人和猪的毒性更大的直接威胁，特别是如果人类大流行性病毒在猪群中成为流行病。

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.