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.