Combating Swine Influenza Initiative (model project)

The first human influenza pandemic in more than 30 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 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 Great 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 population 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 presentation, including the host or 'patient' mechanisms that result in disease signs, and the transmission of the virus. 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 swine influenza, immunological and virological studies of infection of pigs with the 'normal' swine and pandemic strains of the virus. We will study the level of transmission of the virus from pig to pig and investigate the clinical impact of the disease. This project will substantially add to the amount of data available on swine influenza so that we can properly estimate how much future risk is posed by this infection. Through comparing data from the pig studies and that derived from human cases occurring as the pandemic virus spreads we will be able to evaluate the pig as an animal model for suitability to studying pandemic influenza consequences for humans. The data generated from this grant will be used to 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. This will enable us to better predict 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.

Through a multi-factorial design we will address multi-variant parameters as a consequence of infection of pigs with pandemic [H1N1] 2009 (H1N1v), which will enable significant added value data generation. In this proposal we seek to provide a detailed understanding of the consequences of infection in pigs in both naïve and immune (to endemic strains of swine influenza virus) populations. We will define the intrahost infection dynamics, transmission properties (including at different time points of infection), virus evolution, immune correlates of infection, and relate infection susceptibility to immune protection. Additionally, we will enhance our understanding of the relative pathogenicity and resistance between pigs and humans together with how H1N1v may evolve in pigs and relate this to viral evolution in humans. The studies will be done in 10-12 week old pigs so that data directly applicable to risk periods for field infection and of direct relevance to key age groups of greatest susceptibility in humans. A series of experimental infections will provide a wide range of specimens to study virology, pathology, infection dynamics and transmission. In addition, host-pathogen relationships will be determined and characterized by studying transcriptomics and proteomics of the disease process to determine the host transcriptional response to infection with H1N1v. Detailed determination of all key aspects of innate and acquired immunity in both naïve and prior immune pigs will be made. Infection consequence in pigs relative to virus genomics will be determined to define the viral genetic variability and host selection in pigs during the infection course which in turn may provide direct insights to mechanisms and processes relevant to pandemic influenza in humans.

The current human pandemic caused by pandemic (H1N1) 2009 virus (H1N1v) poses obvious and immediate threats to public and animal health. The results generated from this initiative will directly address questions of importance for human health and will indirectly benefit groups dealing with the pandemic threat. The project will answer questions relating to the spread of H1N1v between pigs and from pigs to humans by quantifying the transmission of the virus. This will be strengthened by immediate analyses and investigation of natural spread to pigs with H1N1v and implications for people working in the pig industry. Understanding pig infection may enable direct comparisons to be made with humans that could be utilised by policy advisors in the field of human health and infection control. Also, it may be possible to identify potential virulence or transmission enhancing mutations, thereby providing data to risk analysts in developing counter measures should these variants become established in either pig or human populations, thereby directing intervention focus where it may have the greatest overall impact. The project will also address concerns of virus reassortment in pigs and inform animal and public health scientists, who will use this information to help prevent future pandemics caused by new variants of swine influenza; this will help to reduce the impact and severity to both public health and the UK economy. The work of this project will also allow scientists to assess the comparative value of the pig as a model for human H1N1v cases in predicting disease severity and treatment development and may further validate the pig model for the development of human influenza vaccines. The studies will determine whether infection with endemic H1N1 influenza virus provides cross-protection against H1N1v in pigs. The data generated and knowledge gained from this study will be invaluable for planning for mitigating the effects of spread of H1N1v virus to pig populations and thereby reducing public health risk from reverse zoonoses. This project will inform the pig industry, including farmers, abattoirs, veterinarians and associated workers about risk factors for spread of swine influenza, including H1N1v. Should infection with H1N1v become established in pigs, the epidemiological modelling data will assist with the control of the spread of disease within the UK pig population, including management of its occupational health implications. The information will provide a strong scientific evidence base for European and global policy for dealing with swine influenza and will be communicated directly or via government organisations such as Defra. It will help the industry to control outbreaks within their community and reduce their impact, in turn facilitating protection of important trade markets through effective knowledge of disease status of the national herd. The project should indirectly affect the UK economic competiveness by generating information to assist decision making on pandemics in both humans and pigs, particularly in relation to targeting surveillance systems for detecting and controlling outbreaks and initiating any appropriate future vaccination programmes. The consequences of a severe outbreak in both pigs and humans has far reaching repercussions for the UK economy, including loss of confidence in the UK pig consumer market and loss of business in the agricultural sector. Outbreaks put a huge strain on the Health Sector and costs companies millions in downtime. The consortium has developed a plan for disseminating the results of the project. Government agency involvement facilitates direct communication between the consortium and the policy makers. Communication of the outputs to the scientific community will be by timely peer reviewed publication. Results will also be presented at scientific meetings and conferences.