US-UK BBSRC-NIFA Collab. Swine Immune Toolkit: Development of new immune reagents for swine health, vaccine and disease studies

Pigs are widely reared as food animals in the UK and the US and contribute significantly to both economies. In addition, they are increasingly important in south-east asian economies. However, infectious disease is still a major problem for pig producers: best estimates suggest that the annual costs of swine influenza alone might be between £6-11M from an estimated 10 million pigs to slaughter in the UK alone. Vaccination is a key element in controlling infectious diseases, but relatively few of the vaccines available for pigs provide solid, long-lasting protection for the whole of the vaccinated population. In addition, many of the most important infectious diseases have evolved ways of avoiding normal immunity. Increasingly, therefore, understanding the fundamental mechanisms involved in the immune response to natural infection and to vaccination is becoming important for designing successful vaccines with long commercial lifespans. Similarly, pigs are widely used in biomedical research on human diseases, since they are very close to humans in physiology, size, genetics and immunity. Areas in which pigs are used in research include obesity, heart disease, and infectious diseases.

Despite their importance, and despite work over 35 years on developing the tools and reagents to study the pig immune system, we are still a long way behind research in humans and mice, such that we are unable to study some of the newly identified ways in which the immune system works. In some cases this has been because reagents have not been developed, but in some cases the reagents which have been developed have been lost through exclusive commercial agreements or because they were held in a single site and vulnerable to accidents. We propose to identify the gaps in the available reagents and to fill the most important. This will be achieved by canvassing scientists working with pigs worldwide, a process which we have already begun and which has provided us with an initial list of priority targets. The project will develop and validate these reagents and others identified, and share and commercialise them under non-exclusive agreements in order to ensure their continued availability.

Pigs are a major food animal species for the US, UK and the world. Losses caused by infectious disease demonstrate the need for effective vaccines, biotherapeutics and nutritional interventions, particularly those relevant to mucosal infections. The pig is also an important biomedical model for development, obesity, cardiovascular, transplantation, and vaccine research. Current research efforts require a broad range of immune reagents, but those available for pigs are limited. Our goal is to generate these priority reagents and pipeline them for marketing. The project team will prioritize research targets based on international input from researchers. Newly identified immune pathways, updated listing of commercially available reagents, and open communication with peers will determine targets and avoid duplication . Based on our combined research expertise, and the experience gained from the US VIRN, the team has identified best immunization and screening strategies, developed plans to collaborate with commercial partners for protein expression and monoclonal antibody (mAb) production, and updated protocols to efficiently evaluate specificity and utility of reagents.

The UK partner will focus on chemokines and chemokine receptors important in site-specific recruitment of lymphocytes and macrophages to tissues including intestine, respiratory tract and skin, all critical for understanding mucosal immune responses to infections; and immunoglobulin E (IgE) involved in responses to endo- and ecto-parasites and critical for studies of allergic disease. UK studies will be complemented by US expertise in expression of soluble proteins and CD molecules, and by the chemokine proteins and monoclonal antibodies produced in the US. In addition, the UK partner will contribute expertise in multi-colour immunofluorescence histology to screening and validating US-made proteins and antibodies.

Human health and the economy will benefit from the work in this proposal in three ways.

Firstly, the secure, long-term availability of critical immunological reagents will contribute to development of novel and improved vaccines, or to improved vaccination strategies using existing products. In 2011, UK consumption of pigmeat was comparable to that of beef or poultry. However, more than 50% of UK consumption was imported, compared to only 18% and 25% for beef and poultry (source: Defra). The UK's reliance on imported rather than homegrown pigmeat reflects the relative costs of production of the local industry: the UK is amongst the highest for which European figures are available, our costs have risen disproportionately compared to our competitors from 2011 to 2012 (source: BPEX) and UK feed costs per kg of pork produced are among the highest (source: Defra). Thus, increasing the productivity of UK pig production relative to production costs has significant potential to improve the profitability of the UK pig industry, and this industry also has the greatest potential of all the livestock industries for expansion as a consequence of increased international competitiveness. The major factors which are correlated with variation in farm performance are piglet mortality and the amount of food required to grow (food conversion ratio, FCR), at all stages from birth through to slaughter (source: BPEX). While many factors contribute to these outcomes, acute and chronic infectious diseases affecting the health of growing and finishing piglets are a key determinant. Best estimates (2005) suggested that the annual costs of swine influenza alone might be between £6-11M from an estimated 10 million pigs to slaughter. Vaccination is a key element in controlling infectious diseases, but relatively few of the vaccines available for pigs provide solid, long-lasting protection for the whole of the vaccinated population. Most rely on reducing, rather than eliminating, infection and onward transmission rates, such that loss of productivity due to disease outbreaks still occurs. Because of these limitations vaccination is often considered not cost-effective. Thus, increasing the rates of protection afforded by novel vaccines and vaccination protocols offers a way of improving the efficiency of the UK pig industry and its contribution to the economy.

Secondly, pigs are one significant sources of human zoonotic diseases, such as salmonellosis (between 4.5% and 23% of human salmonellosis worldwide have been attributed to pork), influenza (the 2009 pandemic H1N1 influenza A), toxoplasma (7-34% of the UK population are likely to have been infected, about 400 clinical cases diagnosed in the UK annually), Campylobacter (65,000 reported cases in England and Wales, 2012). While other livestock and companion animal species are also reservoirs, controlling these diseases in the pig population will contribute directly to human health. While the development of vaccines in pigs for these diseases may be some way away, it will absolutely require an understanding of the immune responses to natural infection and vaccination.

Thirdly, biomedical research using pigs is largely at the preclinical, translational end of the spectrum, meaning that the approaches being studied are likely to be close to being applied to the human population. This is particularly true where studies involve surgical approaches such as vascular or airway transplantation, and the pig is being used as a way of validating novel approaches immediately prior to their use in humans.