Understanding influenza A virus: linking transmission, evolutionary dynamics, pathogenesis and immunity in pigs

Swine influenza attracts considerable attention because of the threat of zoonotic infections causing human pandemics. During the pandemic, a fear that viruses emerging from pigs may infect people resulted in the widespread destruction of animals in some countries and trade bans. Consequently, the insidious effects of this highly prevalent virus on the health and welfare of pig populations, estimated to increase the cost of production by £7 per finished pig, have not been given due regard. The primary disease caused by influenza virus in usually mild, but results in greater susceptibility to secondary infections. Vaccination will be a key control measure for influenza in pigs to improve general herd health.
Through our studies we will develop a more detailed understanding of the dynamics of virus transmission and the consequences of transmission and vaccination in driving viral evolution. During these studies we will also define a range of parameters, for example local and systemic immune responses and sites of virus replication, which are associated with the onset and cessation of transmission. We need to know if current and proposed novel vaccines not only prevent clinical signs but also stop viruses being transmitted unnoticed. Furthermore, if viruses can be transmitted unnoticed are they changing because of the immune response in the population? To answer these questions we need to understand virus transmission in detail and how the viruses change when they pass between animals. We can then apply this new knowledge to population wide models of disease spread to predict the efficiency of any proposed control measures. This knowledge will also inform the design of novel vaccines.
Vaccination against influenza in pigs is not routinely performed in Europe mainly for two reasons: the cost benefit of vaccination has not been clearly demonstrated and it is not clear that the available vaccines will protect against the strains currently circulating in the pig population. The most striking example of the latter is that current vaccines do not include pandemic H1N1 influenza virus antigen.
These studies will provide essential evidence to design control programmes for influenza in pigs, most notably: i) finding out how efficient are the current prophylactic methods at controlling the spread of infection; ii) what level of immunity is required in a population to prevent the spread of infection and the evolution of new strains of virus and iii) determine whether new, broadly cross protective vaccines are more effective at controlling influenza infections in swine to enhance animal health and livestock production.
Importantly, this type of information is not available for any natural mammalian hosts of influenza viruses, including humans and horses. Therefore, the results of our studies will have a broad impact on influenza control measures.

In this programme of work we will describe and define in detail pig to pig transmission parameters for influenza virus.
We have recently performed a unique series of transmission experiments of an acute viral infection in a natural host species, foot-and-mouth disease virus in cattle. These studies quantified the link between clinical signs and viral shedding and concluded that the infectious period was much briefer than hitherto supposed and demonstrated pathogen detection alone does not correlate with transmissibility. This type of quantitative knowledge is critical for developing efficient, targeted control strategies. Consequently, we will perform a series of one-to-one challenge studies to define transmission parameters for influenza of pigs. Intra- and inter- herd transmission models will be developed based on data obtained from these experiments.
Furthermore, virological, clinicopathological and immunological correlates of transmission will be identified by their relationship to the onset, duration and cessation of infectiousness using standard statistical approaches (logistic regression). Non-metric, multi-dimensional scaling will be used to visualise the temporal dynamics of these relationships. The evolutionary dynamics of influenza will be analysed during a series of transmission chains in naïve and vaccinated animals. Within-host mathematical modelling will be used to estimate the size of any bottlenecks and determine whether selection plays a role in the size and composition of the viral population during and following transmission.
A major strategic goal of this programme is to understand whether current vaccines and novel broadly cross reactive vaccines can block influenza transmission. We will determine the capacity of these vaccines to induce responses that correlates with protection and result in prevention of transmission post challenge.

Mammalian animal health is a key component in safeguarding food security, and livestock viral diseases have very significant direct and indirect impacts. Viruses endemic to the UK, such as swine influenza virus are ubiquitous, causing both disease and welfare problems. Importantly, new or more harmful forms of swine influenza emerge due to viral mutation or cross-species transmissions and can be important causes of zoonoses, for example, H1N1. In addition to progressing our understanding of influenza virus infection, the programme will develop expertise in livestock immunology and pathogenesis to enable swift transfer and application of core skills to address newly emerging viral diseases.
We will provide to Defra advice on national control measures. This research contributes to animal health and welfare and a sustainable UK farming and food sector, specifically addressing Defra's goals to year 2014 on (i) "the maintenance of a disease status amongst the highest in the world, so that we are able to trade our animals and animal products internationally"; and (ii) "to have dealt with all disease emergencies swiftly and effectively using an agreed approach".
There is growing interest from the animal health pharmaceutical industries to develop more effective broadly cross protective influenza vaccines that do not require frequent updating. Industry have been closely involved in the development of the programme of work and will have ongoing involvement to ensure we remain focussed on achieving this strategic goal.
Surveillance and research activities supported by the European Commission (DG Sanco and DG Research) have broadly similar aims to Defra's goals. Other international disease control agencies such as FAO and OIE will also benefit from this research.
This programme will act as a catalyst to develop a national capability to understand disease transmission in livestock. The UK academic community requires access to a comprehensive range of linked facilities to study livestock diseases; spanning high and low containment animal units and laboratories, specialist immunologists and virologists and high throughput sequencing facilities with associated bioinformaticians, statisticians and modellers. The legacy of this programme will the establishment of collaborative team that spans all of these disciplines with access to appropriate state of the art facilities.