Epidemiological and evolutionary investigations of pandemic H1N1 influenza virus in pigs and associated occupational risks

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

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.

Technical Summary

This programme of work considers the origin, impact and consequences of pandemic (H1N1) 2009 virus (H1N1v) spreading in pigs. It will run closely with the interlinking model programme. Specific objectives include: 1) longitudinal investigations of outbreaks of respiratory disease in pigs caused by H1N1v to quantify its detailed within farm dynamics 2) investigation of the health of pig farm and related workers in contact with pigs naturally infected with H1N1v 3) whole genome sequencing of swine influenza viruses from a) archived European swine flu samples available in archives (c250 viruses); b) pig outbreaks caused by H1N1v and occupationally exposed pig workers and then conducting detailed phylogenetic analyses of all sequence data available to understand the emergence of the human pandemic influenza virus, including how swine viruses have been trafficked internationally, host specific adaptations and how these are affected by cross-species transmission events 4) 'deep amplicon' sequencing of viruses from H1N1v infected pigs and humans in contact with infected pigs, to compare rates of viral mutation with H1N1v with those with endemic H1N1 when the viruses are transmitting in pigs. Samples will be derived from experimental transmission studies (from our previous studies for endemic viruses), any outbreaks of H1N1v in pigs and endemic swine flu. These objectives also include identification of any specific viral changes when H1N1v transmits directly between people and pigs 5) quantification of the dynamics of H1N1v virus infection and host responses, synthesising available and new data into mathematical models at the within host level and the British pig herd level, to provide insight into the pathogenesis and transmission of the virus and to estimate the likelihood that H1N1v could become endemic in pigs, helping to target surveillance and quantify risks to pig farmers should novel pig viruses arise.

Planned Impact

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 made with humans which 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.

Publications

10 25 50
 
Description Outbreaks of pH1N1 infection were identified in pigs in most months investigated. These outbreaks outnumbered those caused by the two endemic strains (avian-like H1N1 and H1N2). The severity of clinical signs in pigs due to pH1N1 infection was highly variable and subclinical infections common. Clinical signs did not distinguish pH1N1 from endemic strains. In housed pigs, infection was detected in a single group of pigs for two weeks and spread of infection between two groups occurred within 12
Exploitation Route The work is of direct relevance to the national and international swine industry - and to public health authorities, in particular in consideration of mitigating the transmission of swine influenza viruses between pigs and pig farms - and also in consideration of how to mitigate risks of occupational exposure - and perhaps more importantly of spread of swine derived viruses through occupationally exposed cohorts, The work is being taken forward with a number of different scientific approaches, i
Sectors Agriculture/ Food and Drink

 
Description Ongoing advice to various government bodies and WHO
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description Capacity and Capability Challenge (CCC) Programme grant 
Amount £25,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2011 
End 05/2011
 
Description FLUPIG: FP7 258084
Amount £405,200 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 07/2010 
End 12/2014
 
Description FP7- ANTIGONE
Amount £333,367 (GBP)
Funding ID 278976 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 11/2011 
End 10/2016
 
Description NADIR- transnational access component for swine influenza
Amount £100,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2009 
End 12/2013
 
Description Understanding influenza A virus: linking transmission, evolutionary dynamics, pathogenesis and immunity in pigs
Amount £44,449,823 (GBP)
Funding ID BB/L001330/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2014 
End 03/2019
 
Title Peptide binding motifs 
Description Peptide binding motifs have been determined for the MHC-1 molecules expressed by the in bred pigs owned by IAH. Tetramers are under development to analyse the influenza specific CD8 T cell responses using these reagents. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This work is now being taken forward in the BBSRC sLOLA on swine influenza at the BBSRC Pirbright Institute 
 
Title Plasmids encoding whole influenza virus 
Description This material enables the elucidation of the viral proteins associated with the immune response 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact This material will enable further dissection of the immune basis for cross influenza subtype protection and examination of the genetic correlates of infection 
 
Title Use of Pigs as a Model of Human Influenza 
Description This work has gone some way towards validating the use of pigs in research as invaluable and natural models of influenza in humans 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact BBSRC funded an sLOLA on swine influenza dynamics at the Pirbright Institute - and the model is being actively followed up in that programme 
 
Title Peptide binding motifs 
Description Peptide binding motifs have been determined for the MHC-1 molecules expressed by the in bred pigs owned by IAH. Tetramers are under development to analyse the influenza specific CD8 T cell responses using these reagents. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact This work is now directly feeding into the BBSRC sLOLA on swine flu dynamics 
 
Title Influenza Virus Sequence Data 
Description Full genome viral sequence data has been made publicly available 
IP Reference  
Protection Protection not required
Year Protection Granted 2009
Licensed No
Impact substantial numbers of papers are being drafted on the basis of this work
 
Description Dissemination of findings from the outbreak investigations in pigs- NPA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Presentation at National Pig Association Meeting

As part or larger programme of engagement, significantly contributed to engagement with specialist veterinary profession and aided ongoing research studies and national disease surveillance
Year(s) Of Engagement Activity 2010
 
Description Dissemination of findings from the outbreak investigations in pigs-PVS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Presentation at Pig Veterinary Society Meeting

As part or larger programme of engagement, significantly contributed to engagement with specialist veterinary profession and aided ongoing research studies and national disease surveillance
Year(s) Of Engagement Activity 2010
 
Description Dissemination of findings from the outbreak investigations in pigs-regional 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Presentation at Regional veterinary, pig producer and pig company meetings

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
URL http://www.aiai.ed.ac.uk/project/bayesevidence
 
Description Press release organised by the funders 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact The results of the various funding programmes were summarised for a lay audience

None obvious
Year(s) Of Engagement Activity 2009
 
Description UK National Farmers Union Health Committee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Presentation to UK National Farmers Union Health Committee

Part of an ongoing programme of dissemination of reserach and results to interested stakeholders.
Year(s) Of Engagement Activity 2010,2011