Broadly protective vaccines for porcine reproductive and respiratory syndrome and swine influenza virus infections

Lead Research Organisation: The Pirbright Institute
Department Name: Mucosal Immunology

Abstract

Pig production is the fastest growing livestock sector across Southeast Asia and intensification of pig production has led to an increase in diseases, including respiratory diseases, which are a major cause of economic losses in the pig industry worldwide. Two viruses, porcine reproductive and respiratory syndrome virus and swine influenza virus, are major contributors to respiratory disease in pigs. Prevention of infection with the two viruses would significantly improve the welfare of pigs in Thailand and minimise economic losses due to respiratory disease. To do this, we will collaborate with Thai scientists to test innovative new vaccines against these two viruses, which will prevent infection and disease.

Because there are many strains of both viruses, the vaccines need to be tailored to the virus strains that circulate in Thailand. Our Thai partners have used their detailed knowledge of these strains and sophisticated molecular biology methods to make vaccine candidates that have the best chance of protecting against the diversity of local viruses.

The candidate vaccines will be tested in the UK to determine whether they stimulate a powerful immune response. Thai scientists will come to the UK to learn these immunological methods. The candidate vaccines that stimulate the most powerful immune response will then be tested in Thailand to see if they can protect pigs against infection with the viruses both under laboratory conditions and in the field.

We wish to understand why these two viruses predispose pigs to severe respiratory disease. To study this question, pigs will be infected with each virus separately or together and the immune responses to each virus will be analysed in detail to learn how the immune response is altered leading to exacerbated disease.

The project will develop broadly-protective vaccines tailored to Thai virus strains and will transfer expertise in immunology and vaccinology to Thai scientists to facilitate the implementation of vaccine programmes for porcine reproductive and respiratory syndrome and swine influenza viruses in Thailand. These technologies can then be adapted to other pathogens and livestock species.

Planned Impact

The porcine respiratory disease complex (PRDC) is a major cause of economic losses to the nascent pig industry and poor livestock keepers in Thailand and the wider Southeast Asian region. The porcine reproductive and respiratory syndrome (PRRS) and swine influenza A (SI) viruses that are endemic in Thailand are the two main viral contributors to the PRDC, alone or in combination, together with opportunistic bacterial pathogens. Effective control strategies for PRRS and SI viruses would therefore be of great benefit to the developing Thai pig industry.

Animal health and welfare:
Key aims of this proposal are: first, to develop and test novel PRRS and SI vaccines that are based on virus strains currently circulating in Thailand; second, to determine the effect of PRRS/SI co-infection on the immune response; and third, to transfer expertise in immunological methods for assessing vaccine immunogenicity and in vivo challenge models for testing protective efficacy, from the UK to Thailand.
The principal beneficiary will be the pig farming industry and livestock keepers in Thailand. Effective vaccination against PRRS and SI will improve both productivity and animal welfare. In addition to reducing the costs directly associated with these diseases, there will be additional benefits from reduced secondary infections. Beyond this, we will transfer to Thailand immunological expertise in immunisation and challenge studies that are essential for developing and implementing successful vaccine strategies. This expertise will be invaluable in developing immunisation programmes for further infectious diseases of pigs and other livestock species. The close relationships of Thai scientists with the local biotech industry and government bodies will allow them to fast track the new vaccines into field use.

General public:
Effective immunisation strategies for PRRS and SI will result in increased productivity in the pig industry, protect the livelihoods of smallholders, and lower costs for the consumer. The zoonotic threat posed by swine influenza viruses will also be reduced.

Food security and environment:
Improved PRRS/SI control will reduce antibiotic treatment for secondary bacterial infections, the risk of contamination of the food chain and the environment, as well as the risk of antibiotic resistance. Broadly protective PRRS vaccines will alleviate the threat that the re-emergence of highly pathogenic strains pose to regional food security.

Benefits to policy makers; Benefits to the commercial private sector:
The transfer of expertise in the development and evaluation of vaccines will provide new options for improving animal health, welfare and productivity in the developing Thai pig industry. Production of novel vaccines based on circulating Thai virus strains will be a highly attractive commercial opportunity for the local animal health industry.

Skills, knowledge and training:
A major objective of the proposal is to transfer expertise in pig immunology and in vivo challenge studies to Thailand. The results will indicate if the consensus sequence strategy for PRRS and the non-structural (NS) gene codon de-optimised strategy based on local SI strains, will generate effective broadly-protective vaccines that could be implemented in the field.

International development:
Development of effective vaccine strategies for PRRS and SI in Thailand will lead to improved animal health and welfare and improved productivity in Thailand and the wider Southeast Asian region. It will reduce the zoonotic threat of new influenza strains that may originate in this area through close contact of birds, pigs and humans.
 
Description Established the optimal conditions for co-infection with Thai PRRS and Swine influenza (SI) viruses, provided by our Thai collaborators.
We have performed a pilot experiment with three groups of animals (singly infected with SI, PRRSV and co-infected) to determine the optimal dose of challenge virus and duration of infection to allow us to detect differences in vial load and immune responses. We showed that co-infection increased immune responses to influenza virus and that both PRRS and SI viral loads were lower in co-infected animals.

Our Thai collaborators have developed a live attenuated influenza virus vaccine encoding a truncated NS1 protein and a single cycle vaccine based on inactivated haemagglutinin. These to be tested for immunogenicity and protective efficacy in pigs

We have shown that co-infection with PRRS and FLU abolishes the protective effect of PRRS vaccination on disease severity and pathology. The antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and Flu virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and Flu in the lung. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identify more effective vaccination strategies against PRDC in the field.

We also examined the changes in the composition of the nasal microbiota of pigs following experimental infection with
PRRSV, SI or both viruses. PRRSV and SI, alone or in combination differentially altered the abundance and distribution of bacterial families. Single and co-infection with PRRS or SI was associated with the expansion of the Neisseriaceae family. A positive correlation between SI viral load and the relative abundance of the Neisseriaceae was observed. However, further mechanistic studies are required to understand the significance of the changes in specific bacterial families following these viral infections.

We investigated immune responses following simultaneous co-infection of pigs with swIAV H3N2 and PRRSV-2. Our results indicate that clinical disease was not significantly exacerbated. In coinfected animals lung H3N2 viral load was reduced and H3N2 specific IgG serum titers and H3N2 specific IFNg CD8b responses enhanced. PRRSV-2-specific CD8ß T cells were also increased in blood after co-infection. PRRSV-2/H3N2 co-infection did not alter gene expression in whole blood at 6 days post infection. Our findings provide evidence that systemic and local host immune responses are not negatively affected by simultaneous H3N2/PRRSV-2 coinfection.
Exploitation Route Research from this award will enable the policy makers to make inform decisions to implement control measures to reduce the impact of PRRS and Influenza in pigs both animals and humans. • More effective vaccines produced through this project will reduce virus circulation in environment leading to reduction of zoonotic transmission to humans. • Enhanced collaboration and co-production through this project is enhancing the science-based in the UK and Thailand

As a results of our collaboration our Thai partners renovated and upgraded their animal facility in Chiang Mai University to accommodate and perform animals experiments requiring containment.

We have also trained them how to carry out the animals experiment, sampling and postmortems.

Our Thai collaborators visited our laboratories and learned how to analyse immune responses by ELISPOT, ELISA and ICS. We communicate at least once every two months by SKYPE with written minutes from the meetings

Without this collaboration the Thai partners would have not been unable to properly assess immunogenicity and efficacy of their vaccine candidates.
Sectors Agriculture

Food and Drink

Healthcare

Manufacturing

including Industrial Biotechology

 
Description Deputy Chair of BBSRC grant Committee A
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact As chair of the committee I influence the decision on grant funding which have effect on animal and human health and food security
 
Description Member of the British Society for Immunology Forum
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact The BSI is very active in lobbying MPs and Government on subjects to do with clinical immunology and immunisations.
URL https://www.immunology.org/
 
Description EU VetBioNet Transnational Access Fund: Evaluation of the immunogenicity of a bivalent PRRS-Nipah virus vaccine
Amount £61,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2021 
End 07/2021
 
Description Market research and technical feasibility of a bivalent porcine reproductive and respiratory syndrome / Nipah virus vaccine
Amount £10,880 (GBP)
Organisation The Pirbright Institute 
Sector Academic/University
Country United Kingdom
Start 06/2019 
End 03/2020
 
Title Scintigraphy of the respiratory tract in pigs 
Description We have used in vivo scintigraphy in pigs to characterize the distribution of large and small droplets, delivered to the respiratory tract using nebulisers or a mucosal atomisation device. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2020 
Provided To Others? Yes  
Impact Scintigraphy and the tools we have developed to analyse the specificity and function of tissue resident memory cells will allow the effects of localised distribution of antigen in the respiratory tract to be studied and established the pig as a useful model for investigating optimal targeting of vaccines for respiratory disease. 
 
Description Evaluation of a PRRSV-vectored Nipah virus vaccine 
Organisation National Center for Genetic Engineering and Biotechnology (BIOTEC)
Country Thailand 
Sector Public 
PI Contribution Expertise in porcine immunology/vaccinology, inc. PRRSV and Nipah
Collaborator Contribution Expertise in PRRSV reverse genetics
Impact None as yet
Start Year 2019
 
Description PRRS and Influenza co-nfection studies 
Organisation Government of Thailand
Department National Science and Technology Development Agency (NSTDA)
Country Thailand 
Sector Public 
PI Contribution The Pirbright team of 4 scientists with expertise in immunology and animal care visited Thailand in July 2018 to train Thai colleagues to perform animal experiments (Chiang Mai) and analyse immune responses by ELISPOT and Flow cytometry (Bangkok). This provided Thailand with trained personnel and expertise in testing vaccines in pigs. As a result of the joint work, the Chiang Mai animal facility is currently being renovated. Development of such an animal facility will promote the production and testing of more vaccines by Thai scientists.
Collaborator Contribution Our Thai colleagues provided us with local Thai PRRS and Influenza virus strains which we use in our co-infection studies.
Impact None yet
Start Year 2018
 
Description Ash Manor Science Workshops; general science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Ash Manor Science Workshops
Year(s) Of Engagement Activity 2019
 
Description BBSRC Newton swine poultry workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Attended BBSRC Newton swine poultry workshop in Beijing - September 2018. Tiphany Chrun, the postdoc employed on the grant gave a presentation about the proposed work and established a working relationship with our Thai collaborator Surapong. The breakout sessions asked a series of questions aimed at generating further insight into the key opportunities that may arise as a result of working collaboratively across the 11 projects, the common challenges faced by the projects, and how these might be overcome collectively.
Year(s) Of Engagement Activity 2018
 
Description BSI congress 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Chaired a session on coinfection sponsored by the BBSRC.
Took part in a debate on the future of veterinary immunology
Year(s) Of Engagement Activity 2021
 
Description BSI report on the future of veterinary immunology and vaccinology 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Organised and published a joint IVVN/BSI report to raise awareness of the UK's research status in veterinary vaccinology and immunology and the importance of maintaining this for the R&D landscape 'Securing Our Future: the value of veterinary vaccines'. This was aimed at influencing policymakers to support and commit to maintaining the UK's leading position.
Year(s) Of Engagement Activity 2021
 
Description Big Bang SE 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Stimulating increased interest in science and research
Year(s) Of Engagement Activity 2019
 
Description Invited presentation: 'Beyond Jenner: The Future of Vaccines', Discovery Day, Dr Jenner House Museum and Gardens 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Invited by the British Society for Immunology to give a presentation on vaccine research at the 'Beyond Jenner: The Future of Vaccines', Discovery Day, Dr Jenner House Museum and Gardens, Berkeley, UK.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar at INRAE, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited seminar to present our recent and ongoing PRRSV research
Year(s) Of Engagement Activity 2019
 
Description Invited speaker at Centre for Innovation Excellence in Livestock webinar on alternatives to antibiotics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Invited speaker at Centre for Innovation Excellence in Livestock webinar on alternatives to antibiotics
Year(s) Of Engagement Activity 2022
URL https://cielivestock.co.uk/events/ciel-insights-member-only-webinar-alternatives-to-antibiotics/
 
Description Invited speaker at Imperial College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Gave a talk on our recent research in swine influenza. Discussions with PIs at Imperial after the talk. Established collaborations.
Year(s) Of Engagement Activity 2018
 
Description Invited speaker at St Mary's Hospital, Imperial College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave presentation on our pig influenza model to colleagues at Imperial College. Established collaboration to evaluate LAIV in pigs and humans.
Year(s) Of Engagement Activity 2019
 
Description Invited speaker, Vienna Veterinary School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Gave a guest lecture at the Veterinary school in Vienna. There were a lot of questions and discussion after the talk. As a result established collaboration with Gerner Wilhelm's group.
Year(s) Of Engagement Activity 2019
URL https://www.vetmeduni.ac.at/de/graduate-school-pig-and-poultry-medicine/
 
Description Laboratory Science Animal association (LASA) meeting in Birmingham, Invited speaker 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave a presentation on the tools we have developed to study swine influenza
Year(s) Of Engagement Activity 2018
URL http://www.lasa.co.uk/meetings/
 
Description Member of BBSRC sLoLa grants committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Member of sLoLa Committee to shortlist outline applications and review/assess application at the full stage of submission.
Year(s) Of Engagement Activity 2021
 
Description Member of a BBSRC expert group on the use of animal models in research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Reviewed the key findings of the survey and identify key trends and emerging opportunities. Reviewed the proposed recommendations, discuss the challenges and barriers surrounding the use of models, and suggest how UKRI-BBSRC can help overcome these.
Identified key stakeholders that UKRI-BBSRC could partner with to act on recommendations and how the report should be disseminated.
Year(s) Of Engagement Activity 2021
 
Description Newton Fund Swine and Poultry interim workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented progress from both UK and Thailand partners of the project and planned the next stage of animal experiments. Update from other grant holders. Networking with other delegates. Identified the future challenges and how to develop further the findings from the awards.
Year(s) Of Engagement Activity 2019,2020
 
Description Organised IVVN/BSI meting on T cell biology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organised virtual T cell meeting: invited 8 speakers, opened the meeting, chaired session and closed the meeting. Highly successful meeting with 170 delegates from 28 countries and excellent feedback on scientific content, engagement and organisation. Brought together immunologists from the mouse, human and veterinary filed, facilitate exchange of ideas and new collaborations.
Year(s) Of Engagement Activity 2021
URL http://www.immunology.org/frontiers-in-comparative-immunology-series-t-cell-biology-virtual-conferen...
 
Description Summer School at Greifswald 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Gave a talk about the use of the pig as a model to study influenza and other respiratory diseases. Discussion about the utility of the model and what lessons should be learned from the Covid pandemice
Year(s) Of Engagement Activity 2022
 
Description Talk at Large animal research network (LARN) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave a talk on the tools we have developed to target different parts of the respiratory tract and how to analyse local immune responses.
Year(s) Of Engagement Activity 2021
 
Description Vet School Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact University of Surrey School of Veterinary Medicine Open Day - introduced The Pirbright Institute and the research we conduct to prospective students and parents.
Year(s) Of Engagement Activity 2018
 
Description careers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Stimulating increased interest in science and research
Year(s) Of Engagement Activity 2019