Host resistance mechanisms to bovine respiratory syncytial virus (BRSV), African swine fever virus (ASFV) and Bluetongue virus (BTV)
Lead Research Organisation:
THE PIRBRIGHT INSTITUTE
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The aim of this project is to advance understanding of the mechanisms of immunity to and the pathogenesis of African swine fever virus (ASFV), bluetongue virus (BTV) and bovine respiratory syncytial virus (BRSV). The knowledge gained will contribute to the development of new or improved vaccines. Developments in DNA technology have created new opportunities for vaccine production, both through genetic manipulation of pathogens and by enabling the identification of defined antigens that induce protective immune responses. These opportunities, together with a detailed understanding of the components of the immune response that mediate protection or which contribute to the pathogenesis of disease, and knowledge of how these responses can be induced and regulated at an appropriate location in vivo, will provide a conceptual framework for the rational development of new or improved vaccines against BRSV, ASFV and BTV.
Planned Impact
unavailable
Organisations
- THE PIRBRIGHT INSTITUTE (Lead Research Organisation)
- Institute of Health Carlos III (Collaboration)
- HUMABs Biomed, Bellinzona,Switzerland (Collaboration)
- Swedish University of Agricultural Sciences (Collaboration)
- Royal Veterinary College (RVC) (Collaboration)
- National Institutes of Health (NIH) (Collaboration)
- Gift of Life Michigan (Collaboration)
- French National Institute of Agricultural Research (Collaboration)
People |
ORCID iD |
| Geraldine Taylor (Principal Investigator) |
Publications
Blodörn K
(2015)
A bovine respiratory syncytial virus model with high clinical expression in calves with specific passive immunity.
in BMC veterinary research
Stevens L
(2019)
A low-passage insect-cell isolate of bluetongue virus uses a macropinocytosis-like entry pathway to infect natural target cells derived from the bovine host
in Journal of General Virology
Goatley LC
(2020)
A Pool of Eight Virally Vectored African Swine Fever Antigens Protect Pigs Against Fatal Disease.
in Vaccines
Midgley R
(2013)
A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection.
in The Journal of general virology
Schäfer A
(2022)
Adaptive Cellular Immunity against African Swine Fever Virus Infections.
in Pathogens (Basel, Switzerland)
Sastry M
(2017)
Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.
in PloS one
Netherton CL
(2013)
African swine fever virus organelle rearrangements.
in Virus research
Dixon LK
(2013)
African swine fever virus replication and genomics.
in Virus research
Diaz AV
(2012)
African swine fever virus strain Georgia 2007/1 in Ornithodoros erraticus ticks.
in Emerging infectious diseases
Seago J
(2013)
An infectious recombinant foot-and-mouth disease virus expressing a fluorescent marker protein.
in The Journal of general virology
| Description | In humans and mice, ?d T cells represent approximately 5% of the total circulating lymphocytes. In contrast, the ?d T cell compartment in ruminants accounts for 15-60% of the total circulating mononuclear lymphocytes. Despite the existence of CD4(+)CD25(high) Foxp3(+) T cells in the bovine system, these are neither anergic nor suppressive. We have demonstrated that bovine ?d T cells are the major regulatory T cell subset in peripheral blood. These ?d T cells spontaneously secrete IL-10 and proliferate in response to IL-10, TGF-ß, and contact with antigen-presenting cells (APC). IL-10-expressing ?d T cells inhibit antigen-specific and nonspecific proliferation of CD4(+) and CD8(+) T cells in vitro. APC subsets expressing IL-10 and TFG-ß regulate proliferation of ?d T cells producing IL-10. ?d T cells appear to be a major regulatory T cell population in the bovine system. Bovine respiratory syncytial virus (BRSV) causes inflammation and obstruction of the small airways, leading to severe respiratory disease in young calves. The virus is closely related to human (H)RSV, a major cause of bronchiolitis and pneumonia in young children. The ability to manipulate the genome of RSV has provided opportunities for the development of stable, live attenuated RSV vaccines. The role of the SH protein in the pathogenesis of BRSV was evaluated in vitro and in vivo using a recombinant (r)BRSV in which the SH gene had been deleted. Infection of bovine epithelial cells and monocytes with rBRSV?SH, in vitro, resulted in an increase in apoptosis, and higher levels of pro-inflammatory cytokines compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSV?SH and WT rBRSV, in vitro, were similar, the replication of rBRSV?SH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSV?SH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSV?SH-infected calves was significantly reduced compared with that in calves inoculated with WT rBRSV, 6 days previously. Virus lacking SH appeared to be as immunogenic and effective in inducing resistance to virulent virus challenge, 6 months later, as the parental rBRSV. Furthermore, intranasal vaccination of calves with maternally-derived antibodies induced protection against viruelnt virus challenge.These findings suggest that rBRSV?SH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity. The immunogenicity and protective efficacy of a virus-vectored human RSV vaccine was evaluated against BRSV in calves and a heterologous prime/boost regimen was shown to give sterile immunity against BRSV. Bovine plasmacytoid dendritic cells produce high levels of IFN, some of which is acid labile, when exposed to live, but not UV-inactivated, BTV. The response is enhanced when BTV is complexed with BTV-specific antibodies. Different serotypes of BTV differ in their ability to induce IFN In contrast to the well-described, CAR-dependent mechanism of adenovirus attachment and penetration of permissive cells, we demonstrated that adenovirus enters skin-draining dendritic cells via actin-dependent endocytosis African swine fever virus (ASFV) inhibits autophagy at early times post infection. This has implications for induction of adaptive immune responses. ASFV ORFs recognised by ASFV-immune lymphocytes from cc, dd and bb pigs have been identified and cloned into replication-defective adenovirus vectors for development of ASFV vaccine candidates. Vaccination of a small number of pigs with a pool of adenovirus-vectored vaccines induced protection against severe disease and reduced viraemia in 50% of the pigs. A number of tagged ASF viruses have been generated that encode a fluorescent-virus structural fusion protein in the place of a non-essential gene. These will be of value in studying the pathogensis of ASFV in pigs and ticks. A prefusion form of the BRSV F protein induced higher levels of neutralising antibodies and a greater level of protection against BRSV infection than the postfusion form of the F protein. Further studies have demonstrated that protection against BRSV in calves with maternally-derived serum antibodies can be induced by intramuscular injection of the prefusion form of the bRSV F protein. |
| Exploitation Route | A grant has been submitted to further develop rBRSVdelta SH as a vaccine for calf respiratory disease. A PhD student will investigate the effect of ASFV on autophagy further. A grant has been submitted to extend studies on bovine gamma/delta T cells and determine their role in combatting virus infection. A Bill & Melinda Gates grant was awarded to determine the minimum protective dose of the Ad-vectored PPR vaccine in African goats. Clinical trials of the virus-vectored RSV vaccine have been undertaken in man. The prefusion form of the BRSV F protein could be developed as a vaccine |
| Sectors | Agriculture Food and Drink Healthcare |
| Description | African swine fever is a devastating disease of pigs which has spread to the borders of the EU in recent years. We have identified antigens that are recognised by ASFV immune lymphocytes and these have been expressed in replication defective adenovirus vectors and will be evaluated as potential vaccine candidates. A patent application for ths novel ASFV vaccine is being prepared. An Adenovirus-vectored vaccine expressing the surface glycoproteins of peste des petits ruminants virus (PPRV) has been developed and was shown to induce complete protection against PPR challenge, 3 months after a single intramuscular dose of vaccine. This vaccine has the potential to distinguish vaccinated from infected animals and would be of value in the end stages of a PPR eradication campaign. An adenovirus-vectored and MVA-vectored RSV vaccine for use in man against human RSV has been developed and was shown to be effective against the closely related BRSV in calves. this vaccine is now in clinical trials in man. A prefusion form of the BRSV F protein has ben shown to elicit higher tires of neutralising antibodies and greater protection against BRSV infection than the post-fusion BRSV |
| First Year Of Impact | 2016 |
| Sector | Agriculture, Food and Drink,Healthcare |
| Impact Types | Societal Economic |
| Description | DEFRA Expert elicitation on CSF and ASF |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | ERA-NET Cofund on International Coordination of Research on Infectious Animal Diseases (ICRAD) |
| Amount | £1,526,000 (GBP) |
| Funding ID | SE1518 |
| Organisation | Department For Environment, Food And Rural Affairs (DEFRA) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 03/2024 |
| Description | Grand Challenges Explorations |
| Amount | $100,000 (USD) |
| Funding ID | OPP1098823 |
| Organisation | Bill and Melinda Gates Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 01/2014 |
| End | 04/2015 |
| Description | Horizon 2020 |
| Amount | € 239,067 (EUR) |
| Funding ID | 633184 |
| Organisation | European Commission |
| Sector | Public |
| Country | Belgium |
| Start | 03/2015 |
| End | 02/2019 |
| Description | SFS-10-2017 - Research and approaches for emerging diseases and pests in plants and terrestrial livestock: Addressing the dual emerging threats of African Swine Fever and Lumpy Skin Disease in Europe (DEFEND) |
| Amount | € 5,986,250 (EUR) |
| Funding ID | 773701 |
| Organisation | European Commission H2020 |
| Sector | Public |
| Country | Belgium |
| Start | 05/2018 |
| End | 05/2023 |
| Description | Studentship: Autophagy and African swine fever virus |
| Amount | £21,909 (GBP) |
| Funding ID | BBS/E/I/00002120 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2015 |
| End | 09/2019 |
| Description | BRSV prefusion F |
| Organisation | HUMABs Biomed, Bellinzona,Switzerland |
| Country | Switzerland |
| Sector | Private |
| PI Contribution | Evaluation of the immunogenicity and protective efficacy of different forms of the bovine respiratory syncytial virus F protein in calves. |
| Collaborator Contribution | Production of purified BRSV F proteins |
| Impact | None yet |
| Start Year | 2015 |
| Description | BRSV prefusion F |
| Organisation | National Institutes of Health (NIH) |
| Department | Vaccine Research Center (VRC) |
| Country | United States |
| Sector | Public |
| PI Contribution | Evaluation of the immunogenicity and protective efficacy of different forms of the bovine respiratory syncytial virus F protein in calves. |
| Collaborator Contribution | Production of purified BRSV F proteins |
| Impact | None yet |
| Start Year | 2015 |
| Description | EMIDA |
| Organisation | French National Institute of Agricultural Research |
| Department | INRA Versailles |
| Country | France |
| Sector | Academic/University |
| PI Contribution | The establishment of a standardised experimental BRSV calf model and the wide exchange of sampling and laboratory techniques. The immunogenicity and protective efficacy of a live recombinant bRSV lacking the SH gene, which we had previously shown to be attenuated and induce protective immunity in bRSV-seronegative calves was compared with two subunit vaccines supplied by collaborators, in calves with maternally-derived antibodies. The 3 vaccine candidates had DIVA potential, and calves were challenged 3 months after vaccination.. The SH protein was identified as potential DIVA protein, after screening of antibodies specific for several candidate proteins in naturally infected animals. |
| Collaborator Contribution | Collaborators developed and supplied bRSV subunit vaccine candidates and undertook initial evaluation in calves with maternally-derived bRSV-specific antibodies, who were challenged with bRSV 5 weeks after initial vaccination. DIVA assays were set up based on artificially produced peptides and proteins. |
| Impact | Publications: 10.1371/journal.pone.0100392; 10.1128/CVI.00162-14; 10.1186/s12917-015-0389-6; 10.1371/journal.pone.0186594. Multidiscipinary: Immunology, virology, veterinary, biochemical, proteomics, bio-informatics Further funding: Horizon 2020 |
| Start Year | 2011 |
| Description | EMIDA |
| Organisation | Swedish University of Agricultural Sciences |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | The establishment of a standardised experimental BRSV calf model and the wide exchange of sampling and laboratory techniques. The immunogenicity and protective efficacy of a live recombinant bRSV lacking the SH gene, which we had previously shown to be attenuated and induce protective immunity in bRSV-seronegative calves was compared with two subunit vaccines supplied by collaborators, in calves with maternally-derived antibodies. The 3 vaccine candidates had DIVA potential, and calves were challenged 3 months after vaccination.. The SH protein was identified as potential DIVA protein, after screening of antibodies specific for several candidate proteins in naturally infected animals. |
| Collaborator Contribution | Collaborators developed and supplied bRSV subunit vaccine candidates and undertook initial evaluation in calves with maternally-derived bRSV-specific antibodies, who were challenged with bRSV 5 weeks after initial vaccination. DIVA assays were set up based on artificially produced peptides and proteins. |
| Impact | Publications: 10.1371/journal.pone.0100392; 10.1128/CVI.00162-14; 10.1186/s12917-015-0389-6; 10.1371/journal.pone.0186594. Multidiscipinary: Immunology, virology, veterinary, biochemical, proteomics, bio-informatics Further funding: Horizon 2020 |
| Start Year | 2011 |
| Description | Interferon stimulated genes |
| Organisation | Royal Veterinary College (RVC) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Hosted meetings and carried out preliminary experiments |
| Collaborator Contribution | Contributed reagents and expertise |
| Impact | Preliminary data was used to support an MSc project. This has since led to a publication and a PhD project. |
| Start Year | 2016 |
| Description | Prefusion HRSV F |
| Organisation | Institute of Health Carlos III |
| Country | Spain |
| Sector | Public |
| PI Contribution | Evaluation of the immunogenicity and protective efficacy of the different forms of the human respiratory syncytial virus F protein in mice. |
| Collaborator Contribution | Provision of purified proteins for vaccination & analysis of serum antibody responses |
| Impact | A manuscript has been published |
| Start Year | 2015 |
| Description | Swine haplotyping |
| Organisation | Gift of Life Michigan |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | Prepared and shipped samples |
| Collaborator Contribution | Sample analysis |
| Impact | Data generation. Not multi-disciplinary |
| Start Year | 2016 |
| Title | RSV vaccine |
| Description | Pre-clinical studies have demonstrated efficacy in small animal models of RSV infection and against bovine RSV infection in calves, a natural host of BRSV. These studies demonstrated that the vaccine was safe and effective in calves without any enhancement of respiratory disease. As a result of this, the vaccine has now undergone phase I clinical trials in Oxford, funded by Okairos and GSK and was shown to be safe and immunogenic (http://bmjopen.bmj.com/content/5/10/e008748.full). |
| Type | Therapeutic Intervention - Vaccines |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2014 |
| Development Status | Under active development/distribution |
| Clinical Trial? | Yes |
| UKCRN/ISCTN Identifier | 35082/0003/001-0001 |
| Impact | None yet |
| Description | Advances for an RSV vaccine |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Interview with a reporter from a Surrey radio station about recent advances in the development of a vaccine to protect against RSV in babies following publication of a paper (http://stm.sciencemag.org/content/7/300/300ra127.short), which was broadcast the next day. |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://stm.sciencemag.org/content/7/300/300ra127.short |
| Description | Babraham Institute Ethics event |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Approximately 50 school children attended the event at the Babraham institute to learn about the use of animals in research and the three Rs - Refinement, Reduction and Replacement - which govern such use. They heard about breakthroughs in medicine and healthcare treatments that have only been possible through doing research with animals, about the work of The Pirbright Institute in the development of vaccines and control strategies to prevent viral diseases in livestock and transmission of viruses from animals to humans, and about research that is currently being carried out by the Babraham Institute into Alzheimer's disease. The workshop broadened the pupils' knowledge of biomedical research and its applications and encouraged them to think about the wider social and ethical implications of scientific discoveries they hear about in the news and other media. |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://babraham.ac.uk/get-involved/secondary-schools/ethics-workshops |
| Description | Oxford Human & Veterinary Vaccinology course |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Paper Presentation |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | 30 people (post-graduate students, scientsits from academia and industry) attended. Presentations and workshops sparked questions and discussion. Not known |
| Year(s) Of Engagement Activity | 2012,2013,2014,2015 |
| URL | https://www.conted.ox.ac.uk/courses/C900-1 |
| Description | Pig and Poultry Fair 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | Discussed Institute research with pig and poultry farmers, related industry and the general public. Received requests for more information related to research, business and studentships. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.pigandpoultry.org.uk/ |
| Description | Presentation to U3A |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Presented an overview of African swine fever virus to members of the University of the Third Age, which sparked plenty of questions and interesting debate. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Talk as part of the University of Veterinary Medicine (Vienna) doctoral school "Infectious Diseases of Pig and Poultry" |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Talked about the Pirbright Institute's work on African swine fever virus to researches in Veterinary Medicine (Virology and Immunology) in Vienna. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Talk at Tamil Nadu Veterinary and Animal Services University |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Undergraduate students |
| Results and Impact | Participated in an online webinar organised by the Tamil Nadu Veterinary and Animal Services University in Chennai India as part of their Transboundary Animal Diseases - Emerging Threats to India seminar series. I talked to around 60 participants about African swine fever and African swine fever vaccine research. There were questions on vaccine development and also control of African swine fever in India. |
| Year(s) Of Engagement Activity | 2020 |
| Description | Talk at VIV Virtual Summit -Asia Edition |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | Talk to just over 100 attendees to the "Genetic Futures - Productivity, Animal Health and Clean Growth" session, part of the VIV Virtual Summit -Asia Edition. The session was organised by UK Technology for Agriculture and Genetics to showcase UK scientific expertise in the livestock sector to a Asian audience. |
| Year(s) Of Engagement Activity | 2012,2021 |
| URL | https://www.vivasia.nl/viv-virtual-summit/ |
| Description | Talk at World Vaccine Congress Europe |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Described research progress on ASF vaccines |
| Year(s) Of Engagement Activity | 2019 |
| Description | University MSc course |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Approximately 10 MSc students at Surrey University each year, which sparked discussion and questions |
| Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017 |
| Description | Vaccinology in Africa course |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Paper Presentation |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | 30 scientists from Africa working in the Vaccinology field attended. The presentations and workshops sparked questions and a lot of discussion. There were requests to repeat the course in other regions in Africa |
| Year(s) Of Engagement Activity | 2013,2014 |