Development and comparative evaluation of three new generation BRSV DIVA vaccines and a corresponding DIVA test

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

Bovine Respiratory Syncytial Virus (BRSV) is the single most important viral respiratory pathogen of calves causing high morbidity and mortality in the European cattle industry. The extensive use of antibiotics to control secondary infections following BRSV increases the likelihood of the emergence of antibiotic-resistant bacteria. Consequently, the impact of BRSV on economics, animal welfare and public health makes the control of this virus a high priority. To control BRSV, sanitary measures need to be combined with effective vaccination. However, current vaccines are unsatisfactory, especially in young calves with maternally derived antibodies (MDA). In this project, three novel BRSV vaccines, BRSV Immunostimulating Complexes (BRSV-ISCOMs), RSV nucleoprotein subunits (N nanorings) and live attenuated, genetically modified BRSV (rBRSV mutants) will be evaluated to identify the safest and most efficient vaccine protocol that will induce early, long-lasting clinical and virological protection against BRSV. All three vaccine approaches enable the development of a test for differentiation of infected from vaccinated animals (DIVA). This will facilitate vaccine evaluation in the field and sero-epidemiological investigations. It will also provide a key tool for any future disease control progammes.

Technical Summary

Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in young calves. This project aims to ameliorate and compare three novel BRSV vaccine candidates; and to identify the safest and most efficient vaccine protocol that will induce early, long-lasting clinical and virological protection. This approach will be compatible with large scale use and will have a DIVA characteristic. Initial studies will improve and generate new subunit vaccines based on BRSV Immunostimulating Complexes (BRSV-ISCOMs) and RSV nucleoprotein subunits (N nanorings). Selected recombinant BRSV proteins will be produced and incorporated into ISCOMs, and N nanorings will be decorated with B cell epitopes from BRSV surface glycoproteins. The immunogenicity of these vaccines will be evaluated and optimised in mice and lambs. The protective efficacy of the two best subunit vaccines will then be compared with that of a novel live attenuated rBRSV mutant in calves with BRSV-specific maternally-derived antibodies. The duration of protection induced by the two most effective vaccine candidates will be compared with that of a heterologous prime/boost vaccine combination, in MHC-defined calves. The use of MHC-defined calves will allow a more detailed analysis of T-cell priming by the various vaccines. Finally, DIVA tests compatible with the most effective vaccine protocol, will be developed and evaluated.

Planned Impact

Pneumoviruses are a major cause of acute respiratory disease in a variety of animals including man. Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in young calves, resulting in estimated losses to the UK farming industry in excess of £60 million. The development of safe and effective vaccines against these viruses has been beset by difficulties. This project will evaluate several promising novel approaches for the development of a new generation of BRSV vaccines (10). These include immunostimulating complexes (ISCOMs), RSV nucleoproteins as circular nanoparticles, and live attenuated, genetically modified BRSV. The proposed studies have direct relevance to the rational development of stable, safe and effective BRSV vaccines, will provide insights into the future development of a vaccine for human pneumoviruses and will have implications for the understanding the epidemiology of pneumovirus infections. We anticipate that this research will be of benefit to DEFRA by improving the control of disease in cattle and by contributing to a reduction in green-house gases as a result of increased productivity in the livestock industry. Other beneficiaries will be the vaccine industry as the information from this project will facilitate the development of improved BRSV and human pneumovirus vaccines and the farming industry as more effective BRSV vaccines will improve animal welfare, increase productivity and improve profitability for farmers. In addition, an improved BRSV vaccine will reduce antibiotic usage in calves and the subsequent risk from antibiotic resistant bacteria in the food chain. By increasing productivity in the livestock industry, more effective BRSV vaccines will contribute to food security by helping to deliver the UN estimate that world food production will have to increase by 50% by 2030 to meet demand caused by population increases and rising prosperity and to double by 2050 to feed an anticipated population of 9 billin. Staff working on the project will gain research and professional skills. Research training will include a broad range of molecular virology and cellular immunology techniques and experience in a variety of animal disease models. Transferable professional skills will include writing and presentation skills for both academic and non-academic audiences, and time and management tools. Communication of the findings from the research will be undertaken by presentation at conferences, peer reviewed publications, presentations at farming events; talking to schools and veterinary vaccine companies; and via the web-sites and communications offices of the 3 organisations involved in this project. IAH has a product development pipeline which ensures early identification and protection of Intellectual Property. Genecom is the IAH commercialisation partner and provides documentation and advice on agreements relating to research results, collaborations and exploitation.

Publications

10 25 50
 
Description Bovine respiratory syncytial cirus (BRSV) is a major cause of respiratory disease in young calves. Two novel vaccines have been developed that will help to distinguish vaccinated from infected calves (DIVA), which could help in control of this virus. One is a live attenuated virus vaccine given intranasally and the other is a nanoparticle given with adjuvant intramuscularly. Both vaccine candidates induced good protection in young calves with maternally-derived antibodies. Priming intranasally with the live attenuated BRSV, which has the a deletion in the SH gene followed by boosting with the N-nanoparticle provided complete protection against BRSV challenge, 3 months later, in calves with maternally-derived antibodies at the time of initial vaccination.
Exploitation Route The live attenuated virus has been licensed to a Veterinary Pharmaceutical company who are interested in it's further development. A recombinant human RSV containing a deletion in the SH gene is now in clinical trials in man.
Sectors Agriculture, Food and Drink

 
Description Horizon 2020
Amount € 239,067 (EUR)
Funding ID 633184 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2015 
End 02/2019
 
Description EMIDA 
Organisation French National Institute of Agricultural Research
Department INRA Versailles
Country France 
Sector Public 
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 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