US-UK BBSRC-NIFA Collab: Control of emerging bunyaviruses

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Arboviruses are viruses transmitted by arthropod vectors such as mosquitoes, biting flies or ticks, and can infect both man and livestock. Bunyaviruses are one group of arboviruses and include the well-known Rift Valley fever virus that causes devastating epidemics among sheep and cattle in Africa, and a new virus, Schmallenberg virus, that appeared in Europe in 2011 and rapidly spread throughout the continent causing abortions, stillbirths and malformations of calves and lambs. In order to prepare for future outbreaks of bunyavirus disease we need to understand why certain insect vectors are able to spread a particular virus whereas others cannot, and whether local insects would be capable to supporting transmission of an introduced virus. This will be addressed by infecting different mosquito and midge species with different viruses, and determining the factors involved in a successful transmission. Should a new outbreak occur, we need to be able to respond rapidly with vaccines to contain the disease. We will use our ability to genetically modify viruses to produce weakened viruses that can no longer cause disease but are able to induce protective antibodies in the host animal that will preventive subsequent infection. The candidate vaccines will be assessed for their efficacy in sheep and will establish general principles for the development of further vaccines in the future.

Technical Summary

The overall goals of this collaborative project are to increase our understanding of bunyavirus-vector interactions, and to generate new live-attenuated vaccines that can be rapidly deployed to protect against emergence of new bunyavirus disease. Bunyaviruses include the mosquito transmitted Rift Valley fever, that is a continual threat for emergence outside of Africa, and the midge transmitted Schmallenberg virus, a new virus that emerged in Europe in 2011 and which quickly spread. Using selected bunyaviruses, the roles of viral proteins in the ability to infect and be transmitted by different mosquito and midge species will be studied. The effect of the insect innate immune response in shaping the nature of the infection will be analysed in detail. Exploiting reverse genetics, recombinant attenuated viruses, lacking the nonstructural NSs and NSm proteins, will be tested for their efficacy to protect against homologous wild type virus challenge in sheep. These studies will lay the foundation for a new vaccine platform against any new bunyavirus that will emerge in the future.

Planned Impact

Who might benefit from this research?
The immediate beneficiary of this research will be the national and international academic community in the direct field of this research and more broadly, through the acquisition of new knowledge. The general public will also be a direct beneficiary of this work. The results of this project will be of interest to animal health pharmaceutical companies and also to national, international and inter-governmental policy makers, including bodies such as the Animal World Health Organisation (OIE) who have responsibility for monitoring and controlling the spread of animal viruses.

How might they benefit from this research?
This project aspires to develop a vaccine platform for the rapid generation of new vaccines against emerging bunyaviruses. If successful, this technology will significantly enhance our readiness and preparedness to respond to outbreaks of emerging and re-emerging bunyaviruses in animals. Therefore, the outcomes of the proposed work are likely to have potential for commercial exploitation that will directly benefit animal health pharmaceutical companies. We enjoy established collaborations with both Pifzer and Merial Animal Health, both of which are supported by BBSRC through CASE studentships and an Industrial Partnership award. These partnerships are a route through which to manage and maximize the findings of our research and to explore commercial exploitation of the results of this project to realize these impacts.

Exploitation of our findings by the pharmaceutical industry is likely to have a direct impact on the UK economy by reducing morbidity and mortality in economically significant farmed animals and therefore be of benefit to the general public. The availability of a bluetongue virus vaccine has been estimated to have saved the UK economy £485M and 10,000 jobs. Therefore we will endeavour to disseminate our findings to the non-scientific community to explain our work and why it is important. CVR staffhave a strong track record of engagement with the general public, and our activities to inspire school children to study science include workshops and science fairs, and student placements in research laboratories.

The ready availability of effective vaccines targeting emerging and re-emerging bunyaviruses can be expected to be of significant benefit to policy makers with responsibility for the control and containment of animal viruses, nationally and internationally. The CVR is an OIE Collaborating Centre and we will use our links to OIE to share the outcomes of this work and provide regular updates. This project is also likely to come under the umbrella of the Global Uncertainties Programme of projects and so we will also take advantage of opportunities for 'enhanced impact' through discussion with Dr Tristram Riley-Smith, the Global Uncertainties Programme's External Champion.

The development and application of new techniques, generation of new knowledge and exposure to different research environments will also benefit the career development of the Research Assistant to be employed on this project. In addition to acquiring new scientific expertise, the research assistant will also contribute to project management of this study, will assist in managing the project budget, provide support and training to other members of the group and be responsible for presenting results generated from this work in the form of written manuscripts and oral conference presentations. Development of these transferable skills will enhance the future employability of the individual, irrespective of the career path they chose to pursue.
 
Description Reverse genetics systems for both Cache Valley (CVV) and Kairi (KRIV) orthobunyaviruses, two animal pathogens were developed; such systems make it possible to introduce mutations into viral genome. With these systems, interferon antagonist-lacking NSs deletant as well NSm-deletant viruses (and double deletants) have been produced and characterised in detail for use of potential vaccine candidates. It was decided to focus more on CVV instead of the related Schmallenberg virus, as work planned originally for the latter virus was published by others at the start of the project. Moreover, orthobunyaviral reassortment was assessed using these reverse genetics systems, and to what extent glycoprotein ectodomains can be exchanged to assess the potential of a versatile vaccine platform based on orthobunyavirus reverse genetics; where obtained, such viruses will be further characterised. We have also developed highly specific antibodies against both KRIV and CVV N proteins which we have been outsourced to Cambridge Research Biochemicals. Work with mosquitoes could at CVR was no carried out as planned due to focus on specific objectives to be carried out, following the death of Professor Elliott who led this project (Professor Kohl -originally co-PI- took over over leadership of the UK part of the project) and recruitment and training of Dr Dunlop (replacing Dr Navarro, who left the project after Professor Elliott's death). Note: this describes findings by the CVR partner.

Attenuated CVV and KRIV (delNSs/delNSm mutants) and also specific Rift Valley fever virus mutants (developed by Professor Elliott and proposed to be tested in the context of this project) are currently being tested as vaccine candidates by partner BRI/KSU, who also assessed transmission potential of CVV by Culex tarsalis.
Exploitation Route We have developed the CVV and KRIV attenuated virus vaccine platform based on reverse genetics, and transfered these viruses to collaborators at BRI/KSU as planned in addition to Rift Valley fever virus mutants that were outlined in the proposal. These vaccine candidates are currently tested, and will provide a generate information on 1) suitability as vaccines, and 2) potential infection and transmission of vaccine candidates by vector arthropods. This is generally relevant and interesting information for the field; viruses or reagents such as reverse genetics systems will be available to other interested partiers for fundamenal and applied studies (subject to MTA) on bunyaviruses, including, if applicable, further work on vaccine development. In addition we developed antibodies to CVV and KRIV N proteins that were outsourced to Cambridge Research Biochemicals.
Sectors Agriculture, Food and Drink,Other

 
Title Antibodies to Cache Valley and Kairi orthobunyavirus N proteins 
Description Highly specific for N protein and not cross reactive with related orthobunyavirus N proteins. 
Type Of Material Antibody 
Year Produced 2017 
Provided To Others? Yes  
Impact Antibodies were outsourced to Cambridge Research Biochemicals and are are part of their commercial catalogue. See http://www.discoveryantibodies.com/anti-cache-valley-virus-cvv-nucleocapsid-antibody and http://www.discoveryantibodies.com/anti-kairi-virus-kriv-n-protein-antibody Their description was also published: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006884 
URL http://www.discoveryantibodies.com/
 
Title Reverse genetics for Cache Valley and Kairi viruses 
Description cDNA-based reverse genetics system to produce genetically modified viruses. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Reverse genetics systems for both viruses were used to produce attenuated vaccine candidates. 
URL https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006884
 
Title Investigation of host response antagonism and reassortment potential for Cache Valley and Kairi viruses, two emerging orthobunyaviruses of the Americas 
Description Data underlying publication doi: 10.1371/journal.pntd.0006884 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Not known. 
 
Description Bunyavirus-host interactions and replication 
Organisation University of Glasgow
Department MRC - University of Glasgow Centre for Virus Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Arthropod innate immunity reagents and expertise; bunyavirus expertise and reagents including viruses and infectious clones; experimental design and data evaluation.
Collaborator Contribution Bunyavirus expertise and reagents including viruses, infectious clones, minireplicon systems, protein expression clones; experimental design and data evaluation. With Professor Richard M. Elliott until he passed away in 2015 and currently with Dr Benjamin Brennan.
Impact Publications as listed with the relevant awards; novel infectious clones and minireplicon systems for specific bunyaviruses and new functional data on bunyavirus proteins, bunyavirus replication, bunyavirus-host interactions including immunity.
Start Year 2013
 
Description US-UK BBSRC-NIFA Collab: Control of emerging bunyaviruses 
Organisation Kansas State University
Country United States 
Sector Academic/University 
PI Contribution Development of novel infectious clones for orthobunyaviruses Cache Valley virus and Kairi virus including production of attenuated viruses; provision of Rift Valley fever virus fever vaccine candidates; vector innate immunity expertise; experimental design and data evaluation. This project was originally led by Professor Richard M. Elliott with Professor Kohl as co-investigator; following his deah Kohl took the lead. This collaboration is within a listed award "US-UK BBSRC-NIFA Collab: Control of emerging bunyaviruses".
Collaborator Contribution Vaccination experiments in sheep with attenuated bunyaviruses and vector competence work; vector infections for innate immunity experiments and transmission studies with vaccine candidates. With Professor Stephan Higgs within the listed award.
Impact Data on competence of North American vectors for Cache Valley virus; reverse genetics and minireplicon systems for Cache Valley and Kairi viruses; virulence factor deletant Cache Valley and Kairi viruses as vaccine candidates; specific antibodies for nucleocapsid proteins of Cache Valley and Kairi viruses that are now sold under license to Cambridge Research Biochemicals. Publications are listed with the relevant award.
Start Year 2015
 
Title Antibodies to Cache Valley and Kairi virus N proteins 
Description Highly specific antibodies to nucleocapsid (N) proteins. See http://www.discoveryantibodies.com/anti-cache-valley-virus-cvv-nucleocapsid-antibody and http://www.discoveryantibodies.com/anti-kairi-virus-kriv-n-protein-antibody 
IP Reference  
Protection Protection not required
Year Protection Granted 2017
Licensed Yes
Impact Not known.
 
Description MRC Parliamentary Event 6 February 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The CVR participated in the MRC parliamentary event on 6 February 2019. This event was coordinated by the MRC Executive and was hosted by Lewis MacDonald MSP. Invitations were extended to all MSPs by the MRC. Richard Lochhead, Minister for Further Education, Higher Education and Science attended and gave a short speech. Cabinet Secretary for Health and Sport, Jeane Freeman also attended. From the CVR Alain Kohl, Claire Donald and Ben Brennan displayed at a stand with a poster, film clip of mosquitoes and augmented reality viruses with tablets. Massimo Palmarini and John McLauchlan attended as guests in the room. The CVR also extended the invitation to Vice Principal for Research Prof Miles Padgett, Dean for Research Prof Graeme Milligan and Head of Institute Prof Iain McInnes. In the run up to the event, the CVR followed up with 9 MSPs informing of our presence at the event. We received positive responses from Miles Briggs and Patrick Grady.
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/centreforvirusresearch/