Vector-borne transmission of lumpy skin disease virus

Lead Research Organisation: The Pirbright Institute
Department Name: Large DNA Viruses

Abstract

Lumpy skin disease virus (LSDV) is the causative agent of lumpy skin disease (LSD), an endemic disease of cattle in Africa and the Middle East where it produces significant economic loss and acts as a barrier to trade. Since 2012 LSDV has spread into Turkey, Europe, the Caucasus and Russia . The epidemic has resulted in the slaughter of thousands of cattle, mass vaccination campaigns, animal movement restrictions and export bans. One of the key knowledge gaps hampering control efforts is an understanding of how LSD is transmitted from animal to animal and herd to herd. LSD expert panels and numerous LSD-themed workshops in recent years have all identified research into vector-borne transmission of LSD as a high priority. This will be addressed in this research project.

The project hypothesis is:

Viable LSDV persists in insect vectors at suitable sites and for sufficient time to allow onward transmission to cattle hundreds of kilometres distant.

This proposed work involves two objectives running in parallel over 18 months.

Objective 1 To identify the most likely vector group responsible for transmission of LSDV.
This objective will undertake experimental transmission of LSDV from infected cattle by potential insect vectors in the high containment facilities at The Pirbright Institute. These studies will use contemporary virus detection techniques to distinguish between mechanical and biological transmission, and estimate the risk of different insect vectors that are present in Europe.
The vector potential of four insect species, Stomoxysis calcitrans (stable flies), Culicoides nubeculosus midge, and Aedes aegypti and Culex quinquefasciatus mosquitoes, will be investigated. The four species were each selected on the basis of their distribution in affected and / or threatened areas, evidence from the literature of their experimental or epidemiological link to LSDV transmission, and because they represent different feeding mechanisms (solenophagous vs telmophagous).

Objective 2 To assess the risk posed by LSDV and the potential impact of different control measures.
This objective will integrate the experimental results into models of LSDV and, hence, explore the risk of disease and impact of different control measures.

Overall the project will provide scientific evidence on vector-borne transmission of LSDV to enable effective and proportional LSD control programmes to be designed and the current Eurasian LSD epidemic to be contained.
The project utilises the unique and world-class expertise at Pirbright in lumpy skin disease research, multi-scale modelling of viral diseases of livestock, the biology of blood-feeding insects, in vivo transmission studies of viruses between natural ruminant hosts and vectors, and cutting-edge bioimaging of arthropods to study vector-borne transmission of LSDV.

The project is sponsored by an industrial partner MSD Animal Health, producer of the widely used Lumpyvax vaccine against LSD. MSD Animal Health are partnering Pirbright in this project to enable LSD vaccination campaigns to be augmented with scientifically rational control programmes aimed at reducing vector-borne transmission of LSDV. This approach is in accordance with Merck Animal Health's philosophy that their responsibilities extend beyond their primary business goals. By supporting this research project they aim to add value to efforts to control and eradicate LSD and thereby provide benefit to the environment and wider society as a whole.

The project is also supported by DEFRA, the UK government department responsible for protecting the UK from exotic diseases such as lumpy skin disease (LSD). This support emphasises the impact this research will have on reducing the risk of LSD incursion into the UK, and facilitating its rapid eradication if it does occur.

Technical Summary

Project hypothesis:
Viable LSDV persists in insect vectors at suitable sites and for sufficient time to allow onward transmission to cattle hundreds of kilometres distant

Objective 1 will undertake experimental transmission of LSDV by insect vectors in high containment facilities at The Pirbright Institute. Cattle will be inoculated with wildtype LSDV and then used as donor animals for insect feeding. Colony bred stable flies (Stomoxys calcitrans), midges (Culicoides nubeculosus) and mosquitoes (Aedes aegypti, Culex quinquefasciatus) will be fed on the cattle and processed for virus detection by multiple methodology at several incubation time points.
Insect will be processed either whole or dissected to process heads and body separately. Viral DNA and live virus will be quantified in the insects by qPCR and titration.
The location of the virus in the insects will be determined using immunofluorescence and electron microscopy.
Viral replication in the insects will be studied by examining insect tissues for viral mRNA transcripts, and looking for intracellular viral factories using electron microscopy.
The likelihood of onward transmission of LSDV by the insects will be estimated using a swab feeding system.
Viraemic donor blood as potential LSDV source will be trialled using a hemotek membrane feeding system as a future replacement for feeding insects on donor animals.

Objective 2 will address the current lack of a suitable mathematical model of LSD. A model will be built and used to calculate the basic reproduction number (R0) of LSD. This is a powerful tool with which to assess the risk posed by a disease. The experimental results from objective 1 will be used to build and optimise the model. The risk posed by LSD to regions of Europe, including the UK, and the impact of different control strategies will be explored.
This project will provide scientific evidence on vector-borne transmission of LSDV to enable LSD control programmes to be designed

Planned Impact

What is the benefit of this research?
Better control of lumpy skin disease. Ever since LSD entered Europe and the Caucasus in 2015 it has spread rapidly. Application of all available tools for LSD control (vaccination, quarantine and stamping out) has so far failed to halt the spread of the disease and it now threatens cattle in the rest of Asia and Europe including the UK. The outcomes from the proposed research project will supply information on vector-borne transmission of LSDV which will facilitate development of more effective, evidence-based control plans for LSD in the UK and elsewhere. The research project will answer key questions:
Which insects are capable of spreading LSD, and how long do they remain infective for (obj 1)?
This information is needed to (a) determine how wide restriction zones around an outbreak of LSD need to be, (b) identify which insects should be targeted in vector elimination programmes, and (c) calculate which climatic conditions and geographic regions of Europe are most conducive to rapid LSD spread, and therefore where pre-emptive vaccination programmes should be targeted towards.
Are subclinically infected cattle, which develop LSDV viraemia but no skin nodules, important in the epidemiology of LSD, and should they be targeted in LSD control programmes (obj 1 and 2)?
In other words should stamping out campaigns stipulate killing all cattle on affected farms or only the clinically disease cattle? Total stamping out is currently mandated by EU legislation but has been very unpopular with many rural groups and is very expensive.
Can vaccination campaigns alone prevent the spread of LSD (obj 2)?
Widespread vaccination to prevent LSD is relatively cheap compared to movement restrictions and stamping out policies. However it is unclear if it alone is efficacious at preventing LSD spread. Comparison of R0 under different conditions will allow policy makers to make informed decisions about which control strategies to implement.

Who will benefit?
For each beneficiary the timescale of the impact has been estimated as immediate (during the time frame of the project), medium term (1-5 years after the project has been completed) or long term (>5 years after the project has been completed)

1. Rural communities. This research will result in better LSD control and prevention strategies worldwide. Further spread of the virus into Europe and Asia will be inhibited and the impact of the disease in endemic areas reduced. This will result in direct economic and social benefits to rural communities in Africa, Asia and Europe. Medium to long term.
2. UK economy. The risk of LSDV reaching the UK will be reduced as a result of this research, therefore avoiding the loss of lucrative trade markets. The main trade-related economic consequence of a LSDV outbreak in the UK is loss of semen and embryo markets (there is very little live cattle trade from the UK). Medium to long term.
3. Vaccine companies. Knowledge of vector-borne LSD transmission will enable regions at most risk of LSD to be identified resulting in more effective targeted use of available vaccines. The benefit of this research to vaccine companies is highlighted by the participation of MSD Animal Health as an industrial partner in this project. Immediate, medium and long term.
4. Non-governmental agencies. LSD is a target for eradication by charities such as GalvMed and The Bill and Melinda Gates Foundation who will seek to implement the outputs from this research. Immediate and medium term.
5. International governments. The research proposed will provide information that can be used in programmes to eradicate LSD from low and middle income countries. LSD is endemic in many countries in Africa and has never been eradicated once it has entered a new region. The findings from the proposed research will contribution to the design of effective and economically viable vector control plans.

Publications

10 25 50
 
Description This grant focused on understanding the transmission of LSD. An experimental in vivo bovine model of LSD was developed and characterised. The model was then used to investigate the transmission of LSD. The work was carried out in collaboration with and supported by BBS/E/I/007036 and BBS/E/I/007037.
Key findings:
LSDV inoculation caused either a clinical or a non-clinical form of disease.
Clinical cattle developed multiple cutaneous nodules. High levels of virus were detected in the nodules of the skin.
Non-clinical cattle did not develop skin nodules, but low levels of LSDV were intermittently found in their skin and / or blood.
No direct transmission of LSD from clinical to in-contact non-inoculated control cattle occurred.
All four species of insects tested (Stomoxysis calcitrans (stable flies), Culicoides nubeculosus (midge), and Aedes aegypti and Culex quinquefasciatus (mosquitoes)) acquired LSDV from the nodules of clinical animals. Very few insects acquired LSDV from non-clinical cattle.
Insects retained LSDV for up to 8 days post feeding. The amount of virus present in the insects did not increase over time, indicating mechanical rather than biological transmission.
The data from the experiments was integrated into models of LSD transmission and used to predict the risk posed by different insect vectors in the transmission of LSDV.
The results of this research suggest a very specific model of LSDV transmission based on vector-borne transmission from clinical cattle only. Direct transmission plays little if any role, and non-clinical cattle play little if any role.
Exploitation Route The modelling of results from this grant indicated that the greatest uncertainty was associated with the insect to bovine transmission. This has been taken forward to a new grant (BB/T005173/1, Jan 2020 - Dec 2021) which will investigate the risk of insect to bovine transmission of LSDV.
The new knowledge from this project has been and will continue to be shared with key policymakers such as Defra and European government bodies, and used to optimise LSD control and prevention programmes.
Sectors Agriculture, Food and Drink,Environment

 
Description Lumpy skin disease virus is a neglected pathogen with many knowledge gaps present in our understanding of the virus and how it causes disease. This project has provided a much-needed evidence-base that has enabled policy makers to answer vital questions about the control and prevention of LSD such as: How wide should quarantine zones around a LSD outbreak be? Is vector control likely to be an effective component of LSD control programmes, and if so which vectors should be targeted? Are subclinically infected cattle important in the epidemiology of LSD? Should stamping out programmes be applied only to animals with clinical disease or all animals in an affected herd? Which climatic conditions are most suitable for rapid spread of LSD? Should pre-emptive vaccination programmes be implemented, and if so which areas should they be implemented in? We can now provide answers, or at least parameters, to help address these questions. These answers have been provided to key stakeholders including Defra and European policymakers as well as vaccine companies. The stakeholders have used the knowledge to devise more effective and proportionate control programmes.
First Year Of Impact 2019
Sector Agriculture, Food and Drink
Impact Types Economic

 
Description EFSA working group on lumpy skin disease
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
Impact Advice to European Commission and affected countries about control and surveillance for lumpy skin disease
URL https://efsa.onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2018.5452
 
Description Expert advice on a LSD vaccination strategy for the UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Expert advice on a Lumpy skin disease vaccine bank for the UK
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description I provided images of the gross pathology of lumpy skin disease (LSD) to Defra and to the Swiss veterinary authorities for the purpose of educating veterinarians and promoting rapid diagnosis of LSD should it emerge in Switzerland or the UK
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Livestock Viral Diseases Pathology Slide Set. A set of histology slides of tissues from livestock affected by notifiable viral diseases, provided free of charge to eleven veterinary training schools and institutes in the UK and Ireland.
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description BBSRC responsive mode funding
Amount £356,484 (GBP)
Funding ID BB/T005173/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2020 
End 12/2021
 
Description BBSRC-funded Oxford Doctoral Training Partnership in vivo skills award
Amount £15,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2020 
End 06/2021
 
Description Biotechnology and Biological Sciences Research Council (BBSRC) and University of Oxford joint Doctoral Training Project
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 08/2022
 
Description The Pirbright Institute Flexible Talent Mobility Account Innovation Fellowship
Amount £19,636 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2020 
End 10/2020
 
Title Ex vivo skin model 
Description An in vitro model of bovine skin has been developed, designed to allow feeding of dipteran species. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2019 
Provided To Others? No  
Impact This has already reduced the number of procedures carried out on cattle in our studies by providing an alternative to insects feeding on cattle. 
 
Title Microbiopsy method 
Description We have optimised a technique for cutaneous skin biopsy of cattle. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2019 
Provided To Others? No  
Impact The microbiopsy technique is less invasive and less painful than the traditional biopsy technique 
 
Description Livestock Viral Diseases Pathology Slide Set 
Organisation Scotland's Rural College
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Pip Beard (The Pirbright Institute) and Dr Sandra Scholes (Scotland's Rural College) designed a set of histology slides of tissues from livestock affected by notifiable viral diseases. The Livestock Viral Diseases Pathology Slide Set contains examples of lumpy skin disease, African swine fever, bluetongue, rift valley fever, and peste des petits ruminant. The slide set has been provided free of charge to eleven veterinary training schools and institutes in the UK and Ireland. This activity was included in the Pathways to Impact of BB/R002606.
Collaborator Contribution Dr Pip Beard (The Pirbright Institute) and Dr Sandra Scholes (Scotland's Rural College) designed a set of histology slides of tissues from livestock affected by notifiable viral diseases. The Livestock Viral Diseases Pathology Slide Set contains examples of lumpy skin disease, African swine fever, bluetongue, rift valley fever, and peste des petits ruminant. The slide set has been provided free of charge to eleven veterinary training schools and institutes in the UK and Ireland.
Impact None yet
Start Year 2018
 
Description MSD Animal Health and LIMT 
Organisation MSD Animal Health
Country United Kingdom 
Sector Private 
PI Contribution The Pirbright Institute is investigating the transmission of lumpy skin disease virus in partnership wtih MSD. MSD Animal Health are the industrial partner for this IPA award. The Pirbright Institute is developing a model of bovine LSD and using it to examine the risk posed by different insect vector species to the spread of LSD.
Collaborator Contribution MSD Animal Health are the industrial partner for this IPA award and provide 10% of the project funds. MSD Animal Health are the producers of one of the biggest selling LSD vaccines currently on the market (Lumpyvax). MSD intend to use the outputs of this project to enable LSD vaccination campaigns to be augmented with scientifically rational control programmes aimed at reducing vector-borne transmission of LSDV. This approach is in accordance with Merck Animal Health's philosophy that their responsibilities extend beyond their primary business goals. By supporting this research project they aim to add value to efforts to control and eradicate LSD and thereby provide benefit to the environment and wider society as a whole.
Impact See relevant sections of this form
Start Year 2018
 
Description 2019 Culture of Care Meeting Pirbright 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The fourth annual Culture of Care and 3Rs meeting was hosted at The Pirbright Institute on 16 October 2019. Dr Beatriz Sanz-Bernardo presented the advancements made in applying the 3Rs to lumpy skin disease research. These include refining biopsy procedures to minimise animal suffering and replacing laboratory experiments with simulations modelling host-vector interactions.
Year(s) Of Engagement Activity 2019
URL https://www.pirbright.ac.uk/news/2019/10/pirbright%E2%80%99s-2019-culture-care-meeting-focuses-anima...
 
Description Cheltenham Science Festival 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Attended the Cheltenham Science Festival and presented "Pandemic Live" an interactive debate on the spread of viruses in livestock. The audience were guided through the decision making processes that accompany an outbreak of an exotic livestock disease outbreak.
Year(s) Of Engagement Activity 2018
 
Description LSD Epizone 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Oral presentation at 13th annual epizone meeting, Berlin 2019. "Risk of transmission of LSDV from experimentally infected cattle to insect vectors". Beatriz Sanz Bernardo.
Year(s) Of Engagement Activity 2019
 
Description Livestock Viral Diseases Pathology Slide Set 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Pip Beard (The Pirbright Institute) and Dr Sandra Scholes (Scotland's Rural College) designed a set of histology slides of tissues from livestock affected by notifiable viral diseases. The Livestock Viral Diseases Pathology Slide Set contains examples of lumpy skin disease, African swine fever, bluetongue, rift valley fever, and peste des petits ruminant. The slide set has been provided free of charge to eleven veterinary training schools and institutes in the UK and Ireland. The aim of the slide set is to improve the ability of veterinary pathologists to diagnose exotic and notifiable livestock diseases of high consequence to the UK. The slides are also likely to be used in undergraduate veterinary training to increase the awareness of veterinary practioners of these diseases.
Year(s) Of Engagement Activity 2019
 
Description Microbiology Society talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Oral presentation at Microbiology Society Annual Conference 2019
Year(s) Of Engagement Activity 2019
 
Description Poster at IMAV 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Poster presentation at IMAV 2019: INTERNATIONAL MEETING ON ARBOVIRUSES AND THEIR VECTORS
05 - 06 September 2019
"Lumpy skin disease virus: transmission to dipteran vectors using animal and ex-vivo models" Beatriz Sanz-Bernardo
Year(s) Of Engagement Activity 2019
 
Description RAIG Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I presented the 3Rs aspects of the LSD bovine model we have developed in this project to the Research Animal Interest Group at University of Edinburgh veterinary school
Year(s) Of Engagement Activity 2019
 
Description eMergence autumn 2019 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Article for the MSD online publication eMergence.
Year(s) Of Engagement Activity 2019
URL http://www.emergence-msd-animal-health.com/