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TSE Capability - SE1961

Description
Classical BSE, first detected in the mid 1980s, is currently the only form of animal TSE that is accepted to be zoonotic, with human disease being associated with dietary (as opposed to occupational) exposure. However, animal TSEs in the form of scrapie have been endemic in some sheep populations for almost 300 years. The evidence that sheep could be experimentally infected with BSE resulting in a disease clinically indistinguishable from scrapie, and the detection of naturally-occurring BSE in two goats (one in France, and one in the UK) has led to EU-wide legislative controls to combat the BSE epidemic in cattle, and scrapie in small ruminants. Over the last two decades, these control policies, have resulted in the successful reduction and control of these diseases to a point where classical disease in the UK has been confirmed in only 2 cattle, 2 sheep and 25 goats in the last three years, compared to approximately 36,000 confirmed cases of BSE in cattle and 500 confirmed cases of classical scrapie in sheep per annum at the height of the BSE epidemic. Rigorous controls on the disposal of certain ruminant tissues (the Specified Risk Materials) have also minimised the exposure of the human population through food.
At an international level both surveillance requirements and disease control measures are gradually being relaxed (eg increasing the age threshold for the testing of fallen stock) or removed (active surveillance of healthy slaughter is no longer required; culling of affected sheep flocks is no longer mandatory, nor are breeding for resistance programmes), and food and feed chain controls are also being relaxed (eg the recent revision of the SRM Regulations).
Despite the success of these control measures in reducing the incidence of disease, there are still many things that remain unknown or unclear with regard to TSE. The nature of the agent is still debated, although the central role played by the prion protein is well established. How this abnormal protein gave rise to the BSE epidemic is more uncertain, however. Did BSE originate spontaneously in cattle, for example, or was it spread inadvertently from small ruminants prior ro its dissemination to the wider population via meat and bone meal? It has been demonstrated that different isoforms of this protein can encode for different ‘strains’ of disease, with varying biological properties, but very little is known about the stability of these ‘strains’. How much is inherent in the protein structure and how much is influenced by the species and/or genetics of the host, and – crucially – which aspects of a particular isolate or strain might confer zoonotic potential. There is also still very little known about how strain properties may change following, for example, passage through a different host, attempted inactivation or prolonged environmental exposure.
Since the introduction of EU-wide mandatory active surveillance in 2001 (EU reg 999/2001), atypical forms of disease have been recognised in both cattle and sheep at a very low but consistent prevalence, and with a global geographical distribution. These atypical diseases do not conform to the same epidemiological pattern as classical disease, and it has been speculated widely that these may be rare spontaneous disorders of older animals, that have no significance for animal health. This is the view currently supported by the OIE since, unlike classical BSE and scrapie, they do not meet the criteria for List B disease. Their different epidemiology also means that current disease control measures are ineffective. As a consequence, the presence of these diseases has not stopped the planned relaxation of the various classical disease control measures. However, experimental studies in cattle and sheep, as well as transgenic laboratory models have demonstrated that these ‘strains’ can transmit disease through inoculation and, in some cases oral exposure. However, in certain instances the biological properties of the agent can be altered to something resembling BSE, leading to speculation that the recycling of these atypical forms may in fact have been the origin of the feed-based epidemic.
Humanised transgenic mice, and macaques, have also been shown to be susceptible to experimental challenge with L-BSE, raising concerns about its zoonotic potential through the food chain. The current SRM measures, which have recently been relaxed, are based on our knowledge of the tissue distribution of infectivity in classical BSE, from oral challenge pathogenesis studies. There is no equivalent data for atypical BSE, and therefore no knowledge of the potential long term consequence of removing such regulations without any disease controls.
We also do not know if the sensitivity of surveillance is equivalent for classical and atypical forms of disease. Atypical scrapie was identified following the development of tests which happened to detect it, and it became apparent that cases had occurred previously but had not been detected by the surveillance methods available at the time. Some tests were subsequently delisted by the EU because they did not perform well on this subset of ovine cases. There is currently no systematically generated data on test sensitivity for atypical BSE in cattle, so we cannot estimate how sensitive the overall surveillance system is for these cases. However, historical surveillance data shows that approximately half of the cases detected in the EU were identified through the active screening of healthy slaughter animals, so by dropping this activity in 2013 we have effectively halved our detection rate. These cases have never presented through passive surveillance, possibly due to the experimental evidence that clinical disease in these animals is very different from classical BSE. It does however mean that atypical BSE should be on the list of differential diagnoses for any downer cow, so it reflects a lack of awareness/willingness to report suspicion, or that the wider clinical picture of cattle TSE is not well understood in the field.
The overall sensitivity of a field surveillance system depends both on the sensitivity of the tests used, and the way in which animals are sampled for screening in the first place. Cattle surveillance still requires that all fallen stock over a certain age must be tested. For small ruminants, however, the pragmatic need to focus on large throughput abattoirs for healthy slaughter screening of sheep, and the exclusion of some low throughput fallen stock centres for logistical reasons means that the target test numbers can be reached without all areas of the country being included. This leaves us with an anomalous situation that some goat herds and sheep flocks that have been depopulated and re-stocked do not currently undergo any surveillance, so we have no data on the effectiveness (or otherwise) of these policies, despite evidence in the literature of these methods not being fully effective. This then makes understanding the background to individual cases (eg the most recent classical scrapie case) more difficult.
There is also some evidence that the detected prevalence of atypical scrapie is dropping in the UK, but not elsewhere. This might suggest a drop in sensitivity of the surveillance system, rather than a biological phenomenon. An understanding of the power of our surveillance data is critical to underpin future risk assessments, and applications for negligible disease status.
Under EU Regulation 999/2001 we have an obligation to undertake the prescribed minimum surveillance activities including confirmation of disease, classification of any positive isolates and the systematic reporting of surveillance data. As the designated NRL for the UK, APHA Weybridge needs to maintain competence and capacity to provide, or coordinate, and troubleshoot all of these activities.
As a research group we have been active in the investigation of these diseases since the start of the BSE epidemic, and have a wealth of experience and data to build upon. The following work packages propose a range of work which builds upon and supports our personnel skill base across the full range of expertise, thereby helping us to maintain these skills for statutory applications, while building the body of knowledge on topics such as tissue distribution, test sensitivity, agent stability/variability, surveillance sensitivity in the field. This will ensure that our provision of outbreak consultancy and risk assessment in support of policy requirements are built on robust and current knowledge. We will also ensure that such data is disseminated as widely as possible through publication in peer-reviewed scientific journals, and the provision and dissemination of educational material relevant to farmers, and private and official veterinarians. APHA has contracted its TSE programme dramatically over the past 5 years but continues to provide an excellent delivery and expertise to Defra and the DAs of statutory and reference laboratory functions. Current strengths mirror its historical areas of expertise in pathology and epidemiology and we are developing and maintaining a network of excellence with other centres of prion research to cover shortfalls in molecular skills which have recently been exacerbated by retirements of key staff. This “outreach”, notably to past collaborators in Cambridge, Edinburgh and London, gives us a geographical balance and potential sources of expertise if we need to increase capability in the future by external training or recruitment.
Overall, the main policy questions that this proposal will help to address are:
• How robust is current UK surveillance?
This question encompasses testing sensitivity and specificity, sampling and population coverage, and the impact of species specificity, in particular the distinction between sheep and goats (not made in the legislation) but now an issue because goat scrapie is becoming more of a problem in UK than sheep scrapie, despite the disparity in population size.
• How effective is response to disease outbreak?
How do we ensure appropriate surveillance follow-up in premises, to monitor the effectiveness of culling, cleaning and disinfection, and subsequent re-stocking strategies.
• How likely is our system to detect ‘unknowns’?
For example, could we detect new and emerging (or re-emerging) strains, or previously undetected forms of TSE, and how confident are we that we would be able to classify them? How quickly would we be able to detect a re-emergence of existing forms?
• How much do we know about the risk that unknowns/atypicals present through the food chain?
What data do we have on tissue infectivity distribution to enable us to model this?
What data do we have on interspecies transmission of strains, and markers for zoonotic potential?
This proposal divides the work up into 4 main thematic workpackages which broadly reflect the main disciplines at APHA, but many of the deliverables are interdependent, and multidisciplinary.
Whilst the work carried out in Defra-funded projects is published as a final project report, publications in peer-reviewed journals are also desirable because they provide an assessment of the validity of the results, make the research results more visible to interested parties (particularly if published in open-access journals), raise the profile of the agency and may lead to further studies, including collaborations with others. They are not always, however, deliverable within the timeframe of the project, or may arise retrospectively from data analysis or cross-project collaborations. Where relevant, this proposal also identifies outstanding publications that will provide information that may be useful to make evidence-based decisions that affect TSE policy on national and international (EU) level.
Objective
WP 1 – Bioassay models
Objective 1.1: Assessment (by mouse bioassay) of the biological stability of atypical TSE isolates following experimental challenge of food animal hosts
Objective 1.2. Assessment of strain stability (by mouse bioassay) of isolates passaged experimentally through more resistant hosts
Objective 1.3 Assessment of strain characteristics following forced amplification in vitro
Objective 1.4 Assessment of strain characteristics (by bioassay) following prolonged exposure to the environment (in colaboration with Nottingham University, and ADAS)
Objective 1.5. Gather data on the diversity of UK goat scrapie isolates
Objective 1.6 Comparison of the sensitivity of bioassay and in vitro methods for the detection of infectivity in peripheral tissues
Objective 1.7 : complete the bioassay component of SE1867
Objective 1.8 Assess transgenic flies as a tool for infectivity assays (in collaborationwih Cambridge University)
Objective 1.9. Assess whether strain characteristics are preserved following amplification in transgenic flies
Objective 1.10. Freeze down current mouse lines to future-proof this resource against future genetic drift or colony problems
WP 2 - Models of infection and transmission in food animal species
Objective 2.1 Complete bioassays of atypical scrapie in other food animal species
Objective 2.2. Subpassage ovine H-BSE in sheep, and characterise the resulting disease, if any
Objective 2.3 Assess transmissibility efficacy of classical BSE in VRQ/VRQ sheep and assess strain diversity.
Objective 2.4 Complete data collection and analysis regarding peripheral tissue pathogenesis to assess the power of alternative surveillance approaches
Objective 2.5 to evaluate whether electrophysiological abnormalities suggestive of impaired auditory or visual function are linked to TSE diagnostic biomarkers
Objective 2.6 Challenge cattle with H or L BSE and collect full panel of policy relevant tissues (edible/SRM)
Objective 2.7 Monitor offspring of atypical scrapie ewe for evidence of disease
Objective 2.8. Introduce clean susceptible sheep to Ripley, following further decontamination, and look for evidence of disease
Objective 2.9 Screen management culls from repopulated goat herd to look for evidence of re-emerging infection
Objective 2.10. Establish disease prevalence and tissue distribution by screening LRS and brain from the 150 animals sampled in the context of the initial cull of scrapie infected goat herd.
Objective 2.11 Review current open-access data on TSE passive surveillance, create new training material as appropriate and identify dissemination strategies.
WP 3 – Molecular Sciences
Objective 3.1 Establish the field diagnostic limitations of PMCA for detection and isolate classification
Objective 3.2 Identify any MS markers that correlate with specific biological properties
Objective 3.3 Define the sensitivity limits of rapid tests in relation to strain types, tissue types and species that have not been formally assessed
WP4 – Epidemiology, Modelling and Risk Assessment
Objective 4.1 Research support for BSE in cattle
Objective 4.2 Assessment of Cleaning and Disinfection Protocols for TSE on farms
Objective 4.3 Research support for scrapie in sheep
Objective 4.4 Quantitative TSE infectivity risk assessment
Time-Scale and Cost
From: 2016

To: 2020

Contractor / Funded Organisations
APHA (Animal and Plant Health Agency)
Keywords
              
Fields of Study
Animal Health