Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  Commercial kits are available to confirm disease on examination of the brain material removed from an animal. These include automated Western blot and ELISA tests to screen large numbers of samples.

• Commercial diagnostic kits available in Europe

  Commercial kits are available to confirm disease on examination of the brain material removed from an animal. These include automated Western blot and ELISA tests to screen large numbers of samples.

• Diagnostic kits validated by International, European or National Standards

  Yes

• Diagnostic method(s) described by International, European or National standards

  Methods are prescribed in the OIE Manual of Diagnostic Tests and Vaccines. Also in the consolidated EU directive 999/2001.

  Diagnostic examination of brain tissue

  a) histopathology

  b) immunohistochemical methods for PrPsc

  c) western blot

  d) rapid tests-western blot, ELISA

  Serological: no methods available as no immune response seen or other serological markers detected.

• Commercial potential for diagnostic kits in Europe

  Declining, with the reduction in BSE incidence in Europe and the consequent reduction in testing requirements. The validation process is lengthy for any new tests, and it is increasingly difficult to obtain the necessary numbers of samples in a commercially realistic timeframe.

• DIVA tests required and/or available

  Not applicable

• Opportunities for new developments

  There are limited opportunities for new developments in disease detection. There are sufficient tests available for the post mortem detection of PrP, and no alternative specific marker has been identified which might improve any aspect of disease identification or confirmation. Protein Misfolding Cyclic Amplification (PMCA), Real-time quaking-induced conversion (RT-QuIC) and Amyloid Seeding Assay (ASA) tests might be an opportunity since these methods are often (but not always) more sensitive than the bioassay, However the problem of false positives is difficult to tackle due to the ‘self nature’ of the agent. The development of such tests for widespread screening applications may be unrealistic considering the unusually high specificity demanded of TSE tests, although Rt-QuIC has been successfully piloted for surveillance applications in humans.

  GAPS:

  It would be useful to have form of in vivo screening test which could be used at a population level, most probably in the context of international trade of live animals

  The obvious gap is a live animal test which would identify animals in the pre-clinical phase of disease, and could be applied to the screening of populations such as whole herds, or specific import/export animals.

  Given the high sensitivity of these amplification tests their application could allow an in vivo diagnosis. The current uncertainties in the specificity of these techniques and the absence of standardisation between laboratories, will require the use of ad-hoc control sample and to replicate the experiments to achieve statistical significance. The is a lack of data also on the universality of such tests, and their ability, or not, to consistently detect and amplify all possible field isolates. A test which could be used for environmental testing would also be very useful.

• Vaccines availability

• Commercial vaccines availability (globally)

  None

• Commercial vaccines authorised in Europe

  None

• Marker vaccines available worldwide

  None.

• Marker vaccines authorised in Europe

  None

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Not applicable

• Commercial potential for vaccines in Europe

  None

• Regulatory and/or policy challenges to approval

  None

• Commercial feasibility (e.g manufacturing)

  None

• Opportunity for barrier protection

  None

• Opportunity for new developments

  If an in vivo test was developed which enabled the identification of disease at a sufficiently early stage, there may be the opportunity to develop therapeutic approaches for the treatment of human cases.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None available. Some chemicals such as pentosan are thought to delay disease progression in humans, and antibody therapies have been investigated experimentally. The literature in this area is sparse and in places appears contradictory.

• Future therapy

  None

• Commercial potential for pharmaceuticals in Europe

  None

• Regulatory and/or policy challenges to approval

  None

• Commercial feasibility (e.g manufacturing)

  None

• Opportunities for new developments

  None

• New developments for diagnostic tests

• Requirements for diagnostics development

  Live animal test is the gap in the market, although there are no potential methods for development at this point. See also Section “Diagnostics availability - Opportunities for new developments”

  GAP: Further developments in in vitro conversion tests should be encouraged. To develop new diagnostic tests for BSE and appropriately apply these to the correct target tissues, the availability of pathogenic material from preclinical animals is important. Previous pathogenesis studies for C-BSE performed in Europe have provided a lot of tissue useful for this goal but from development through validation to commercial availability will be time consuming and would take years. Equivalent tissues are not available for atypical BSE.

• Time to develop new or improved diagnostics

  The current problem with the development of tests is the availability of pathogenic material and of live animals known to be incubating the disease. This makes the development and validation of tests very time consuming and dependent on experimental models and/or on others providing the material for the laboratory and field validation. From development through validation to commercial availability would take years.

• Cost of developing new or improved diagnostics and their validation

  The development and validation of new tests for BSE is time consuming and labour intensive, which is costly. Costs cannot be specified as they will depend on the nature of the test and the cost of producing reagents and supplying reading or processing machines if necessary. Once validated there would need to be a commercial company willing to market the test.

• Research requirements for new or improved diagnostics

  Identification of an appropriate in vivo specific marker in an accessible body fluid (realistically this limits it to blood or urine).

  GAP:

  There is limited data on the consistency of performance of diagnostic tests for atypical BSE compared to classical BSE.

• Technology to determine virus freedom in animals

  Needs a live animal test to identify infected incubating animals

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  None

• Time to develop new or improved vaccines

  In the event of vaccines being required the time will be lengthy as the pathogenesis is not fully understood and there is currently no evidence of an immune response.

• Cost of developing new or improved vaccines and their validation

  Very high with the research needed to unravel the pathogenesis and to identify whether a vaccine is feasible.

• Research requirements for new or improved vaccines

  None

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  None

• Time to develop new or improved pharmaceuticals

  With the complexities involved in BSE pathogenesis the development of any pharmaceutical agent with be very time consuming and costly. Success is unlikely.

• Cost of developing new or improved pharmaceuticals and their validation

  Very costly.

• Research requirements for new or improved pharmaceuticals

  None required for animal health applications. While some therapeutic potential would be highly desirable in the human field, the number of cases likely to occur is too low to drive this as a commercial interest.

Disease details

• Description and characteristics

• Pathogen

  The BSE agent is considered to be a prion which is comprised largely of a self-replicating protein. The presence of a protease resistant isoform of a normal host cellular protein known as PrPSc is diagnostic. PrPSc is involved in the pathogenesis of the disease and is considered to be its main or only component. However, infectivity can be identified in the absence of detectable PrPSc, which may simply represent a test sensitivity issue, although it has been speculated that disease-specific but non protease-resistant forms of PrP may also exist. An alternative, less accepted, theory is that the agent is virus-like and possesses nucleic acids although these have never been demonstrated. Similarly, an essential involvement of co-factors (eg protein, mRNA etc.) has been mooted but not adequately identified or proven.

  GAPS: The pathogen cannot be isolated for diagnostic or typing purposes. PrPSc can be extracted from affected tissues such as brain, and used to categorise certain forms of disease, but this on its own does not constitute strain typing. The pathogen elicits no consistent host immune response that can be measured in the live animal. Due to the fact that PrPSc is an isoform of a normal host protein, immune tolerance should be expected. Identifying the mechanisms of PrP protein aggregation/deposition and the deleterious effect of such accumulations of protein is central to prevent this or to counteract the pathogenic consequences.

• Variability of the disease

  The first cases of BSE were recognised in the UK 1986 as a neurological disease of adult cattle. BSE is a transmissible spongiform encephalopathy (TSE) which is a degenerative disease of the brain in humans and some domestic and wild animals. Cattle are the main species affected, although people have been infected as well as captive wild ungulates, goats and felines. Currently, where sufficient surveillance data are available, the most relevant world-wide epidemiological pattern is a general and constant decline in the frequency of BSE in the field. Where the disease has occurred in other countries, it tends to have the same phenotype as the disease in the UK cattle population, and in many cases has been linked to the UK (either by movement of cattle or cattle feedstuffs). Studies on the lesion profile indicate uniform brain pathology, including after transmission in mice, suggesting only a single strain of BSE agent was present during the epidemic. Rare variants in predominantly older animals (classified as H- or L-type depending on their molecular characteristics in Western blots) have now been described in a number of countries. Given the rarity of these cases, their occurrence in aged animals and their widespread geographical distribution (including countries with no history of BSE) it is speculated that these cases may be spontaneous.

  Recently some C-type BSE cases in 5-8 year old cattle born several years after the feed ban implementation have been detected through active surveillance in both Canada and Europe. This may suggest that C-type BSE could also be a rare sporadic disease like the H- and L-type forms. However all those cases, unlike atypical forms, have only occurred in countries that experienced C-BSE epidemics and where residual sources of exposure may still exist.

  GAPS:

  The link – if any – between atypical and typical (classical) forms of BSE is still not known. It has yet to unequivocally established if these represent distinct pathogens, or are biological variants of the classical BSE pathogen (or vice versa). The zoonotic potential of these atypical forms is not known, but is strongly suggested by experimental data for one of the two atypical forms (L-type BSE). The pathogenesis of any form is still unclear.

  No agent or PrPSc is detectable in the infected animal for much of the incubation period, but it has not been established how much of this is due to test sensitivity limitations. Infectivity is known to be demonstrable in tissues prior to the accumulation of detectable PrPSc. The extent of the distribution of this undetectable infectivity is not known.

• Stability of the agent/pathogen in the environment

  The BSE Agent is extremely stable and resistant to freezing, heating, drying and cooking at normal temperatures, particularly if adhering to a surface. Pasteurisation and sterilisation will not destroy the agent, nor does chemical fixation for histology. Infectious titre can be reduced by some/all of these methods, but they are not absolute. However, as for all proteins, prions when sufficiently accessible to water can be destroyed by using warm alkaline conditions which hydrolyse the peptide bonds.

  GAPS: In practice, there is still no fully effective/practical decontamination method. Also no clear understanding of how any of these methods might affect the biological properties of any agent subjected to them. Could incomplete decontamination alter the pathogen in a way that might change pathogenicity/ host species range?

• Species involved

• Animal infected/carrier/disease

  BSE is primarily a disease of cattle. Disease in household cats (FSE) and in ruminant and feline species in zoos has been caused by the same agent. The pure silent carrier state has not been shown to exist. To our knowledge, infected animals ultimately develop the disease and die, although it could be argued that exposed animals which may be pre-clinical for their entire production lifespan, are effectively carriers. There have been two cases of BSE confirmed in goats in commercial herds, one in France and one in the UK. There is no evidence from retrospective studies that BSE has become established in the commercial sheep population, but experimental data confirms that sheep are susceptible orally, and can transmit the disease under normal husbandry conditions. They were exposed to the same meat and bone meal feed components as cattle during the epidemic. Work in transgenic mouse models has indicated that BSE, once passaged through a sheep, has a wider host range and an increased ‘virulence’.

  GAPS:

  There is no knowledge about how BSE might behave in a co-infection situation with another TSE, particularly scrapie in sheep, and how this might affect zoonotic potential. There is no reliable means of detecting infection in a live, clinically normal animal, so population screening cannot be undertaken. There is no understanding of what, if any, effect intercurrent illness or infection might have on susceptibility or disease progression, or shedding of infectivity. It is not known why only very small numbers of animals in a herd succumb to disease, when all animals in a cohort will be exposed to the same feed. It is assumed that the non-affected animals are not infected because there is no evidence of disease, or of the disease marker PrP. However, no effective means exists to screen a population for evidence of whether low level infectivity may be present in such animals, which were definitely exposed. The recent isolated occurrences of C-type BSE in some countries have been in animals born several years after feed ban implementations this still fits with the hypothetical ‘epidemic tail’ predicted by mathematical models.

  The lack of data on the pathogenesis of atypical disease forms, and therefore the absence of diagnostic sensitivity data for H and L-Type BSE in the field means that it is difficult to know if current surveillance approaches are fully effective for the detection of these atypical forms. It has already been demonstrated that approximately half of the cases detected so far have been in the healthy slaughter populations that are no longer tested. True prevalence data therefore does not currently exist.

• Human infected/disease

  Creutzfeldt-Jakob disease (CJD) is the human form of TSEs which can occur sporadically or associated with a hereditary predisposition or following iatrogenic contamination. Variant CJD first reported in March 1996 affects younger patients and is linked to exposure to BSE probably through food. Typical (C-type) BSE as well as L-type BSE has been shown to have the potential to affect humanised transgenic mice and primates. No equivalent data exists yet for H-type BSE. Iatrogenic spread in humans has occurred through blood transfusion only for variant CJD linked to the BSE agent. Iatrogenic spread of other, exclusively human, forms of CJD has occurred through growth hormone preparations, and corneal or dura mater grafts.

  GAPS: There is no substantial information on the zoonotic potential of atypical forms of BSE, or sufficient epidemiological data with which to undertake any effective risk analysis. There is a lack of clarity/agreement on which humanised transgenic models are the most appropriate for the assessment of zoonotic potential. Recent retrospective screening of human lymphoid tissue from the UK, sampled during the BSE epidemic, has revealed a prevalence of approximately 1:2000 samples containing PrP. The significance of this data in term of human disease risk, or evidence of dietary exposure, is unclear.

• Vector cyclical/non-cyclical

  None

• Reservoir (animal, environment)

  The role of environmental contamination and spread on fomites has been established for TSE in other species, such as scrapie in sheep and CWD in cervid populations. Environmental persistence of BSE has also been demonstrated under experimental conditions, but the limited peripheral tissue distribution of BSE in cattle probably reduces the likelihood of substantial shedding into the environment. Epidemiology certainly supports the assumption that the disease does not transmit readily if at all through direct animal to animal contact or via the environment, unlike TSE in sheep or cervid populations. In an experimental flock using normal husbandry measures, BSE was shown to spread between related sheep, where shedding and environmental contamination are likely to play a part, although modelling of this data suggests that infection might not be self-sustaining within this experimental flock.

  On farm burial has been banned in most areas for more than 10 years. However, there has been a recent derogation for outlying areas.

  GAPS:

  There is no data on the potential means or route of transmission or acquisition of infection in individual animals other than through feedstuffs. The recent C- type BSE cases in some countries indicate that residual feed contamination may have been problematic for several years after the feed bans came into effect.

  There are no effective methods to detect/confirm environmental decontamination – apart from infection studies.

• Description of infection & disease in natural hosts

• Transmissibility

  In cattle, transmission resulted from oral exposure to the prion agent in feed which contained protein derived from meat and bone meal originating from ruminants. BSE could be transmitted experimentally to a number of species by oral or parenteral exposure to infected cattle brain tissue. It can transmit naturally from animal to animal (route unknown) in sheep.

  The more recently identified forms in cattle (H and L-type) can both be transmitted experimentally by direct inoculation into the brain of cattle.

  Both L-BSE and H-BSE agents are able to propagate in other species following experimental challenge. There is a wider host susceptibility for L-BSE, with transmissions demonstrated in mice, sheep, voles, primates and hamsters, as well as in transgenic mice expressing heterologous, i.e. non-bovine, PrP sequences.

  Transmission of H-BSE isolates originating from France and Poland to bovine PrP transgenic mice has been reported.

  H-BSE failed to infect one line of “humanised” mice (Met129 PrP) supporting the view that the transmission barrier of H-BSE from cattle to humans (expressing this allele) might be quite robust.

  It has not yet been shown whether other routes could also be effective, although it has been suggested that the food-borne prion disease reported in ranch-raised mink in the past could have been the result of exposure the L-type BSE agent. Non-human primates have been shown to be highly permissive to L -type BSE, including the oral route.

  GAPS:

  Means or route of transmission or acquisition of infection in individual animals other than through feedstuffs. No data is yet available on the oral transmissibility of H- and L-types BSE, although this will be of particular relevance as and when feed controls are relaxed. Proof is lacking for excluding the existence of C-type BSE as a sporadic entity worldwide.

  The full interspecies transmission potential of H and L type BSE is not yet known for food animal species, or man. Further studies to determine this are currently ongoing. H-BSE has not yet proven transmissible to sheep or hamsters. The permissiveness to Atypical BSEs of “humanised” transgenic mice expressing the valine allele at codon 129 is currently unknown.

  The results from some experimental transmissions indicate that there may be an aetiological relationship between Atypical and Classical BSE, but further studies would be necessary to consolidate this.

• Pathogenic life cycle stages

  Not applicable

• Signs/Morbidity

  The commonest clinical signs are apprehension, hypersensitivity to touch and sound and ataxia. A range of signs can be seen related to changes in the mental state, sensation and alterations in posture and movement. General signs include weight loss and reduced milk yield. In general, morbidity is low, with the majority of cases arising as single cases on a farm despite all the animals on that farm being exposed to the same batches of feedstuffs. However in the UK some clustering of cases within the same herd was demonstrated. Signs may be different for the atypical forms of disease, at least at some stages of the disease. In these cases, dullness, difficulty in rising and ataxia feature most consistently. However, most of these cases have been detected through active surveillance and have not presented clinically, so this clinical data is derived mostly from a very small number of experimentally challenged animals. With 100 reported atypical cases worldwide over 10 years, it can be assumed that morbidity of these forms is also extremely low.

  GAP:

  There are no signs or diagnostic indicators of infection in infected animals during the long preclinical period. Information on the pathogenesis and tissue distribution of Atypical BSE in cattle through the study of field cases and experimental transmission studies is lacking.

• Incubation period

  The median incubation period is 4-5 years although a small proportion of cases early in the epidemic developed disease at less than 30 months. Incubation period is broadly related to infective dose. The pre-clinical period for the atypical forms is unknown, but they are detected predominantly in older animals under natural conditions. Most atypical field cases are older than 8 years of age, and some considerably more than this. It is speculated that these diseases are spontaneous neurodegenerative diseases on this basis, as well as on the basis of epidemiological trends. In experimental inoculation models in cattle, the incubation periods of H and L types are similar to that observed with classical BSE.

  GAP:

  All field-based incubation periods make the assumption that animals are effectively exposed within the first year of life. Cattle challenge studies investigating this age relation are presently being completed. There is some experimental evidence in sheep that age at exposure affects incubation period, with older animals becoming relatively less susceptible, but this has never been unequivocally established for cattle.

• Mortality

  Mortality is very low, as morbidity is, whereas lethality is 100% as there is no cure. Once an animal is infected death occurs within weeks to months of the onset of clinical signs.

• Shedding kinetic patterns

  None identified. There is limited involvement of gut associated lymphoid tissues which in other species, such as sheep, is linked to the possibility of shedding in faeces. Infectivity and PrPSc have been detected in tissues such as tonsil in cattle, so again low level shedding cannot be ruled out.

  GAP:

  It is not known if the failure to detect shed infectivity/ PrPSc is a consequence of test sensitivity or disease pathogenesis. It is possible that there is some shedding from infected cattle that is below the threshold of detection of the methods available to look for it, but there is no epidemiological evidence that this is a significant route of infection.

• Mechanism of pathogenicity

  BSE results in spongiform changes (vacuolation) in specific neuroanatomical areas throughout the brain which are visible on histological examination. Scrapie associated fibrils can be seen by electron microscopy. The misfolded protease resistant protein PrPSc is a very consistent component in the pathogenesis of the disease and accumulates mainly in the central nervous system and variably in the lymphoreticular system, in general more significantly in some of the affected species such as sheep. However it is not known which - if any- of these abnormalities directly results in clinical disease or death.

  GAP:

  There is a very poor understanding, not least because of the lack of a good experimental model, of the precise pathogenesis of disease at either the cellular or the whole animal level, or what leads to strain differences or zoonotic potential. Until it can be established whether infection is acquired through ingestion, or another route, or whether atypical cases are all spontaneous neurodegenerative diseases, it is not possible to know which experimental route offers the best model for studying pathogenesis. Currently data on the anatomical distribution of PrP is confined to end-stage disease, and predominantly intracerebrally-challenged animals. The limited availability of infected brain material prevents larger pathogenesis studies or a fulsome exploration of susceptibility by other routes. Similarly, the possibility that a small proportion of cases are genetic in origin cannot be excluded.

• Zoonotic potential

• Reported incidence in humans

  The annual incidence is extremely low, with most cases occurring in the UK. Analysis of vCJD diagnoses and deaths from January 1994 to December 2011 indicates that the peak was around 2000 and no second wave is evident (the last case of vCJD in the UK was diagnosed in 2013 and died the same year; no cases have been reported subsequently). However, it is not possible to rule out that the incidence of vCJD may increase again, particularly if different genetic subgroups with longer incubation periods exist.

  GAPS:

  The zoonotic potential of variant H and L type BSE is unknown, although primate and humanized transgenic mice susceptibility to L-type has been demonstrated.

  It still remains to be assessed whether a link between atypical forms of BSE and some sporadic CJD cases may exist.

  A key gap is that while we have good data on the prevalence of BSE infection in the cattle population we have very limited data on the prevalence of vCJD infection in the human population. This means that it is difficult to model possible second waves in people of the less susceptible non-MM genotype (at codon 129 of the human PrP gene), or the risk of secondary spread.

  A recent retrospective study of more than 30,000 UK human appendix samples identified PrP accumulation in approximately 1:2000 of the samples examined. All codon 129 polymorphisms were represented in the positive group. The relevance of these findings for the risk of clinical disease in humans is unknown, although it can be established that none of the known cases of vCJD are represented in this population. Unlike the situation recorded for clinical cases, all codon 129 polymorphisms were represented in the positive sample population.

• Risk of occurence in humans, populations at risk, specific risk factors

  Most cases of vCJD are believed to be of dietary origin, following ingestion of food containing the infective agent, particularly before the requirement to remove risk materials. The annual incidence of vCJD in the UK has declined but there is the possibility of a second wave in different genetic groups with longer incubation periods. There is also a risk of further cases infected via transfer of material such as blood or organs taken from infected individuals not yet showing clinical signs of vCJD, particularly before risk mitigation measures such as leukodepletion of blood. Sterilisation of instruments used in dentistry and surgery is critical to prevent the spread of infection, but this is not always fully effective and wherever possible disposable instrumentation is recommended.

  GAP:

  The human appendix study findings cannot be directly linked to any assessment of dietary exposure risks, because the study was double-blinded and there is no epidemiological data for these cases.

• Symptoms described in humans

  vCJD is a fatal neurodegenerative condition generally affecting younger persons (the median age at onset is 26 years) with a longer duration of illness (median 14 months) compared to other forms (median 4 months in the case of sporadic CJD).

  GAP:

  It is unknown whether all BSE transmissions in humans would manifest as vCJD.

• Estimated level of under-reporting in humans

  Low, as the clinical signs are quite distinct although differential diagnosis from other neurodegenerative conditions can be difficult in the living person. Within the UK, the establishment of the CJD surveillance unit, and the use of retrospective studies both greatly reduce the possibility of under-ascertainment of cases. However, surveillance levels may differ greatly between countries. At the European level, the EuroCJD network was established in 1993 to conduct epidemiological surveillance for Creutzfeldt Jakob disease. The surveillance of variant Creutzfeldt Jakob disease (vCJD) was regulated in the EU in 2000, and since 2007 Member States are requested to report all new vCJD incident cases upon official notification to the European Centre for Disease Prevention and Control (ECDC).

  GAPS:

  The differential diagnosis of CJD from other neurodegenerative diseases can be difficult in the living person.

  The screening of cases in other countries where the risk of vCJD is thought to be low, or negligible, may not be as rigorous.

  In all countries, surveillance in man is passive rather than active which may lead to significant underestimation of prion-related disorders as was seen in cattle and sheep when active surveillance programmes were introduced.

• Likelihood of spread in humans

  Low, as person to person transmission is unlikely with the exception of iatrogenic spread. The main risk is therefore through material derived from an infected asymptomatic person such as blood for transfusion, or organ transplants, which in turn is dependent on the prevalence of infection in the donor population. Leucodepletion of blood and risk-based sourcing provide risk mitigation.

  GAP:

  The latent period from exposure to tissue infectivity in humans is not known.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  BSE has an impact on the welfare of the affected animal.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  Wild species can become infected especially if fed contaminated meat and bone meal, or infected animals, but this has only been recorded in artificial situations such as zoos. It has not been identified as a problem for free-living species.

• Slaughter necessity according to EU rules or other regions

  Currently, in the EU it is required to slaughter clinical cases, cohorts which may have been fed the same ration within 1 year of the positive case, and recent offspring of BSE confirmed cattle, although this is optional i.e. there is the possibility of applying for a derogation to allow these offspring to live to the end of their productive lives. Indirectly it has also resulted in the slaughter of large numbers of small ruminants in the context of scrapie control measures which have been brought in because of the hypothetical risk of BSE in sheep and the identification of two naturally-occurring BSE cases in commercial goats.

• Geographical distribution and spread

• Current occurence/distribution

  Cases have occurred mainly throughout most of Europe. BSE has also been identified in the Americas and Asia. As a result of effective control measures the incidence has declined to very low levels in the past 5 years. Atypical cases have been identified in several European countries, in North America, Brazil and in Japan. Atypical cases might be considered sporadic, potentially unrelated to the epidemic of C-type BSE.

  GAP: Widely differing levels of surveillance are in place in different countries, so direct comparison is very difficult.

• Epizootic/endemic- if epidemic frequency of outbreaks

  The BSE epidemic was linked to an extended common source which was the result of the inclusion of ruminant derived protein (meat and bone meal) in cattle rations. Once meat and bone meal was eliminated from the rations the source of the infection was removed. However, the initial source of contamination was never identified. H- and L-type variants of BSE are hypothesised to be rare spontaneous diseases, although many of the cases identified so far were born before the implementation of fully effective feed bans in the respective countries. It is possible that classical BSE, like H and L-types are hypothesised to be, is a rare spontaneous disease which could once again be amplified through feed if the ban on intra-species recycling of meat and bone meal is relaxed. Cases of all three types of BSE have been born after the most rigorous feed bans, but the numbers of animals are too small to make any robust epidemiological assessment of this.

  GAPS:

  Occasional cases still arise, many years after the feed bans were put in place. It is unclear whether these can still be attributed to poor implementation/policing of the feed bans, or whether this now supports the notion that – like the more recently identified atypical forms of disease- BSE was originally a rare (possibly spontaneous) disease of cattle, in which case occasional cases will continue to occur. Moreover in light of recent experimental findings it cannot be excluded that L or H-type BSE might have been the origin of BSE. This highlights the fact that the origin of BSE has never been conclusively identified. This has implications for the time when existing bans and levels of surveillance are both relaxed.

  Similarly, the possibility that a small proportion of cases are genetic in origin cannot be excluded.

• Seasonality

  There is some seasonality to disease occurrence, but this is probably linked to seasonal stress factors arising from management e.g. calving patterns, which might precipitate clinical onset, rather than seasonality of the disease itself.

• Speed of spatial spread during an outbreak

  Not applicable.

• Transboundary potential of the disease

  The disease is generally spread by infected meat and bone meal. Occasional cases have arisen in imported animals in countries without a pre-existing case. If some categories of cases are sporadic, it is anticipated that such cases are present world-wide.

  GAP: If the disease is spontaneous in origin, then there is every likelihood that it could arise in any cattle population, and it would only be detected in a population with a comprehensive active TSE surveillance programme.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Ingestion of feed containing infective material.

  GAP:

  The means of disease acquisition is unknown for atypical forms of BSE.

  Some relatively young (5-8 year old) cases of classical BSE have also been identified recently, born almost a decade after the implementation of the feed bans: the role of possible residual sources of exposure is not known.

• Occasional mode of transmission

  There is no evidence of animal to animal spread. A very low level of maternal transmission may have occurred during the epidemic in the UK (this is also consistent with some of the statistical models applied to the C-BSE epidemic); it is also possible that this was due to a confounder effect and that both the dam and the offspring were infected via feed. Experimental sheep to sheep transmission of BSE has been demonstrated under normal commercial husbandry conditions, but modelling suggests that his would not be self-sustaining.

• Conditions that favour spread

  Feeding meat and bone meal or other protein derived from cattle in rations fed to cattle has been the principal reason for the spread of disease. Moreover the use of meat and bone meal or other protein in the feed of other species (e.g. pigs, poultry) facilitated accidental feed cross-contamination..

  In sheep, certain PrP genotypes – such as T rather than M at codon 112, and allelic variation at codon 168 have been shown to confer resistance to BSE specifically.

  GAP: There is no understanding of why only single animals out of groups fed the same feed will succumb. Some genetic factors have been explored, but there is no clear link to susceptibility to date. Other factors such as age at exposure and the presence of intercurrent disease are speculated to play a part, but none have been proven. Stress appears to predispose to clinical onset. The possible heterogeneous distribution of infectivity in feed could also play a role.

• Detection and Immune response to infection

• Mechanism of host response

  The disease does not elicit a conventional immune response in an affected animal, so this cannot be used as an in vivo marker of infection or disease. The accumulation of PrPSc in the brain, which is the earliest consistent and detectable disease-specific change, occurs without eliciting a classical host immune response, although there is activation of glial cells in the CNS. Antibodies can be raised against the prion protein in antibody production models, but there is no measurable humoral response in an affected individual, presumably because the majority of the abnormal protein is host generated.

• Immunological basis of diagnosis

  No measurable humoral immune responses have been detected in BSE cases, and although the glial response in the brain constitutes a form of immune response, it is not one that results in a measurable diagnostic parameter. Various immunochemical tests have been developed for surveillance purposes using PrP-specific antibodies, but these can only be applied post mortem. There is therefore no immunological basis for diagnosis in the live animal.

• Main means of prevention, detection and control

• Sanitary measures

  • Disease notification
  • Slaughter and disposal of suspected cases
  • Controls on the removal and disposal of specified risk material: i.e. tonsils and intestines in cattle at all ages; brains, eyes, spinal cord, skull and vertebral column form animals over twelve months of age (Key public health measure)
  • Ban the recycling of ruminant meat and bone meal (Key animal health measure)
  • Strict controls and enforcement
  • Separation of feed production lines to prevent cross-contamination
  • Option of culling cohorts of animals which may have been fed as calves on the same rations as the BSE confirmed case
  • Option of culling the recent offspring of confirmed BSE cases.
  GAP:

  There is very limited data on the distribution of PrP and/or infectivity in H- and L-type BSE affected animals. The data that does exist is confined to end-stage disease (i.e. no data on pathogenesis) and is largely derived from animals that have been experimentally inoculated intracerebrally. Peroral challenge studies are ongoing. This becomes an issue when SRM regulations are relaxed based on the prevalence of C-type BSE, when there is still no real understanding of the potential human health risks from dietary exposure to atypical types of the disease.

• Mechanical and biological control

  • Identification of all cattle
  • Movement controls, records, passports and traceability.

• Diagnostic tools

  Immunoblotting and ELISA are used to detect PrPSc in unfixed brain tissue. Diagnosis can also be made/confirmed on formalin fixed brain tissue using immunohistochemical or immuno-chemical methods to detect PrP. Methods using in-vitro protein amplification are shown to be very sensitive for the detection of some prion diseases, but have not yet been formally evaluated for application within statutory surveillance systems, although some have been successfully piloted for surveillance applications in humans.

  GAP:

  No diagnostic test exists to consistently detect BSE in the live animal. Protein amplification methods have been shown to be effective in BSE in sheep models but there is no data on the surveillance potential for these methods in cattle.

• Vaccines

  None available

• Therapeutics

  None available

• Biosecurity measures effective as a preventive measure

  BSE is a containment category 3 pathogen for humans (with derogations because it is not air-borne). Precautions should be taken when handling BSE infected material. There is no evidence that the live animal presents any specific risk to human health (apart from risk of injury from unpredictable behaviour). While there is no evidence from epidemiological studies that there is any proven occupation link between BSE and related human disease, recent evidence that other forms of TSE (CWD and scrapie) can transmit effectively through aerosol exposure (which is distinct from the pathogen being truly airborne) would nonetheless support the continuing use of precautionary principles when reviewing containment levels for this pathogen.

  GAPS:

  Clear consistent methods of decontaminating lab waste that are accepted internationally are required.

  Revision of containment category in light of the zoonotic disease statistics and lack of occupational occurrence.

• Border/trade/movement control sufficient for control

  Strict controls are imposed as recommended in the OIE Terrestrial Animal Health code. These controls are based on risk, BSE status of a country and species of animal moved.

• Prevention tools

  Current animal disease prevention focuses on the ban on the recycling of ruminant meat and bone meal. Current routine surveillance methods detect bone fragments and muscle fibres in feed. There are both serologic and PCR-based methods to distinguish the species of origin of any feed contaminants, and regulations stipulating feed screening requirements.

  Controls on the removal and disposal of specified risk material protect the human food chain.

  GAP:

  Comprehensive and appropriate detection systems for banned protein in feed, eg methods which would also detect soft tissue and fluids are being further developed.

• Surveillance

  Passive surveillance involves notification of the suspicion of clinical BSE to the authorities by the cattle owners and veterinarians. Active surveillance, using rapid diagnostic tests was introduced to identify pre-clinical and unidentified clinical cases, and demonstrated the poor performance of passive surveillance in terms of detection of TSEs. Active surveillance requires the removal of the obex section of the medulla from adult cattle either at slaughter, post mortem or point of disposal. Fallen stock are targeted as the most likely to be affected. The obex is tested using one of the validated tests, as defined in the EU regulations and the OIE Manual.

  GAP:

  Due to the low prevalence of the disease, surveillance systems may be unable to detect the disease if the number of tested animals is not very large. To demonstrate freedom from the disease in a country, the OIE requires the implementation of a surveillance system able to detect BSE at a design prevalence of at least one case per 100,000 in the adult bovine population, at a confidence level of 95 %.

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  The epidemic declined once the feed controls were strictly enforced and the specified risk materials banned. Isolated cases have occurred after the feed bans enforced in the EU. The origin of these is not clear. The epidemic continues to decline in countries where BSE existed. Additional control measures are in place to safeguard the human food chain as well as the animal one.

  GAP:

  There is still no satisfactory conclusion regarding the origin of the BSE epidemic. If C-BSE is, like H and L type are hypothesised to be, a rare spontaneous disease, then relaxation of the ban on intra-species recycling of meat and bone meal could ultimately result in a repeat of the epidemic. If it were confirmed in cattle that, as in experimental mouse models, H- and L-BSE can produce a TSE agent similar to that isolated from C-BSE , these atypical BSE cases may also represent a source of the disease.

• Costs of above measures

  All aspects of disease control are expensive. The greatest costs are surveillance, SRM and feed controls.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes. http://www.oie.int/animal-health-in-the-world/oie-listed-diseases-2016/

  In 2014, 12 countries (including the UK) reported a total of 12 cases (8 of which were atypical), and in 2015, a total of 7 cases (3 atypical) were recorded globally (all surveillance streams). Throughout the course of the epidemic a total of 28 countries have reported at least one case (in three countries, only atypical BSE has been reported), with a global total of 190,659, 97% of which occurred in the UK, with a peak of 37,280 in 1992. In March 2016 one case, born in 2011, was reported in France.

• WOAH disease card available

  Yes. http://www.oie.int/fileadmin/Home/eng/Media_Center/docs/pdf/Disease_cards/BSE-EN.pdf

• WOAH Terrestrial Animal Health Code

  http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_bse.htm

• WOAH Terrestrial Manual

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.04.05_BSE.pdf

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  High impact on individuals with vCJD, which is a chronic degenerative condition leading to death. However, the limited number of cases means that the overall impact in a country has always been low.

  As at April 2016 the majority of the vCJD cases had occurred in the UK (177) followed by France with 27 cases. The remaining 10 countries recorded between 1 and 5 cases only. Some of the cases outside the UK and France are thought to have become infected whilst in the UK.

• Zoonosis: cost of treatment and control of the disease in humans

  Treatment expensive, and currently unsuccessful, for individuals affected with vCJD. Animal disease is not treated and the animals are culled.

• Direct impact (a) on production

  Limited impact as most farms only had one case of BSE for which compensation was paid. However, this may not cover consequential loss. Also, the impact of a cohort cull could be greater as it might involve a number of animals in a herd.

  Currently the impact of the disease worldwide is really low. The UK is making good progress towards the eradication of BSE. Following a peak of over 37,000 clinical cases in 1992, the number of new cases now detected by active and passive surveillance continues to decline year on year, with just 1 case confirmed in the UK in 2014, 2 cases (1 classical case, and 1 atypical case confirmed in 2015 and no cases confirmed so far in 2016. A similar picture, although on a much smaller scale, is seen in the other affected countries.

• Direct impact (b) cost of private and public control measures

  Control measures, as follows, are expensive:
  • investigation, slaughter and compensation, disposal of carcasses.
  • culls of offspring, cohorts.
  • active surveillance of any cattle for slaughter, with over 10 million cattle tested each year in the EU.
  • disposal of cattle over 30 months for a 10+year period in the UK.
  • collection and disposal of SRM from abattoirs
  • enforcement of the controls.
  • trade bans

• Indirect impact

  Variable impact depending on the status of the country and the loss of export markets for animals and their products. Little impact on food security or on livestock production. Major impact on public confidence in food production.

• Trade implications

• Impact on international trade/exports from the EU

  Major impact on international trade in live cattle, meat and other products which were banned from countries with high incidence of BSE, as it was not possible to provide BSE clearance to herds or individual animals, and restrictions and bans on movements were imposed. Bans were also imposed on milk, semen and embryos although there was no evidence that they posed a risk.

  GAPS:

  If it is shown that BSE cases - including C-type BSE – are indeed sporadic, then the trade limitations currently imposed for EU countries would also have to apply to other continents where SRM measures are not in place if animal protein is not actively excluded from animal feed in those countries.

• Impact on EU intra-community trade

  Major impact, with bans on imports from countries considered to have a high incidence of BSE and which were thought to pose a risk in cattle.

• Impact on national trade

  Variable depending on the country and the measures imposed. In some countries whole herds were slaughtered following a single confirmed case. Overall the impact on national trade was minimal.

• Main perceived obstacles for effective prevention and control

  Lack of a diagnostic test to identify BSE in live animals.

  Inability to screen herds to identify those which were completely free of BSE.

  Sparse cases and long incubation periods make difficult to carry out epidemiological studies able to identify: (1) the causal relationships and the risk factors; (2) changes in the temporal trends and in the reoccurrence of the disease.

• Main perceived facilitators for effective prevention and control

  • Improved tests
  • Test for use in live animals.
  • Inexpensive tests for routine checking of animals at slaughter (although it can be argued that these are not necessary if SRM regulations stay in force).
  GAPS:

  The facilitators listed are also the current gaps. There is currently an uneven distribution of testing cost responsibilities across the EU. Some Member States subsidise testing costs, while others now view this as an industry cost.

• Links to climate

  Seasonal cycle linked to climate

  No

• Distribution of disease or vector linked to climate

  No

• Outbreaks linked to extreme weather

  No

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  No

Risk

• Provided infected material (SRM) is prohibited from entering the animal feed chain BSE cases should continue to decline. The current classical strain of BSE does not spread between cattle as, for example, scrapie will do in sheep. If new strains of BSE should appear which have the pathogenic characteristics of scrapie then control would be considerably more difficult, and with the potential for higher risks to humans.

  Unusual or atypical types of BSE have been identified. Two different molecular PrPSc patterns have been described, the L-type with low molecular mass and the H- type with high molecular mass of the protease-resistant prion protein. These do not have the same pathology, such as pattern of lesions in the brain, and the distribution of the PrPSc is also different. The animals do not display the same clinical signs as classical BSE. Laboratory transmission experiments indicate that the L-BSE agent has a significant zoonotic potential, which appears even higher than that of the C-type BSE agent.

Main critical gaps

• • Lack of a diagnostic test to identify BSE in live animals.
  • Absence of a test for the detection of environmental and/or feed contamination
  • Multiple areas of uncertainty in the understanding and knowledge of BSE remain, especially in relation to pathogenesis, immunology and epidemiology.
  There is current pressure to relax feed controls, and at the same time pressure from other sources to reduce surveillance. While the cost benefit argument can be applied successfully to either of these approaches, it would be necessary to maintain the ban on intraspecies recycling, and some baseline surveillance. However, the potential risk is not limited to intra-species recycling; recycling with cross-species transmission may be an ideal way to select or/and modify properties of TSE agents in the future.

Conclusion

• The case numbers of C-type BSE have declined rapidly, which is undoubtedly related to the strict controls on ruminant protein and its use in animal feed. Occasional cases still occur (including recently in animals 5-8 year old, both in the EU and North America), many years after the feed bans were put in place. It is unclear whether these can be attributed to poor implementation or policing of the feed bans, or whether they support the hypothesis that, like the atypical types of disease, C-type BSE was originally a rare, potentially spontaneous disease of cattle, in which case occasional cases will continue to occur. In light of recent experimental findings it cannot be excluded that atypical BSE might have been the origin of C-type BSE. This highlights the fact that the origin of BSE has never been conclusively identified. All of this will have implications once existing bans and levels of surveillance are both relaxed.

Sources of information

• Expert group composition

  Expert group members are included where permission has been given

  Marion M. Simmons - Veterinary Laboratories Agency (VLA- Weybridge) - [Leader]

  Angus Wear – APHA, UK

  Giuseppe Ru - IZS del Piemonte Liguria e Valle d'Aosta, Italy

  Cristina Casalone – IZS del Piemonte Liguria e Valle d'Aosta, Italy

  Barbara Iulini - IZS del Piemonte Liguria e Valle d'Aosta, Italy

  Maria Mazza - IZS del Piemonte Liguria e Valle d'Aosta, Italy

  Jan Langeveld – ID-DLO, The Netherlands

  Thierry Baron - ANSES, France

  Torsten Seuberlich – University of Bern, Switzerland

  Stefanie Czub - Canadian Food Inspection Agency, Canada

• Reviewed by

  Project Management Board

• Date of submission by expert group

  May 2016

• References

  WHO

  http://www.who.int/zoonoses/neglected_zoonotic_diseases/en/index.html

  CJD

  http://www.cjd.ed.ac.uk/vcjdworld.htm

  http://www.cjd.ed.ac.uk/documents/figs.pdf - accessed 8th April 2016

  http://www.cjd.ed.ac.uk/documents/worldfigs.pdf - accessed 8th April 2016

  OIE

  http://www.oie.int/eng/info/en_esbmonde.htm

  http://www.oie.int/animal-health-in-the-world/bse-situation-in-the-world-and-annual-incidence-rate/ - accessed 8th April 2016