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From: TSS ()
Subject: UK Strategy for Research and Development on Human and Animal Health Aspects of TSEs 2005-2008
Date: August 21, 2005 at 9:35 am PST

UK Strategy for Research and

Development on Human and Animal

Health Aspects of Transmissible

Spongiform Encephalopathies




Since the announcement in 1996 of a possible link between BSE in cattle and vCJD in

humans two strategy documents for research and development into transmissible

spongiform encephalopathies (TSEs) have been produced by the UK government. TSE

research has advanced significantly during the past few years, and as senior

representatives of the UK public funders of TSE research, we considered it timely to

review the current understanding of these diseases and set out a new research strategy

that reflected the changes in knowledge.

This document represents the first UK joint human and animal health strategy for TSE

research and addresses issues that affect livestock, the food chain and public health. It

highlights the improved co-ordination that has taken place between government

departments since the publication of the Phillips Report and reflects the overlapping

issues of relevance to both human and animal health.

In the production of this document, we have drawn on a wide range of advice from all of

the UK’s major funders of TSE research and from members of specialist advisory

committees such as SEAC, which are detailed within. We have also undertaken wide

consultation in the UK and overseas in an attempt to ensure the accuracy of the

information included. We are particularly indebted to Professor Chris Bostock (formerly

director of the Institute for Animal Health) for his 2004 review of the science, which

forms the backbone of this document.

With numbers of BSE cases continuing to fall and vCJD cases apparently stabilising in the

UK, it would be easy to be complacent. However, the increasing incidence of chronic

wasting disease in the USA reinforces the concern that TSEs are an international problem

and one that will need to be monitored carefully for a number of years. In the UK, there

remain key issues that continue to pose threats to animal and human health. Not least is

the possibility of a non-symptomatic carrier state or the emergence of BSE-like illness in

another species such as sheep.

While every attempt is made to reduce exposure to disease it is not always possible to

eradicate it completely. Disease management is thus often based on risk assessments of

potential exposure and these are based on the latest scientific results.

This document aims to highlight the major scientific uncertainties relating to TSEs and

how these will be addressed by the research and development strategies of the major UK

funders. The necessary experience of managing BSE and producing scientific evidence

upon which to base control policies has led to the development of an extensive UK

research base in human and animal health aspects of TSEs.

The UK has a special responsibility to share its expertise in TSEs with Europe and the rest

of the world to minimise the effects of TSE infection in other countries.

Although considerable progress has been made, further studies are required to fill in the

many gaps in our basic understanding of TSEs and in our knowledge of how TSE

epidemics can be effectively controlled. It is therefore vital that the UK research base is

maintained and that a co-ordinated and effective funding strategy is adopted for new

research. Science develops and inevitably this strategy will require regular reassessment.



Professor Sir John Pattison

Director of Research

Department of Health

Dr John Bell

Chief Executive

Food Standards Agency

Professor Colin Blakemore FRS

Chief Executive

Medical Research Council

Professor Julia Goodfellow CBE

Chief Executive

Biotechnology and Biological Sciences Research Council

Professor Howard Dalton FRS

Chief Scientific Adviser

Department for Environment, Food and Rural Affairs



Executive Summary

1. Transmissible spongiform encephalopathies (TSEs) have been present in human

and animal populations for centuries. Interest in them has intensified since BSE

became significant in British cattle in the 1990s and especially since its human

version became a hazard to the UK population.

2. The number of human fatalities from TSEs in the UK is relatively small, in the low

hundreds, and on this criterion TSEs currently appear to present a smaller risk to

public health risk than vascular disorders such as heart disease or strokes, which

are the UK’s biggest killers, or cancers.

3. However, the impact of TSEs has been high and they remain important for a

number of reasons. There may be human TSEs with longer latency periods than

those that have appeared clinically to date. This could mean a further cost in

terms of human life and suffering and to the healthcare system, where

considerable resource has already been committed to importing blood products

and improving safety measures such as the decontamination of surgical

instruments. Identification of another TSE in another species (e.g. BSE in sheep)

would affect consumer confidence in British produce, which would add a further

burden to a slowly recovering farming and meat industry.

4. The five major UK funders of TSE research each have their own remits, strategies

and approaches. The Department of Health and the Department for Environment,

Food and Rural Affairs are government departments with responsibility for human

and animal health, the environment and the agricultural industry. The Food

Standards Agency is a public body established to protect the public from food

hazards. The Medical Research Council and the Biotechnology and Biological

Sciences Research Council are non-departmental public bodies that fund research

in human and animal biology and health.

5. These bodies have different but related interests in TSE research. Although the

research councils pay attention to the applicability of the research they fund, they

have a strong interest in pursuing excellent science independently of its possible

use. The three government departments have responsibilities for human and

animal health, and for the environmental and economic ramifications of TSEs, and

require sound scientific information on which to base their policies.

6. These organisations are currently (2004/05) spending approximately £35M per

year on TSE research. The programmes supported by the five funders are

coordinated and discussed with other interested organisations, including devolved

UK administrations, the voluntary sector, industry and organisations outside the

UK, including the European Commission and research groups in the USA. Central

to this cooperation is the TSE R & D Funders Co-ordination Group.

7. Research on TSEs will continue to be necessary in part because of their economic

consequences for agriculture, an industry that is already under pressure from a

variety of sources. The National Scrapie Plan, which involves eliminating scrapie

from the UK sheep flock by removing sheep with lower levels of genetic resistance

to it, is costly and requires an adequate base of research knowledge.

Furthermore, as a large proportion of the UK population may have been exposed

to BSE-contaminated material, the implications for public health and the

additional burden on the NHS could be severe. Consequently it is imperative that

accurate estimates of the size of the human epidemic are obtained, methods to

prevent its spread are continually updated and potential treatments investigated.



8. Research in this area, especially that funded by the research councils, forms part

of the general process of advancing knowledge as well as being of practical value.

It has been informed by, and in turn informs, advances in our understanding of

protein and gene science, and knowledge of human and animal epidemiology. It

illuminates important areas of knowledge such as the strength and nature of

species barriers and infection processes, including species-to-species and possible

mother-to-offspring transmission.

9. Currently, TSEs are one of the rare disease groups where infection leads

invariably to death. For this reason, possible treatments are a target for both

human and animal TSE research. These might take the form of drug therapy or

immunological interventions such as vaccines. If developed for the human

population, such interventions would have a high value for patients and their

families despite the small number of people affected.

10. TSE research is a growing international field in which the UK has made a

significant contribution. The UK is likely to be a valued partner in TSE research

for other nations and for international organisations. TSE research has featured in

previous European Commission framework programmes for research and is likely

to be further funded under the sixth framework programme. The UK is a leader in

TSE science and in the cross-agency organisation needed to support the full range

of TSE research.

11. The approach to TSE research described in this report includes a number of shortterm

targets. One of the most pressing is the need for a preclinical diagnostic test

for humans and animals. Also important is work on the safety of medical

instruments, which is needed by the Department of Health and the UK National

Health Service. Other health-related research is directed towards the needs of

agencies such as the National Blood Service, which has an interest in blood

transfusion hazards. Research is also being pursued on methods for monitoring

food for TSE hazards, on animal feed hazards and on animal slaughter practices.

This is of interest to Defra and the FSA. Defra has a strong interest in research to

support the National Scrapie Plan, to investigate the possibility of BSE in sheep

and to establish the risk of TSEs in other farmed animals.

12. The aim of this research is to uncover the science of TSEs, in particular their

nature and means of transmission; to develop countermeasures at many points in

the food chain; to protect the health of the UK population; and to engage the

public in the research and its application.



2.5 The challenge of TSE strains

2.5.1 TSE agents are not uniformly infectious and they each cause disease with different,

predictable and specific characteristics.



2.5.2 The existence of distinct strains was recognised when sources of sheep scrapie were

serially transmitted to mice. A single inbred line of mice, in which all individuals make the

same PrPC, can propagate several different strains of scrapie, each with its own distinctive

incubation period, pattern of damage in the brain and PrPSc properties42, 43. Strain

variation also occurs in natural scrapie, and the recent discoveries of previously

unidentified strains, such as 221C44 and Nor9845, suggests that the spectrum of different

strains may change with time. Since different strains can have very different patterns of

pathology and distribution of PrPSc, their presence may be missed by the application of

standard sampling and testing protocols used for surveillance45. Although a single strain of

BSE appears to be responsible for the vast majority of cases around the world46, 47,

evidence is emerging that suggests that there may be other strains which have different

properties when transmitted to mice48 or result in different pathology or properties of PrPSc

in infected cattle49, 50.

2.5.3 Since different strains can be replicated in an identical PrPC background the

proteinaceous component of PrPSc produced by each strain must be the same. Thus, if PrP

is the only component of the infectious agent, the distinguishing features of strains must

be enciphered in hypothetically different shapes adopted by PrPSc. At least one of the

properties of strains, the size of the PrP fragment remaining after protease digestion, can

be transmitted to PrPC during conversion to PrPRes in vitro, which shows that PrPSc can pass

on elements of its distinctive 3-D structure to PrPC (51). Whether this structure determines

the properties of a strain, or is a consequence of it, can not be resolved in this system

because it has not yet proved possible to produce newly formed PrPRes that is infectious.

PrPSc isolated from brains of hamsters infected with various strains of TSEs have different

degrees of resistance to unfolding and, by implication, different structures52. This is

consistent with the idea that the shape of PrPSc is unique to a strain, but at present there

is no molecular model of what these different conformations might be or how they could

have such diverse biological effects.

2.5.4 Many strains of TSEs, even those that have been biologically cloned by repeated

passage within a species, can change their characteristics when transmitted from one

species to another. This is perhaps not surprising, if the prion hypothesis is correct, given

that different species have PrPCs with different amino acid sequences. BSE has been

transmitted to a number of different species either "naturally", through contaminated food,

as with cats, exotic ruminants, and humans, or experimentally, through injection or

feeding, for example sheep, goats and pigs. Each of these species has a different PrPC, but

where it has been tested, the strain characteristics of their BSE-derived TSEs are the same

as for BSE from cattle. This "stability" of the BSE strain in different PrP backgrounds

challenges the notion that shape of PrP in PrPSc encodes the properties of a strain. The

shape that, according to the prion hypothesis, defines the BSE strain must be independent

of differences, often large, between the amino acid sequence in PrPC. Alternatively, there

may be one or more other molecules (yet to be identified) that associate with PrP to

determine the strain properties. Knowing the molecular basis of TSE strains is, therefore,

at the heart of understanding the nature of the TSE agent.


2.6.11 Susceptibility-linked mutations in Prnp can be mapped to the molecular structure of

PrP to give pointers to the pathogenic roles played by different parts of the molecule. The

mutation that is associated with human GSS changes the amino acid proline to leucine at

position 102, but cannot be mapped to a structure because it is in the disordered Nterminal

tail. This mutation has been studied in transgenic mice with mixed results.

Transgenic mice that over-expressed the mutant PrP succumbed to a spontaneous

neurodegenerative disease and, although little PrPSc was present in the brains of the

affected mice, the disease was transmissible to other transgenic mice expressing low

amounts of the same mutant PrP, and to hamsters73. At the time this was an exciting

result, because it seemed to provide experimental evidence in direct support of the basic

tenet of the prion hypothesis – the spontaneous creation of an infectious form of the prion

protein. Recent attempts to repeat this result using "gene replacement" transgenic mice

have not resulted in mice which go down with a spontaneous spongiform encephalopathy

or which have infectious material in their brains74. Compared to their non-transgenic

littermates, however, they have dramatically altered response to a number of TSE

strains75, and the mutation that they carry extends the incubation periods of four different

strains of murine scrapie, although the extension varies considerably between the different

strains76. It is not known how this important mutation exerts its many effects, but it does

show the importance of the unstructured N-terminal tail of PrP in affecting the behaviour of

PrP and disease outcome. As noted above, there are many other mutations associated

with inherited forms of human TSEs. The ability to study them individually in transgenic

mice or cell culture, and map them on the structures of PrP, provides an opportunity to

understand how they affect the behaviour of PrPC and result in disease.


2.7 Inactivation of TSE infectivity

2.7.1 TSE agents are notoriously difficult to inactivate and are largely resistant to the

conditions normally used to kill viruses and bacteria. Of all TSE strains, BSE is amongst

the most resistant, a characteristic perhaps selected by its past need to have survived

multiple rounds of rendering in the production of meat and bone meal.

2.7.2 Much of the research into TSE inactivation has been pragmatic, exposing infected

material to harsh physical (heat, pressure) or chemical (acid, alkali, hypochlorite)

conditions and measuring the amount of infectivity that survives. From this have

developed several effective methods86, but understanding why TSEs are resistant to

inactivation should also give insight to the nature of the causative agent. Different TSE

strains vary enormously in their resistance to inactivation, which is consistent with the idea

that strains adopt different PrP conformations. The relative resistance of a strain to heat is

unaffected by the amino acid sequence of the PrP of the infectious material87. Thus if heat

resistance is determined by PrP structure, it must, like the other properties of the BSE

strain in different species, be independent of the sequence of PrP in PrPSc. There are three

phases to the heat inactivation of a TSE agent in wet conditions. In the first there is no

loss of infectivity as the temperature rises to a threshold, which varies widely between

strains, but is characteristic for a strain. The second phase follows this threshold and

involves rapid loss of some but not all infectivity. The third phase is prolonged with little

further inactivation88.

2.7.3 The survival of this "resistant" fraction presents the biggest challenge to ensuring

the safe disposal of TSE infectivity. The amount of surviving TSE infectivity can be greatly

influenced by prior conditions, for example drying, that may "fix" the infectious agent in a

dehydrated structure that is stable to disruptive physical or chemical conditions89. This

retention of an infectious state through dehydration is reminiscent of the survival of

infectivity with unaltered strain properties in material chemically fixed by formaldehyde for

the preservation of fine biological structure for analysis under the microscope90 (see also

Section 2.8). The ultimate example of a resistant core is the reported survival of a small

fraction of infectivity following exposure to dry heat at 6000C91.

2.7.4 The notion that fixed or dehydrated material can be infectious suggests that, under

some conditions, a "dead" or "dried" template can initiate an infection. If so, complete

inactivation of a TSE will only be achieved under conditions that allow the inactivating

agent access to the core of the infectious agent. It is important to determine what the

resistant material is, both to develop effective methods of inactivation as well as to

understand the chemical and physical forms of this infectious material.


2.11.1 A TSE begins when an infectious agent gains entry to the body, although for

sporadic and familial forms of CJD it may be that the infectious agent is formed

spontaneously within the body. The most likely routes of natural infection are through the

mouth or gut following consumption of contaminated food or water (oral) or through the

skin if cuts or abrasions are exposed to infectious material (cutaneous). Spread through

medical interventions (iatrogenic) has also happened, though rarely, in both animals164, 165

and humans166.

2.11.2 Unlike most other TSEs, scrapie is maintained in flocks naturally and must therefore

be transmitted horizontally and, perhaps, vertically, but it is still not understood how this

occurs. PrPSc is detected in about 80 per cent of placentas formed in scrapie-infected

sheep167, but is restricted to only the maternally derived caruncular endometrium and the

foetally derived cotyledonary chorioallantois. This suggests that the developing foetus

may never be exposed to infection in the uterus because it is separated from the PrPScpositive

allantois and chorioallantois by the PrPSc-negative amnion168. The accumulation of

PrPSc in the placentas of scrapie-infected ewes is controlled by the Prnp genotype of the

foetus and is only detected in the placentas of fully (homozygous) susceptible foetuses169,

170. However, the pattern of accumulation of PrPSc in tissues of fully susceptible lambs

after birth is the same for those born to scrapie-infected ewes as it is for those born to

uninfected ewes, strongly indicating that infection of lambs with scrapie is a post-birth

event170. This suggests that a placenta becomes infected with scrapie when a ewe is

infected and its lamb is of a susceptible genotype, and contaminates the lamb at birth.

Any other susceptible lamb in the flock exposed to this risk could also become infected,

but clearly that risk would be higher on farms using group lambing and the same location

each year (see Section 2.15.2). There is, however, much still to learn about how sheep

become infected in scrapie-affected flocks and, if contamination of the environment plays a

role, how long the agent persists.


2.11.9 As with scrapie and experimental BSE infections in sheep, infectivity and PrPSc

appear to be widely distributed in peripheral tissues and CNS in vCJD patients197, 198,

whereas they were thought to be restricted to the CNS in cases of spCJD199. However, the

application of detection methods with greater sensitivity has identified the presence of

PrPSc in the spleen and skeletal muscle of about one third of a group of patients who died

of spCJD in Switzerland between 1996 and 2002. Patients with peripheral PrPSc also had

longer duration of disease200. In view of the potential for ante mortem diagnosis, it will be

important to establish, given sufficient sensitivity of test, whether peripheral PrPSc can be

detected in patients with all forms of CJD.


2.12 The species barrier and the "carrier" state

2.12.1 The "species barrier" refers to the observation that it is usually more difficult to

transmit a TSE between two species than it is within a species. Transmission to a new

species can result in a low proportion of animals succumbing to disease, often after long

incubation periods. Other features of the species barrier include a shortening of the

incubation period for successive transmissions within the new species, the selection of

variant strains and altered pathogenesis. Cattle BSE transmits readily to mice, which

allowed them to be used for measuring BSE infectivity, but there is a significant species

barrier because mice are approximately 500-fold less susceptible to BSE than cattle221 and

there is significant shortening of the incubation period of BSE between primary and

secondary transmission in mice44. This species barrier appears to be removed by the

expression of high levels of bovine PrP in transgenic mice222, although no direct

comparison of susceptibility with cattle has been reported using the same preparation of

infectious material, as was the case for the species barrier between cattle and wild type

mice221. The basis of the cattle-to-mouse species barrier may reside in the difficulty cattle

BSE has in initiating an infection directly in the mouse’s brain, needing instead to be

processed through the lymphoid system. Unlike mouse-to-mouse transmissions,



intracerebral inoculation of mice with cattle BSE results in longer incubation periods than

does intraperitoneal injection90 and SCID mice, which are defective in peripheral replication

of TSEs, are relatively resistant to cattle BSE, even after intracerebral injection223.

2.12.2 One of the favoured experimental models of an extreme species barrier has been

the inability to produce clinical signs of TSE disease in mice following infection with the

263K or Sc237 strains of hamster scrapie, and it had been assumed by many that this

represented a complete block to the infection of mice. However, an absence of clinical

signs does not necessarily mean that the infectious agent has not replicated and spread

within the host, even causing recognisable lesions within the brain. For example,

transmission of six different sources of sporadic CJD to four strains of mice produced no

clinical signs of disease and no significant differences in survival relative to uninfected

controls, but did result in characteristic TSE-related brain pathology in the majority of such

mice surviving beyond 500 days224.

2.12.3 The hamster/mouse species barrier and the nature of the resultant carrier state

have recently been revisited225-227. As expected, transmission of hamster scrapie to mice

produced no overt disease and no evidence of TSE replication for about a year, after which

there was active replication and adaptation of new strains capable of causing disease in

mice, with limited evidence of PrPSc accumulation except after about 600 days. During the

first pass in mice, strains retained their virulence for hamsters, but after three or four

successive sub-passages in mice, mouse-trophic strains emerged.

2.12.4 Subclinical infection indicative of a carrier state can also be established after withinspecies

transmissions. Serially diluted, orally administered, 263K hamster scrapie resulted

in the detection of PrPSc in some healthy animals which survived to be culled at the end of

the experiment, some 239 days after the last clinical case. However, the small difference

between the calculated LD50 (the "lethal" dose which results in 50 percent of the animals

dying of clinical scrapie) and the ID50 (the dose which results in 50 percent of the animals

showing some sign of infection, which includes both scrapie deaths and PrPSc-positive

animals showing no clinical signs) indicates that the number of carrier animals would be

unlikely to exceed greatly the number of clinical cases228.

2.12.5 The potential existence of asymptomatic infected "carrier" animals or humans is of

great relevance to the effectiveness of surveillance and control programmes for BSE,

scrapie and vCJD and needs to be pursued. Lack of detectable PrPSc would preclude

detection by current diagnostic tests and such "carrier" animals or humans would

represent hidden reservoirs of infectivity, implying a risk of onward infection to others

through natural (scrapie) or iatrogenic (human) transmission.


2.15.3 Human disease With the first reported cases of vCJD following some 10 years after the start of

the BSE epidemic, and the recognition that the infectious agents of BSE and vCJD are

indistinguishable, it is generally assumed, although not yet proved, that BSE reached

humans via contaminated meat or meat products309-311. The ongoing case control study68

has not yet identified any major risk factors for vCJD, such as consumption of particular

meat products, but may in the future be important for identifying potential iatrogenic

cases of vCJD. Perhaps the closest link so far between vCJD and contaminated meat is in

the so-called Leicester cluster, five geographically associated cases of vCJD in

Leicestershire. Four of the five may have been exposed through eating beef purchased

from a butcher’s shop where meat could have been contaminated with brain tissue. It is

unlikely, however, that this scenario applies to the majority of vCJD patients. But if the

hypothesis is correct, it points to an incubation period in these four cases of between 10

and 16 years312. Leicester remains the only statistically significant cluster of cases of vCJD

in the UK68. The incidence of vCJD is about twice as high in the North of Great Britain as it

is in the South, but, so far, it has not been possible to link this definitively to dietary

differences313. It is difficult to ensure that all cases of vCJD are correctly diagnosed and

reported and there is always the worry that some could be missed. Variant CJD occurs in

a much younger age group than sporadic CJD68 and it is a concern that cases are perhaps

being missed in children and older adults. A survey of over 1,000 children with

progressive intellectual and neurological deterioration (PIND), a group that would include

vCJD patients, found only previously reported cases of vCJD, indicating that vCJD in

children is not being missed68, 314. Although vCJD has been diagnosed in a 74 year old

patient315, the possibility remains that cases of vCJD are being missed amongst the

elderly. One attempt to estimate the prevalence of infection, as opposed to the incidence

of clinical vCJD, is based on a search for the characteristic presence of PrPSc in infected

lymphoid tissue in archived specimens of tonsils and appendices removed from patients

aged 10 to 50 between 1995 and 1999. The interim findings of this study reported one

PrPSc-positive appendix amongst 8318 samples examined, which gives an estimated

detectable prevalence of PrPSc accumulation in 120 per million of the population316.

However, the finding of a further two PrPSc-positive samples, giving a total of three

positive samples in 12 674 samples examined, confirm the wisdom of screening the

larger number of samples being collected as part of the National Tonsil Archive333. As with scrapie, but not BSE, the Prnp genotype determines the incidence of

vCJD. In the UK about 37 per cent of the population are homozygous for methionine129,

12 per cent are homozygous for valine129 and the remaining 51 per cent are

heterozygous65. So far, all cases of vCJD that have been genotyped have been

homozygous for methionine at coding position 129 68. A similar, relatively greater,

susceptibility of homozygous methionine129 carriers is found in patients diagnosed with CJD

following growth hormone treatment317 and in Fore people succumbing to Kuru318, but it

can not be assumed that valine129 carriers will not also be susceptible to vCJD, albeit with

longer incubation periods. There have been several predictions of the future course of the vCJD epidemic,

based on mathematical models using the limited number of cases at the time319, 320. They

have in common a high level of uncertainty, with the predicted number of infections



ranging from a few hundred to over a million. A recent study321 indicates that, although

the level of uncertainty and the predicted maximum size of the epidemic have decreased

significantly, the estimated number of future cases for the present epidemic ranges from

10 to 7000. The study also confirms significant age-related susceptibility and/or exposure

to infectivity, with those aged between 10 and 20 years of age being at the highest risk of

infection. To accommodate the predictions of large numbers of infections, vCJD must have

a very long average incubation period, beyond that of the current normal life expectancy

of humans, so that only a few thousand would ever present with clinical disease322. The onsets of, and deaths from, vCJD are analysed statistically on a regular basis

to see whether overall trends can be detected. By 2000, onsets and deaths were

increasing year-on-year by 23 per cent and 33 per cent, respectively, indicating that the

epidemic was still increasing exponentially323. A similar analysis in 2002 of deaths from

vCJD suggests that the previously increasing trend may have slowed down with the death

rate having peaked in 2000, at least for the post-1969 born methionine129 homozygotes324.

This is very encouraging, although the situation could change dramatically if there were to

be a further rise in numbers. Indeed, hopes of an early end to the epidemic could be

dashed if the cases of vCJD seen to date represent a particularly susceptible group and

there are waves of infections in more resistant groups still to come.

snip... The relative diversity, in quantitative and qualitative terms, of scrapie strains

circulating in the UK and their significance in the expression and incidence of disease is

not known. Defra continues to fund research and surveillance work that addresses these

issues. For example, atypical patterns of PrPSc in obex samples taken from sheep with

relatively scrapie-resistant genotypes have been detected in surveys of sheep culled at

abattoir. Further investigations on these samples to establish the nature and biological

significance of these findings are in progress. There is also a concern over whether BSE,

if present in sheep, could be distinguished from scrapie when present in a single, or in a

mixed, infection and this is also being addressed. Studies are also in progress to

determine the effect of agent strain on the distribution of infectivity in tissues by

investigating different sheep breeds and genotypes that have been naturally infected

with scrapie. Recently atypical forms of BSE have been described in cattle but until the results

from transmission studies in mice are known, it is uncertain whether these represent

novel strains of BSE. Although the pathology of the BSE strain in cattle is considered to

have remained stable over time, ongoing studies are investigating the strain stability of

BSE within UK in comparison with an isolate found in Switzerland. Atypical cases of BSE

have been reported in other countries (notably Italy and Japan). The Veterinary

Laboratories Agency has quality control functions and is both the Community Reference

Laboratory (CRL) and the National Reference Laboratory for the UK. The CRL has set up

an Expert Group on strain typing, which met for the first time in June 2003. This Group is

responsible for putting in place protocols for investigating unusual samples (involving a

number of EU Reference Laboratories), as well as defining what constitutes an atypical

sample. However, diagnostic uncertainties suggest that confirmation of apparently

different strains of BSE in cattle will be dependent upon a better understanding of

molecular diagnostic techniques. In humans vCJD, thought to arise from exposure to BSE, is seen with a different

presentation from sporadic CJD. The MRC funds a programme of work in its Prion Unit

that is undertaking a molecular and phenotypic analysis of human prion strains. As part

of this work, it has been shown that infecting two different strains of inbred mice with the

same BSE isolate can produce two different types of PrPSc. Work is now ongoing to see

whether these differences will be maintained on passage through the same mouse line



and thus whether the host genes play a role in strain formation. Both DH and the MRC

will continue to support studies in this area.


3.2.1 The species barrier and the carrier state The possibility of ‘carrier’ states in animals and humans, and our present inability

to identify them, pose a potential threat to public and animal health. The susceptibility of

humans to BSE infection, and the ability of the disease to remain clinically silent for

many years, is of major concern to DH. Although the death of a UK blood donor from

vCJD in 1999 three years after making the donation and the subsequent death from vCJD

of the recipient in 2003 have not been causally linked, transmission of infection through

blood transfusion is the most likely explanation327. The case heightens concerns that

‘carriers’ could be transmitting the disease through blood, tissue and organ donation or

by contaminating surgical instruments when undergoing surgery. DH will continue to

support research to detect infectious prions in human tissue, to investigate the

decontamination of surgical instruments and to develop measures to protect blood

supplies. Animal models of some TSEs have detected infectivity in blood. Experiments,

which have involved transfusing large volumes of blood from infected sheep to healthy

recipient sheep, have demonstrated that infectivity can be transmitted by blood

transfusion. A central part of DH policy in this area has been the leucodepletion of blood

donations and the efficacy of this technology can now be tested in sheep. DH is also working with the National Blood Service to prepare for the introduction

of a blood-screening test, should one be developed in the near future. In addition to

preparing the logistics for this exercise, consideration is being given to the ethical issues

associated with screening blood donations. The possibility of interspecies transmission is a principal concern in animals. Food

animals other than cattle including pigs, sheep, poultry, deer and farmed fish have been

exposed to BSE infectivity via meat and bone meal. The FSA is funding research to

establish whether BSE can be or has been transmitted to other food species and if so, to

obtain information on the pathogenesis of the disease. Work funded by Defra is in

progress to investigate whether cattle experimentally challenged with scrapie exhibit a

disease which resembles BSE. Limited studies have shown that pigs experimentally dosed

with scrapie do not succumb to a TSE disease. New research is investigating the

experimental transmission of BSE to deer, and future studies may consider its possible

transmission to farmed fish. These potential risks, coupled with the knowledge of the

recent BSE cases in Canada and the USA, highlight the importance of good surveillance,

which remains a priority for government departments.


v6.1 A greater understanding of factors underlying the species barrier is likely to come

from progress in the research described in the other sections of this chapter, for

example, studies of the structure of PrP in different species, of TSE strains or of the

pathogenesis of TSEs. However, since most TSE infectivity assays are conducted in

mouse bioassays, it is important to know the relative sensitivity of detection when tissue

is titrated across a species barrier. For this reason, studies on comparative titration of

infectivity in cattle, sheep and mice (including transgenics) are being funded by Defra.

These studies will provide valuable scientific input to models of risk analysis and

epidemiological studies. The National Scrapie Plan has proceeded on the understanding that more

scientific information about the potential existence of infectious carrier states will be

pursued as the Plan proceeds, and on the relationship between PRNP and disease

susceptibility and the significance of scrapie strains. A high priority for Defra is to

supplement the existing studies that investigate whether sheep carrying PRNP genotypes

considered to be resistant to TSEs can act as carriers for infectivity (by searching for

infectivity in tissues and bodily fluids) and, if possible, to determine whether such

animals can transmit TSEs.




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