From: TSS ()
Subject: SEAC Draft minutes of the open session of the 89th meeting held on 22nd
Date: November 18, 2005 at 9:54 am PST
Agenda
90th meeting on Thursday 24th November 2005
--------------------------------------------------------------------------------
Item No
Time
Item
Presenter
Paper No.
1
10:00
Introduction
SEAC Chair and Secretary
2
10:05
Approval of draft open minutes from SEAC 89
SEAC Chair
90/1 (167 KB)
3
10:10
Current issues
SEAC Chair
4
10:20
CJD Update
Prof J Ironside (NCJDSU)
90/2* (21 KB)
5
11:00
SEAC Epidemiology Subgroup update
Prof G Medley (Subgroup Chair)
90/3* (30 KB)
6
11:15
BARB case clusters
Prof J Wilesmith (Defra)
7
11:25
Slate paper
SEAC Chair
8
11:40
Horizon scanning
SEAC Assessors
9
12:10
Public Q&A
SEAC Chair
10
12:30
AOB
SEAC Chair
Lunch
* The contents of SEAC 90/2 and Annex 1 and 2 of SEAC 90/3 have not been circulated outside the committee as these documents contain prepublication reports and opinions provided in confidence.
On the afternoon of Thursday 24th November SEAC will consider unpublished data on vCJD infectivity in blood and unpublished research in animal models examining human to human transmission of vCJD and the correlation between abnormal prion protein concentrations and TSE infectivity. This part of the meeting will be held in closed session to allow discussion of this unpublished scientific information. This is in accordance with SEAC's code of practice.
http://www.seac.gov.uk/agenda/agen241105.htm
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©SEAC 2005
SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE
Draft minutes of the open session of the 89th meeting held on 22nd
September 2005
Church House
Dean's Yard
Westminster
London
SW1P 3NZ
Members: Professor C. Higgins (Chair)
Dr. D. Brown
Professor N. Hooper
Mr. P. Jinman (Deputy Chair)
Professor C. Lasmézas
Professor J. Manson
Ms. D. McCrea
Professor G. Medley
Dr. P. Rudge
Assessors: Mr. A. Harvey (FSA)
Mrs. E. Lawrence (DH)
DA Assessors: Dr. M. Simmons (NAW)
Technical Advisors: Dr. P. Barrowman (Defra)
Dr. S. Dixon (FSA)
Dr. D. Matthews (VLA)
Dr. J. Stephenson (DH)
Professor J. Wilesmith (Defra)
SEAC Secretary: Miss K. Richards
Secretariat: Dr. T. Barlow
Dr. N. Ebenezer
Dr. P. Keep
Dr. V. Lund
Dr. C. Ravirajan
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©SEAC 2005
Also in attendance: Mr. P. Burke (Defra) and
Mr. P. Holley (FSA) for item 4.
Professor A. Colchester (University of Kent) for
item 5.
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©SEAC 2005
ITEM 1 – CHAIR'S INTRODUCTION
1. The Chair welcomed everyone to the 89th meeting of SEAC.
2. The SEAC Secretary explained to members of the public that it
was the committee's policy to conduct as much of its business as
possible in open session. Holding open meetings allowed the
public an opportunity to observe the committee at work and
provided an insight into how an advisory committee provides
independent scientific advice to Government. External experts
and researchers involved in the studies that the committee will be
considering are present. During the meeting the Chair may invite
them to the committee table to present their work. Government
officials are also present as members of the audience. As these
officials are responsible for TSE policy in the various government
departments they may also be invited to contribute to
discussions.
3. The committee will also hold a reserved session in the afternoon
to allow discussion of unpublished research on BSE in sheep and
to be updated on current research at the Veterinary Laboratories
Agency (VLA). This is in accordance with the SEAC Code of
Practice.
4. Apologies for absence had been received from Professor
Margaret Stanley and Dr Jacky Chambers. Mr John Bassett
would attend the afternoon session. Members were reminded
that they are obliged to declare any commercial or other interests
they may have in the agenda items. The next meeting would be
held on Thursday 24th November 2005 at the Roxburghe Hotel,
Edinburgh.
5. The Chair announced that following a recruitment exercise
Professor James Nicoll has joined SEAC to replace Professor
Ironside. Professor Nicoll is Professor of Neuropathology at the
University of Southampton and Consultant Neuropathologist at
Southampton General Hospital and an expert in the field of
neurodegeneration with considerable experience of clinical
neuropathology. Unfortunately Professor Nicoll could not attend
this meeting but will attend the November SEAC meeting.
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ITEM 2 – APPROVAL OF MINUTES FROM SEAC 88 (SEAC 89/1)
AND MATTERS ARISING
6. The minutes of the open session of the 30th June 2005 meeting
were agreed as a correct record subject to the following
amendments:
• paragraph 9, ninth bullet point, line 5, change "…relied…" to
read "…relies…",
• paragraph 11, line 6 change "…live diagnostic test for
BSE,…" to "…diagnostic test for BSE in live animals…"
• paragraph 18, line 3 should read "Seprion Western blot test"
lines 5, 7, and 12 change "Prep-specific" to "PrP-specific"
• paragraph 21, line 2 change "…Byroad Platelet …" to
"…BioRad Platelia…"
• paragraph 27, line 4 change "…differential diagnosis…" to
"…definitive diagnosis…"
• paragraph 33, first bullet point, line 6 change "…number of
conditions…" to "…number of clinical conditions…"
• paragraph 65, line 2 change "…genotyping should be
combined if possible…" to "…genotyping data should be
combined if possible for statistical analysis…"
• paragraph 74, line 2 change "…confuse PrPSc with
infectivity…" to "…confuse the amount of PrPSc protein with
levels of infectivity…"
ITEM 3 – CURRENT ISSUES (SEAC 89/CURRENT ISSUES)
7. The committee was updated on the following issues:
• The Chair will meet the Executive Director of the European
Food Safety Authority (EFSA) at the end of September 2005.
The aim of the meeting is to develop a closer working
relationship between SEAC and EFSA.
• The current DH consultation on draft regulations is in
preparation for full implementation of the Human Tissue Act
(2004). The Chair proposed that SEAC should respond
formally to the consultation in relation to any potential
restrictions to TSE research from implementation of the draft
regulations. The SEAC Secretary had sought the views of
Professor James Ironside (NCJDSU), a past member of
SEAC. Professor Ironside responded that the draft regulations
restricted the use of organs, tissues, microscope slides and
blocks of tissue, collected after 1 April 2006, from hospital
autopsies for research or review without the consent of
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relatives or a nominated individual. This may be problematic
for retrospective review of autopsy material for public health
purposes. It was agreed that SEAC would make a formal
response to the consultation in relation to TSE research. The
Secretariat would circulate a draft letter in response to the
consultation along the lines suggested by Professor Ironside
to members for comment.
• The Over Thirty Months Rule would be replaced by a BSE
testing regime, expected to take effect from 7 November 2005.
• A Medical Research Council proposal to monitor the clinical
effect of vCJD treatment with pentosan polysulphate had
recently received ethical approval.
• The Cabinet Office Public Appointments Unit's newsletter aims
to stimulate interest in public bodies such as SEAC. The Chair
encouraged members to contribute to a possible future feature
on the work of the committee by making themselves available
for interview.
• Following advice from the CJD Incidents Panel (CJDIP), DH
announced, on 20th July 2005, an extension of precautionary
measures to reduce the risk of vCJD transmission through
blood transfusion and surgical procedures. DH had notified
around 100 people, who had donated blood to three people
who later developed vCJD, that they may have a greater
chance of being infected with vCJD compared with the general
population. These people had been asked not to donate more
blood or organs and to inform their medical practitioners
before undergoing dental or surgical treatment. This
notification procedure had gone smoothly. DH is awaiting the
outcome of a CJDIP review of the risk to other recipients
(about 1000) of blood from these donors.
• A TSE Joint Funders Group workshop on the research
potential for TSE diagnostic tests in live animals including
humans will be held on 13-14th December 2005. The Chair
will attend and invited members to suggest other suitable
attendees, especially from outside the TSE research
community that might contribute to discussion about
developing tests.
• Following the discussion at SEAC 88 on atypical cases of
scrapie and possible implications for the National Scrapie Plan
(NSP), the Chair wrote to Defra about the SEAC consideration
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of this issue. The Chair will meet Defra policy officials and
Veterinary Laboratories Agency (VLA) researchers in early
November to discuss further research in this area. SEAC or
its Sheep Subgroup will consider this issue further in the near
future. An EFSA opinion on atypical scrapie is expected in
mid-November 2005.
• A pre-publication copy of a paper1 that suggests that
evolutionary selection pressures may have maintained
variation in the prion protein gene in sheep was circulated to
members by email on 21 September 2005. Since the findings
had potential implications for the NSP, members were invited
to send comments to the Secretariat. Two independent
experts would also be invited to comment. SEAC or its sheep
subgroup will be asked to consider the paper in the future.
• A report2 of preliminary findings of natural transmission of BSE
between sheep in an experimental flock had been circulated to
committee members. The committee considered it important
to note that, to date, there has been no finding of naturally
occurring BSE in surveillance of the national sheep flock. This
research would be discussed further in the reserved business
session.
• A report3 describing the use of an automated protein
misfolding cyclic amplification (PMCA) technique to increase
the amount of abnormal prion protein in the blood of scrapie
affected hamsters to a detectable level was considered. After
PMCA, PrPSc had been detected in the blood of 16 out of 18
hamsters showing clinical signs of scrapie. A member
commented that while the method did not appear to give false
positives (PrPSc was not detected in the blood of any of the
non-infected animals) it would be important to examine why
PrPSc was not detected in two of the affected animals since
false negative results would invalidate it as a screening test. It
was noted that the authors suggested that, in these two
samples, PrPSc may not have been sufficiently amplified. It
was noted that the amplification phase of the test in the paper
took several days to complete and the detection was by
Western blot, a relatively insensitive detection method. The
authors had suggested that to develop the test further, the
1 Slate (in press) Molecular evolution of the sheep prion gene.
2 Bellworthy et al. (2005) Natural transmission of BSE between sheep within an experimental
flock. Vet. Rec. 157:206.
3 Castilla et al. (2005) Detection of prions in blood. Nature Medicine published online
28/08/05.
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time taken for amplification could be shortened, and a more
sensitive detection method used. The member considered it
important to see if the method could detect PrPSc in the blood
of pre-symptomatic animals. In addition, it would be important
to verify that other laboratories could reproduce these results
since some laboratories had reported unsuccessful attempts
at repeating a version of the PMCA technique in the past. A
member noted that laboratories in Italy and Germany had now
successfully used the technique but with fewer rounds of
amplification. It was also noted that the amplification step
required normal brain tissue from the same species, which
may hinder its use to screen human samples. Members
concluded that this sensitive technique was potentially
applicable to detection of abnormal prion protein in the blood
of live animals or humans in preclinical stages of infection.
However, it would require significant further development and
evaluation before it could be used routinely. SEAC
recommended that the method be considered at the TSE Joint
Funders workshop on diagnostic test development.
• A very short report4 and a full report5 about the detection of
abnormal prion protein and infectivity, respectively, in some
tissues of the peripheral and central nervous systems (PNS
and CNS) of BSE cases were circulated. It was noted that the
findings could potentially have implications for specified risk
materials (SRM) controls. The committee noted that the
findings from each study were in single animals at the clinical
stage of disease, and that the level of infectivity detected in
PNS tissue was considerably lower than in CNS tissue. The
issue would be discussed in more detail with unpublished data
in the reserved business session.
ITEM 4 – EU TSE ROADMAP (SEAC 89/2)
8. The Chair informed the committee that Defra and FSA have
asked SEAC to consider the European Commission TSE
Roadmap, published on 15 July 2005.
9. Mr Patrick Burke (Defra) explained the background to the request
and summarised the seven strategic goals outlined in the
Roadmap. The Roadmap envisages amendments to EU TSE
4 Iwamaru et al. (2005) PrPSc distribution of a natural case of bovine spongiform
encephalopathy. In Prions. Food and Drug Safety. Springer-Verlag, Tokyo, 2005.
5 Buschmann & Groschup (2005) Highly Bovine Spongiform Encephalopathy-sensitive
transgenic mice confirm the essential restriction of infectivity to the nervous system in
clinically disease cattle. J. Infect. Dis. 192, 934-942.
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controls in light of the decline of BSE in Europe, taking into
account new scientific evidence while continuing the aims of
eradicating BSE and maintaining a high level of consumer
protection. FSA and Defra are preparing for EU discussions on
translating the Roadmap proposals into amendments to
legislation. To inform these discussions, Defra and FSA asked
the committee to consider whether the Commission has identified
all of the risk issues that need to be taken into account. The
committee was not asked to consider the age limit for removal of
vertebral column since it considered this in detail at SEAC 85. It
is intended that Defra and FSA will seek further, more detailed
advice from SEAC in the future on specific proposals as they
develop. While the Roadmap foresees changes to risk
management measures, SEAC was asked to focus on whether
any risk assessment issues have been omitted and whether
additional scientific evidence is likely to be needed in support of
changes to legislation.
10. The committee considered the strategic goals in turn.
Strategic goals for the short- and medium-term (2005 – 2009)
Specified risk material
11. The committee recommended that, since removal of SRM is a
primary TSE-related public health protection measure,
amendments to SRM controls should only be reviewed in light of
emerging scientific findings on the distribution of TSE infectivity.
Measures must maintain the current high level of consumer
protection.
Feed ban
12. Members noted that appropriate feed controls are fundamental to
prevent recycling of potentially infectious material in animal feed
and re-emergence of a BSE epidemic. Any potential changes to
feed controls should therefore be considered very carefully.
Members suggested consideration should be given to
assessment of the risks associated with the use of fishmeal in
animal feed as it was unclear whether fish material would be
sufficiently contaminated with BSE to present a risk. Since there
is a great deal of movement of substances used in animal feed
both within and into the EU, potential risks could arise from
contaminated materials used in animal feed imported from
outside the EU. This might also be an area that required further
examination and risk assessment.
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13. Members asked why animal feed contamination with bone
fragments had been considered only in relation to beet pulp and
not other root vegetables. It was explained that this was because
beet was processed and used in the manufacture of animal feed.
In contrast, other root vegetables were used, unprocessed, at a
local level.
14. The committee was concerned that beet pulp should not be
considered different from other root vegetables without supporting
data. The committee considered it important to examine carefully
all the constituents of animal feed, the sources of those materials,
and then assess the potential TSE risks.
Monitoring programmes
15. The committee considered that appropriate surveillance is
essential to monitor the potential impact of other changes to
control measures. A member pointed out that measuring the cost
of surveillance in terms of the number of positive cases detected
did not reflect the importance of surveillance, and the cost might
best be expressed in terms of the number of negative cases
detected. It was considered that effective surveillance to
ascertain infection prevalence was very important as a public
health protection measure and an effective system should be
maintained.
Categorisation of countries according to BSE risk
16. The committee considered that, both within and outside the EU,
BSE surveillance regimes should be adequate in terms of
numbers of animals tested and testing procedures used to
evaluate the relative BSE risk between countries.
Review of culling policy with regard to TSEs in small ruminants
17. Members noted that culling could partly be driven by surveillance,
but because of the widespread distribution of infectivity in small
ruminants, culling could also be a consumer protection measure.
One key consideration in the assessment of future culling policy
appeared to be how often in the past other cases of the disease
had been identified in the same flock through culling.
18. It was noted that whole flock culling may adversely affect the
reporting of cases. The committee commented that, if maternal
or intra-flock transmission was found to be significant in sheep,
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this might impact on an assessment of culling as a risk reduction
measure.
Cohort culling in bovine animals
19. The committee considered that it was important to determine the
effectiveness of culling as a risk reduction measure and to
consider whether culling a cohort (whether defined by feed or by
birth) remained a proportionate response to risk in light of the
declining BSE epidemic.
UK restrictions
20. The committee agreed that, as the numbers of BSE cases in GB
have declined to similar levels found in the rest of Europe, this
was a logical step. In response to a question about the report of
the recent FVO mission to the UK, Mr Burke informed the
committee that the report was likely to be published soon. Its
conclusions were likely to be broadly favourable to the UK.
Strategic goal for the long term (2009-2014)
To modify measures in line with current technology and new evolving
scientific knowledge
21. The committee agreed that it would be appropriate for SEAC, in
the future, to look at the risks associated with modifying
measures such as SRM rules, in the light of new scientific
knowledge.
22. Members reiterated the view that it would be important to
maintain effective surveillance to ascertain infection prevalence
and to monitor the effect of changes to control measures. An
appropriate level of surveillance of chronic wasting disease
should be maintained in Europe.
23. Professor John Wilesmith (Defra) commented that, in deciding
upon appropriate surveillance measures, it was necessary to
decide upon the reason for the surveillance. Reasons include
preventing diseased animals going into the food chain, to inform
about the epidemiology of disease, or to detect the effectiveness
of control measures.
24. Members suggested that, as a further strategic goal, surveillance
programmes should be capable of monitoring potential changes
to TSE prevalence, and new TSEs or other similar diseases.
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There should also be mechanisms in place to deal with any
changes detected.
25. In conclusion, SEAC welcomed the Roadmap and made three
further general recommendations:
• changes to legislation in any one of the strategic areas might
impact on other areas, therefore no single strategic area
should be considered in isolation;
• there should be a watching brief on emerging science that
may impact on any of the measures under consideration.
• in the event of any changes to TSE legislation it would be
important to communicate effectively to consumers the
reasons for change.
ITEM 5 – HYPOTHESIS ON THE ORIGIN OF BSE (SEAC 89/3)
26. The Chair introduced a paper by Colchester & Colchester
(Lancet, 2nd September 2005)6 presenting a hypothesis that BSE
was originally derived from a human TSE. The hypothesis
suggested that, in the 1960s and 1970s, mammalian bone and
carcass material used in animal feed was imported into the UK
from the Indian sub-continent, particularly the area around the
Ganges, and contained remains from humans infected with CJD.
27. The Chair explained that he and Mr Peter Jinman (Deputy Chair)
had met with Professor Colchester (University of Kent) and Defra
policy officials to discuss the paper prior to publication. The Chair
thanked Professor Colchester for his willingness to discuss his
hypothesis and for the professional manner in which the
hypothesis was raised and presented, allowing a careful review of
the issue. He thanked Professor Colchester for attending the
SEAC meeting. The committee was asked to comment on the
plausibility of the hypothesis and the areas of research to test the
hypothesis suggested in the paper.
28. The Chair noted that from the discussions with Professor
Colchester and Defra policy officials it was entirely possible that
in the 1960s and 1970s animal feed from the Indian sub-continent
was contaminated with human remains. Although this could not
be proved unequivocally, there was good indirect evidence to
suggest that this may have occurred, and that this was a
6 Colchester and Colchester (2005). The origin of bovine spongiform encephalopathy: the
human prion disease hypothesis. Lancet. 366, 856-61.
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plausible route of infection. However, the question remains, how
likely is this route of infection? The committee should consider the
likelihood of whether a human TSE jumped the species barrier to
infect cattle, and the relative amount of such contaminated
material which might have been fed to cattle compared with the
amount of animal (sheep and cattle) carcasses which had been
used in cattle feed, and the biochemical evidence for
similarities/differences between human TSEs and BSE.
29. Members suggested that since prion infections are known to alter
their properties to adapt to new host species, it might be
impossible to establish the origin of BSE from the biochemical
characteristics of prion strains. Currently it is not possible to
predict the ability or likelihood of prion infections to cross species
barriers based on a comparison of the biochemical properties of
prion protein strains in two different species.
30. Dr Mike Simmons (National Assembly of Wales) asked whether it
was more likely that BSE was originally derived from a scrapie
strain or a human TSE. Members noted the possible origin of
BSE from scrapie had been investigated very carefully but it had
not been possible to determine whether or not BSE was originally
derived from a scrapie strain. Dr Danny Matthews (VLA) noted
that when sheep are infected with BSE by the oral route, on
second passage in sheep no reduction in incubation period was
observed. Therefore, it would appear that there is no significant
species barrier for BSE infection from cattle to susceptible sheep.
It was possible that there is also no species barrier for BSE
transmission from sheep to cattle, but this was not known. It was
also possible that BSE may have existed in sheep in the past but
had not been detected. Members noted that, although BSE was
known to be biochemically different from known scrapie strains, it
was also different from sCJD and other prion strains. It was
therefore not possible to establish biochemically whether BSE
originated from CJD, scrapie or other known prion strains.
31. Members noted that, although little information was available on
the relative amounts of human remains that could have
contaminated animal feed in the past, in all probability only a
small amount of human remains could reasonably have entered
feed. In comparison, the quantities of animal remains that
entered animal feed would have been very much larger.
Furthermore, although the size of the species barrier between
cattle and humans was unknown, it was likely that some barrier
existed. Taking both of these factors into account it seemed
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much more likely that the BSE epidemic originated from a
disease in cattle or sheep rather than in humans.
32. A member pointed out that bone material from the Indian subcontinent
was also exported to other countries, for example,
Australia, yet this had not caused an outbreak of BSE in these
countries. A member asked if this material was fed to cattle in
India and, if so, why there was not a similar epidemic of BSE in
that country. Professor Colchester responded that, as cattle feed
was prepared and used on a local level, isolated cases of BSE
might have occurred but such localised use would not result in an
epidemic. Since there was no rigorous surveillance of BSE in
cattle in India, isolated cases would not be detected. Dr
Matthews informed the committee that, although there is a
rendering industry in India, meat and bone meal would be fed
mainly to poultry and pigs, but not cattle for religious reasons.
33. Members noted that Professor Colchester's work had highlighted
the complex nature of production and movement of meat and
bone meal and also the possibility of contamination of feed with
human remains. Mr Burke explained that, although animal byproducts
from India were imported into the UK in the past and
may have been contaminated with human remains, control
measures implemented across the EU would now prevent the
importation of such material for either feed or fertiliser. There are
no EU approved rendering plants in India permitted to produce
meat and bone meal for use in fertiliser in the EU. Professor
Colchester asked for clarification about the controls on exports of
such materials from India to the EU as well as about controls on
imports reaching the UK. Mr Burke explained that exports to the
EU were checked at border inspection posts, but the controls are
rather complex and it would be better if Professor Colchester had
a copy of his report. The Chair said this would be helpful.
34. The Chair asked the committee to comment on the areas of
research to test the hypothesis suggested in the paper. A
number were interesting scientifically but the committee should
consider whether they might be important in terms of Government
policy.
35. The committee agreed that examination of the transmission
characteristics of human TSEs in transgenic mice expressing
forms of the human and bovine prion protein gene, or a human
CJD to cattle experiment, while potentially interesting, are unlikely
to inform TSE controls and are therefore not essential to conduct.
A member informed the committee that a number of experiments
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to test the transmissibility of BSE, vCJD, sheep scrapie and
sheep BSE in transgenic mice were underway to address
different questions, and may inform the above question. These
studies were using transgenic mice expressing human and
bovine forms of the prion protein that had been produced in
identical ways. Professor Colchester suggested that experiments
in transgenic mice might be less clear than studies that examined
transmissibility of human TSEs into cattle directly. Dr
Stephenson reminded the committee that experimental feeding of
human TSE material to animals was previously considered by
SEAC to be unethical.
36. Members noted that investigations of historic production of animal
feed were extremely difficult to undertake and had probably been
investigated as much as possible. Although it was important to
investigate possible feed related origins of BARB cases, further
investigation of feed manufacture processes in the 1960s and
1970s would not be worthwhile. Appropriate controls now appear
to be in place. The committee considered that the other areas of
research suggested in the paper were not within SEAC's remit.
37. In summary, SEAC:
• was grateful that the hypothesis was raised and for the
thoughtful and professional way in which Professor
Colchester had raised the hypothesis with the committee,
• considered the hypothesis plausible but for a number of
reasons considered that it was not the most likely origin of
BSE,
• was reassured that control measures were in place to
prevent possible transmission via the route identified in the
hypothesis,
• considered that although a number of interesting areas of
research had been identified, these were unlikely to affect
policy, and that it was also unlikely that the hypothesis could
be experimentally verified,
• agreed to produce a statement on the hypothesis.
ITEM 6 – SEAC EPIDEMIOLOGY SUBGROUP REPORT
38. Professor Graham Medley (Chair of SEAC Epidemiology
Subgroup) updated the committee on the Subgroup's second
meeting on 13th September 2005 which continued to address the
SEAC request to evaluate the nature and profile of the vCJD
epidemic. The Subgroup had reviewed the available data on the
prevalence of vCJD infection in the UK population and modelling
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studies, making extrapolations in areas where data gaps exist.
The importance of data acquisition in removing uncertainty about
the distribution of infection in the population had been highlighted.
Whilst modelling methods are useful to explore hypotheses on,
for example, the influence of age and genotype on infection,
because the disease incubation period and the level of infection
are unknown, any number of hypotheses were plausible. The
validity of hypotheses could only be tested with further data. A
position statement including a table of options for further data
collection would be prepared with the aim of presenting it at
SEAC 90. The Subgroup would meet early next year when
further modelling work was completed.
39. The Chair asked whether the modelling work underway was
sufficient to allow the Subgroup to address the questions SEAC
had asked the Subgroup to consider. It was explained that
modelling work was useful to provide quantification of
uncertainties around the epidemic but it was crucial that more
data were collected to remove these uncertainties and improve
understanding of the epidemic.
ITEM 7 – BSE DVD
40. The Chair explained that during the SEAC 88 discussion on
differential diagnosis of BSE, members expressed an interest in
viewing the DVD supplied to veterinary surgeons on the clinical
diagnosis of BSE in cattle.
41. Mr Burke informed the committee that the DVD had been
produced by a clinical neurologist at VLA and circulated to a
number of bodies including the State Veterinary Service, Meat
Hygiene Service and organisations representing veterinary
surgeons. The committee was shown extracts covering a number
of diagnostic tests for BSE and differential diagnosis of BSE from
other diseases with similar clinical signs.
42. Members welcomed the development of the DVD and noted it
would be very useful in maintaining knowledge of the clinical
symptoms of BSE, particularly amongst individuals who had not
had practical experience of the disease at the height of the
epidemic.
ITEM 8 – ANY OTHER BUSINESS
43. There was no other business.
http://www.seac.gov.uk/minutes/draft89.pdf
1
SEAC 90/2
CJD UPDATE
There is no discussion paper for agenda item 90/2, however Professor
Ironside will refer to the following papers during his presentation:
Polymenidou et al. (2005) Coexistence of multiple PrPSc types in individuals
with Creutzfeldt-Jacob disease. The Lancet neurology online, 31 October
2005.
Yull et al. (2006) Detection of Type 1 of the Prion Protein in Variant
Creutzfeldt-Jacob Disease. American Journal of Pathology 168, No.1,
January 2006 in Press.
http://www.seac.gov.uk/papers/90-2.pdf
1
SEAC 90/3
EVOLUTION OF THE SHEEP PRION PROTEIN GENE
ISSUE
1. To consider a recent paper on molecular evolution of the sheep
prion protein gene1.
BACKGROUND
2. The susceptibility of sheep to scrapie is known to be influenced by
polymorphisms in the prion protein gene (PRNP) especially at
codons 136, 154 and 171. Fifteen genotypes resulting from
variation at these codons have been identified. The genotypes
occur at widely differing frequencies in different breeds of sheep.
3. The National Scrapie Plan (NSP) for Great Britain consists of a
breeding programme to increase the number of sheep that
genetically are naturally resistant to transmissible spongiform
encephalopathies (TSEs). Its primary aims are to protect animal
health by reducing and eventually eradicating scrapie and to
protect public health from the theoretical risk of BSE (if it is present
and being masked by scrapie) by increasing levels of genetic
resistance to TSEs. The breeding programme consists of different
schemes and initiatives, based on various considerations including
the relative resistance of sheep carrying the ARR allele to scrapie.
4. The NSP implements a recommendation from the SEAC Sheep
Subgroup for a long-term control and eradication programme for
scrapie. At its most recent meeting in July 2004 the Subgroup
concluded that the underlying strategy of the NSP to breed for
scrapie resistance remains appropriate. However, it was
considered that the basis for the strategy should be continue to be
kept under review in the light of emerging scientific findings with
respect to the possible detection of scrapie infections in animals of
genotypes currently thought to be most resistant to infection.
1 Slate (2005) Molecular evolution of the sheep prion protein gene. Proc. R. Soc. B. 272,
2337-2344.
2
5. At SEAC 88, SEAC was informed about a range of studies on
atypical scrapie in sheep. The committee agreed that, now that a
number of issues around atypical scrapie are becoming clearer,
the SEAC Sheep Subgroup should consider the emerging scientific
information in more depth and the possible implications for the
NSP. The Subgroup will meet in January 2006.
SLATE PAPER
6. A paper by Jon Slate (see Annex 1) investigated the evolutionary
selection pressures acting on ruminant PRNP using a theoretical
approach of molecular evolution analyses of ruminant PRNP
sequence data. On the basis of these analyses, the author
concluded that PRNP in sheep has evolved by balancing selection
rather than positive selection. In other words, the natural evolution
of sheep PRNP has resulted in variation in the coding sequence to
include genotypes that are relatively susceptible to scrapie
because variation in the gene is favourable.
7. The author proposes a number of possible hypotheses for the
variation in sheep PRNP:
(i) susceptible genotypes confer some advantage(s) to sheep in
the absence of scrapie thereby maintaining PRNP variation over
time.
(ii) heterozygote genotypes are advantageous because they confer
relative resistance to scrapie compared with homozygous
genotypes.
(iii) relative susceptibility to scrapie is determined by the
compatibility of PRNP genotype of the host and the scrapie strain
such that incompatibility leads to a barrier to infection. Thus,
variation in PRNP could be maintained by exposure over time to
scrapie strains with different compatibilities, and therefore infection
efficiencies, with sheep genotypes.
(iv) variation in an untranslated region linked to PRNP influences
the expression levels of prion protein and therefore, susceptibility
to scrapie, which helps to maintain variation in the coding region.
8. The author suggests that hypotheses (ii) and (iii) appear to be the
most likely. This because there is evidence from humans and
sheep that heterozygote genotypes are more resistant to TSEs. In
addition, there is evidence that conversion of normal prion protein
to an abnormal form is most efficient when the genotype of the
3
host from which infection is transmitted and the recipient host is the
same.
9. The author notes that the aim of the NSP breeding programme is
to induce positive selection of a single relatively resistant genotype
to scrapie infection. Since this results in depletion in genetic
variation, it runs counter to the natural evolution of PRNP in sheep
that appears to favour variation. One possible implication is that
the NSP may produce a genetically uniform population of sheep
that could be susceptible to rare scrapie strain(s). In view of this,
the author recommends that further investigations of the role of
PRNP variation on resistance to rare scrapie strains and on fitness
and production traits be conducted. In addition, it would be
prudent to preserve existing PRNP variation, as frozen semen and
in managed populations.
INDEPENDENT REVIEWS OF THE SLATE PAPER
10. Due to the specialist nature of the molecular evolution approach
and analyses undertaken, the paper by Slate was sent to two
independent genetics experts. The experts were asked to review
the paper and to comment on the methodology used and the
implications for the NSP. The reviews have been anonymised and
are given at Annex 2.
ADVICE SOUGHT FROM THE COMMITTEE
11. The committee is requested to comment on the findings of the
Slate paper and the possible implications for the NSP.
4
SEAC 90/3 ANNEX 1
Slate (2005) Molecular evolution of the sheep prion protein gene.
Proc. R Soc B. 272, 2337-2344.
5
SEAC 90/3 ANNEX 2
Independent expert reviews of the paper by Slate
http://www.seac.gov.uk/papers/90-3.pdf
Lancet Neurology 2005; 4:805-814
DOI:10.1016/S1474-4422(05)70225-8
Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease
Magdalini Polymenidou a, Katharina Stoeck a, Markus Glatzel a b, Martin Vey c, Anne Bellon c and Adriano Aguzzi a
Summary
Background
The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.
Methods
We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.
Findings
We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.
Interpretation
The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.
Affiliations
a Institute of Neuropathology, University Hospital Zurich, Switzerland
b Present address: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
c ZLB Behring, Marburg, Germany
Correspondence to: Dr Adriano Aguzzi, Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
http://www.thelancet.com/journals/laneur/article/PIIS1474442205702258/abstract
what i been saying for years, that the diagnostic criteria differentiating between the nvCJD (i.e. 'the chosen ones') and the sCJD (i.e. 'the forgotten ones') has been terribly flawed from the beginning. ....TSS
Subject: SEAC Draft minutes of the open session of the 89th meeting held on 22nd
Date: November 18, 2005 at 9:54 am PST
Agenda
90th meeting on Thursday 24th November 2005
--------------------------------------------------------------------------------
Item No
Time
Item
Presenter
Paper No.
1
10:00
Introduction
SEAC Chair and Secretary
2
10:05
Approval of draft open minutes from SEAC 89
SEAC Chair
90/1 (167 KB)
3
10:10
Current issues
SEAC Chair
4
10:20
CJD Update
Prof J Ironside (NCJDSU)
90/2* (21 KB)
5
11:00
SEAC Epidemiology Subgroup update
Prof G Medley (Subgroup Chair)
90/3* (30 KB)
6
11:15
BARB case clusters
Prof J Wilesmith (Defra)
7
11:25
Slate paper
SEAC Chair
8
11:40
Horizon scanning
SEAC Assessors
9
12:10
Public Q&A
SEAC Chair
10
12:30
AOB
SEAC Chair
Lunch
* The contents of SEAC 90/2 and Annex 1 and 2 of SEAC 90/3 have not been circulated outside the committee as these documents contain prepublication reports and opinions provided in confidence.
On the afternoon of Thursday 24th November SEAC will consider unpublished data on vCJD infectivity in blood and unpublished research in animal models examining human to human transmission of vCJD and the correlation between abnormal prion protein concentrations and TSE infectivity. This part of the meeting will be held in closed session to allow discussion of this unpublished scientific information. This is in accordance with SEAC's code of practice.
http://www.seac.gov.uk/agenda/agen241105.htm
1
©SEAC 2005
SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE
Draft minutes of the open session of the 89th meeting held on 22nd
September 2005
Church House
Dean's Yard
Westminster
London
SW1P 3NZ
Members: Professor C. Higgins (Chair)
Dr. D. Brown
Professor N. Hooper
Mr. P. Jinman (Deputy Chair)
Professor C. Lasmézas
Professor J. Manson
Ms. D. McCrea
Professor G. Medley
Dr. P. Rudge
Assessors: Mr. A. Harvey (FSA)
Mrs. E. Lawrence (DH)
DA Assessors: Dr. M. Simmons (NAW)
Technical Advisors: Dr. P. Barrowman (Defra)
Dr. S. Dixon (FSA)
Dr. D. Matthews (VLA)
Dr. J. Stephenson (DH)
Professor J. Wilesmith (Defra)
SEAC Secretary: Miss K. Richards
Secretariat: Dr. T. Barlow
Dr. N. Ebenezer
Dr. P. Keep
Dr. V. Lund
Dr. C. Ravirajan
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©SEAC 2005
Also in attendance: Mr. P. Burke (Defra) and
Mr. P. Holley (FSA) for item 4.
Professor A. Colchester (University of Kent) for
item 5.
3
©SEAC 2005
ITEM 1 – CHAIR'S INTRODUCTION
1. The Chair welcomed everyone to the 89th meeting of SEAC.
2. The SEAC Secretary explained to members of the public that it
was the committee's policy to conduct as much of its business as
possible in open session. Holding open meetings allowed the
public an opportunity to observe the committee at work and
provided an insight into how an advisory committee provides
independent scientific advice to Government. External experts
and researchers involved in the studies that the committee will be
considering are present. During the meeting the Chair may invite
them to the committee table to present their work. Government
officials are also present as members of the audience. As these
officials are responsible for TSE policy in the various government
departments they may also be invited to contribute to
discussions.
3. The committee will also hold a reserved session in the afternoon
to allow discussion of unpublished research on BSE in sheep and
to be updated on current research at the Veterinary Laboratories
Agency (VLA). This is in accordance with the SEAC Code of
Practice.
4. Apologies for absence had been received from Professor
Margaret Stanley and Dr Jacky Chambers. Mr John Bassett
would attend the afternoon session. Members were reminded
that they are obliged to declare any commercial or other interests
they may have in the agenda items. The next meeting would be
held on Thursday 24th November 2005 at the Roxburghe Hotel,
Edinburgh.
5. The Chair announced that following a recruitment exercise
Professor James Nicoll has joined SEAC to replace Professor
Ironside. Professor Nicoll is Professor of Neuropathology at the
University of Southampton and Consultant Neuropathologist at
Southampton General Hospital and an expert in the field of
neurodegeneration with considerable experience of clinical
neuropathology. Unfortunately Professor Nicoll could not attend
this meeting but will attend the November SEAC meeting.
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©SEAC 2005
ITEM 2 – APPROVAL OF MINUTES FROM SEAC 88 (SEAC 89/1)
AND MATTERS ARISING
6. The minutes of the open session of the 30th June 2005 meeting
were agreed as a correct record subject to the following
amendments:
• paragraph 9, ninth bullet point, line 5, change "…relied…" to
read "…relies…",
• paragraph 11, line 6 change "…live diagnostic test for
BSE,…" to "…diagnostic test for BSE in live animals…"
• paragraph 18, line 3 should read "Seprion Western blot test"
lines 5, 7, and 12 change "Prep-specific" to "PrP-specific"
• paragraph 21, line 2 change "…Byroad Platelet …" to
"…BioRad Platelia…"
• paragraph 27, line 4 change "…differential diagnosis…" to
"…definitive diagnosis…"
• paragraph 33, first bullet point, line 6 change "…number of
conditions…" to "…number of clinical conditions…"
• paragraph 65, line 2 change "…genotyping should be
combined if possible…" to "…genotyping data should be
combined if possible for statistical analysis…"
• paragraph 74, line 2 change "…confuse PrPSc with
infectivity…" to "…confuse the amount of PrPSc protein with
levels of infectivity…"
ITEM 3 – CURRENT ISSUES (SEAC 89/CURRENT ISSUES)
7. The committee was updated on the following issues:
• The Chair will meet the Executive Director of the European
Food Safety Authority (EFSA) at the end of September 2005.
The aim of the meeting is to develop a closer working
relationship between SEAC and EFSA.
• The current DH consultation on draft regulations is in
preparation for full implementation of the Human Tissue Act
(2004). The Chair proposed that SEAC should respond
formally to the consultation in relation to any potential
restrictions to TSE research from implementation of the draft
regulations. The SEAC Secretary had sought the views of
Professor James Ironside (NCJDSU), a past member of
SEAC. Professor Ironside responded that the draft regulations
restricted the use of organs, tissues, microscope slides and
blocks of tissue, collected after 1 April 2006, from hospital
autopsies for research or review without the consent of
5
©SEAC 2005
relatives or a nominated individual. This may be problematic
for retrospective review of autopsy material for public health
purposes. It was agreed that SEAC would make a formal
response to the consultation in relation to TSE research. The
Secretariat would circulate a draft letter in response to the
consultation along the lines suggested by Professor Ironside
to members for comment.
• The Over Thirty Months Rule would be replaced by a BSE
testing regime, expected to take effect from 7 November 2005.
• A Medical Research Council proposal to monitor the clinical
effect of vCJD treatment with pentosan polysulphate had
recently received ethical approval.
• The Cabinet Office Public Appointments Unit's newsletter aims
to stimulate interest in public bodies such as SEAC. The Chair
encouraged members to contribute to a possible future feature
on the work of the committee by making themselves available
for interview.
• Following advice from the CJD Incidents Panel (CJDIP), DH
announced, on 20th July 2005, an extension of precautionary
measures to reduce the risk of vCJD transmission through
blood transfusion and surgical procedures. DH had notified
around 100 people, who had donated blood to three people
who later developed vCJD, that they may have a greater
chance of being infected with vCJD compared with the general
population. These people had been asked not to donate more
blood or organs and to inform their medical practitioners
before undergoing dental or surgical treatment. This
notification procedure had gone smoothly. DH is awaiting the
outcome of a CJDIP review of the risk to other recipients
(about 1000) of blood from these donors.
• A TSE Joint Funders Group workshop on the research
potential for TSE diagnostic tests in live animals including
humans will be held on 13-14th December 2005. The Chair
will attend and invited members to suggest other suitable
attendees, especially from outside the TSE research
community that might contribute to discussion about
developing tests.
• Following the discussion at SEAC 88 on atypical cases of
scrapie and possible implications for the National Scrapie Plan
(NSP), the Chair wrote to Defra about the SEAC consideration
6
©SEAC 2005
of this issue. The Chair will meet Defra policy officials and
Veterinary Laboratories Agency (VLA) researchers in early
November to discuss further research in this area. SEAC or
its Sheep Subgroup will consider this issue further in the near
future. An EFSA opinion on atypical scrapie is expected in
mid-November 2005.
• A pre-publication copy of a paper1 that suggests that
evolutionary selection pressures may have maintained
variation in the prion protein gene in sheep was circulated to
members by email on 21 September 2005. Since the findings
had potential implications for the NSP, members were invited
to send comments to the Secretariat. Two independent
experts would also be invited to comment. SEAC or its sheep
subgroup will be asked to consider the paper in the future.
• A report2 of preliminary findings of natural transmission of BSE
between sheep in an experimental flock had been circulated to
committee members. The committee considered it important
to note that, to date, there has been no finding of naturally
occurring BSE in surveillance of the national sheep flock. This
research would be discussed further in the reserved business
session.
• A report3 describing the use of an automated protein
misfolding cyclic amplification (PMCA) technique to increase
the amount of abnormal prion protein in the blood of scrapie
affected hamsters to a detectable level was considered. After
PMCA, PrPSc had been detected in the blood of 16 out of 18
hamsters showing clinical signs of scrapie. A member
commented that while the method did not appear to give false
positives (PrPSc was not detected in the blood of any of the
non-infected animals) it would be important to examine why
PrPSc was not detected in two of the affected animals since
false negative results would invalidate it as a screening test. It
was noted that the authors suggested that, in these two
samples, PrPSc may not have been sufficiently amplified. It
was noted that the amplification phase of the test in the paper
took several days to complete and the detection was by
Western blot, a relatively insensitive detection method. The
authors had suggested that to develop the test further, the
1 Slate (in press) Molecular evolution of the sheep prion gene.
2 Bellworthy et al. (2005) Natural transmission of BSE between sheep within an experimental
flock. Vet. Rec. 157:206.
3 Castilla et al. (2005) Detection of prions in blood. Nature Medicine published online
28/08/05.
7
©SEAC 2005
time taken for amplification could be shortened, and a more
sensitive detection method used. The member considered it
important to see if the method could detect PrPSc in the blood
of pre-symptomatic animals. In addition, it would be important
to verify that other laboratories could reproduce these results
since some laboratories had reported unsuccessful attempts
at repeating a version of the PMCA technique in the past. A
member noted that laboratories in Italy and Germany had now
successfully used the technique but with fewer rounds of
amplification. It was also noted that the amplification step
required normal brain tissue from the same species, which
may hinder its use to screen human samples. Members
concluded that this sensitive technique was potentially
applicable to detection of abnormal prion protein in the blood
of live animals or humans in preclinical stages of infection.
However, it would require significant further development and
evaluation before it could be used routinely. SEAC
recommended that the method be considered at the TSE Joint
Funders workshop on diagnostic test development.
• A very short report4 and a full report5 about the detection of
abnormal prion protein and infectivity, respectively, in some
tissues of the peripheral and central nervous systems (PNS
and CNS) of BSE cases were circulated. It was noted that the
findings could potentially have implications for specified risk
materials (SRM) controls. The committee noted that the
findings from each study were in single animals at the clinical
stage of disease, and that the level of infectivity detected in
PNS tissue was considerably lower than in CNS tissue. The
issue would be discussed in more detail with unpublished data
in the reserved business session.
ITEM 4 – EU TSE ROADMAP (SEAC 89/2)
8. The Chair informed the committee that Defra and FSA have
asked SEAC to consider the European Commission TSE
Roadmap, published on 15 July 2005.
9. Mr Patrick Burke (Defra) explained the background to the request
and summarised the seven strategic goals outlined in the
Roadmap. The Roadmap envisages amendments to EU TSE
4 Iwamaru et al. (2005) PrPSc distribution of a natural case of bovine spongiform
encephalopathy. In Prions. Food and Drug Safety. Springer-Verlag, Tokyo, 2005.
5 Buschmann & Groschup (2005) Highly Bovine Spongiform Encephalopathy-sensitive
transgenic mice confirm the essential restriction of infectivity to the nervous system in
clinically disease cattle. J. Infect. Dis. 192, 934-942.
8
©SEAC 2005
controls in light of the decline of BSE in Europe, taking into
account new scientific evidence while continuing the aims of
eradicating BSE and maintaining a high level of consumer
protection. FSA and Defra are preparing for EU discussions on
translating the Roadmap proposals into amendments to
legislation. To inform these discussions, Defra and FSA asked
the committee to consider whether the Commission has identified
all of the risk issues that need to be taken into account. The
committee was not asked to consider the age limit for removal of
vertebral column since it considered this in detail at SEAC 85. It
is intended that Defra and FSA will seek further, more detailed
advice from SEAC in the future on specific proposals as they
develop. While the Roadmap foresees changes to risk
management measures, SEAC was asked to focus on whether
any risk assessment issues have been omitted and whether
additional scientific evidence is likely to be needed in support of
changes to legislation.
10. The committee considered the strategic goals in turn.
Strategic goals for the short- and medium-term (2005 – 2009)
Specified risk material
11. The committee recommended that, since removal of SRM is a
primary TSE-related public health protection measure,
amendments to SRM controls should only be reviewed in light of
emerging scientific findings on the distribution of TSE infectivity.
Measures must maintain the current high level of consumer
protection.
Feed ban
12. Members noted that appropriate feed controls are fundamental to
prevent recycling of potentially infectious material in animal feed
and re-emergence of a BSE epidemic. Any potential changes to
feed controls should therefore be considered very carefully.
Members suggested consideration should be given to
assessment of the risks associated with the use of fishmeal in
animal feed as it was unclear whether fish material would be
sufficiently contaminated with BSE to present a risk. Since there
is a great deal of movement of substances used in animal feed
both within and into the EU, potential risks could arise from
contaminated materials used in animal feed imported from
outside the EU. This might also be an area that required further
examination and risk assessment.
9
©SEAC 2005
13. Members asked why animal feed contamination with bone
fragments had been considered only in relation to beet pulp and
not other root vegetables. It was explained that this was because
beet was processed and used in the manufacture of animal feed.
In contrast, other root vegetables were used, unprocessed, at a
local level.
14. The committee was concerned that beet pulp should not be
considered different from other root vegetables without supporting
data. The committee considered it important to examine carefully
all the constituents of animal feed, the sources of those materials,
and then assess the potential TSE risks.
Monitoring programmes
15. The committee considered that appropriate surveillance is
essential to monitor the potential impact of other changes to
control measures. A member pointed out that measuring the cost
of surveillance in terms of the number of positive cases detected
did not reflect the importance of surveillance, and the cost might
best be expressed in terms of the number of negative cases
detected. It was considered that effective surveillance to
ascertain infection prevalence was very important as a public
health protection measure and an effective system should be
maintained.
Categorisation of countries according to BSE risk
16. The committee considered that, both within and outside the EU,
BSE surveillance regimes should be adequate in terms of
numbers of animals tested and testing procedures used to
evaluate the relative BSE risk between countries.
Review of culling policy with regard to TSEs in small ruminants
17. Members noted that culling could partly be driven by surveillance,
but because of the widespread distribution of infectivity in small
ruminants, culling could also be a consumer protection measure.
One key consideration in the assessment of future culling policy
appeared to be how often in the past other cases of the disease
had been identified in the same flock through culling.
18. It was noted that whole flock culling may adversely affect the
reporting of cases. The committee commented that, if maternal
or intra-flock transmission was found to be significant in sheep,
10
©SEAC 2005
this might impact on an assessment of culling as a risk reduction
measure.
Cohort culling in bovine animals
19. The committee considered that it was important to determine the
effectiveness of culling as a risk reduction measure and to
consider whether culling a cohort (whether defined by feed or by
birth) remained a proportionate response to risk in light of the
declining BSE epidemic.
UK restrictions
20. The committee agreed that, as the numbers of BSE cases in GB
have declined to similar levels found in the rest of Europe, this
was a logical step. In response to a question about the report of
the recent FVO mission to the UK, Mr Burke informed the
committee that the report was likely to be published soon. Its
conclusions were likely to be broadly favourable to the UK.
Strategic goal for the long term (2009-2014)
To modify measures in line with current technology and new evolving
scientific knowledge
21. The committee agreed that it would be appropriate for SEAC, in
the future, to look at the risks associated with modifying
measures such as SRM rules, in the light of new scientific
knowledge.
22. Members reiterated the view that it would be important to
maintain effective surveillance to ascertain infection prevalence
and to monitor the effect of changes to control measures. An
appropriate level of surveillance of chronic wasting disease
should be maintained in Europe.
23. Professor John Wilesmith (Defra) commented that, in deciding
upon appropriate surveillance measures, it was necessary to
decide upon the reason for the surveillance. Reasons include
preventing diseased animals going into the food chain, to inform
about the epidemiology of disease, or to detect the effectiveness
of control measures.
24. Members suggested that, as a further strategic goal, surveillance
programmes should be capable of monitoring potential changes
to TSE prevalence, and new TSEs or other similar diseases.
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©SEAC 2005
There should also be mechanisms in place to deal with any
changes detected.
25. In conclusion, SEAC welcomed the Roadmap and made three
further general recommendations:
• changes to legislation in any one of the strategic areas might
impact on other areas, therefore no single strategic area
should be considered in isolation;
• there should be a watching brief on emerging science that
may impact on any of the measures under consideration.
• in the event of any changes to TSE legislation it would be
important to communicate effectively to consumers the
reasons for change.
ITEM 5 – HYPOTHESIS ON THE ORIGIN OF BSE (SEAC 89/3)
26. The Chair introduced a paper by Colchester & Colchester
(Lancet, 2nd September 2005)6 presenting a hypothesis that BSE
was originally derived from a human TSE. The hypothesis
suggested that, in the 1960s and 1970s, mammalian bone and
carcass material used in animal feed was imported into the UK
from the Indian sub-continent, particularly the area around the
Ganges, and contained remains from humans infected with CJD.
27. The Chair explained that he and Mr Peter Jinman (Deputy Chair)
had met with Professor Colchester (University of Kent) and Defra
policy officials to discuss the paper prior to publication. The Chair
thanked Professor Colchester for his willingness to discuss his
hypothesis and for the professional manner in which the
hypothesis was raised and presented, allowing a careful review of
the issue. He thanked Professor Colchester for attending the
SEAC meeting. The committee was asked to comment on the
plausibility of the hypothesis and the areas of research to test the
hypothesis suggested in the paper.
28. The Chair noted that from the discussions with Professor
Colchester and Defra policy officials it was entirely possible that
in the 1960s and 1970s animal feed from the Indian sub-continent
was contaminated with human remains. Although this could not
be proved unequivocally, there was good indirect evidence to
suggest that this may have occurred, and that this was a
6 Colchester and Colchester (2005). The origin of bovine spongiform encephalopathy: the
human prion disease hypothesis. Lancet. 366, 856-61.
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plausible route of infection. However, the question remains, how
likely is this route of infection? The committee should consider the
likelihood of whether a human TSE jumped the species barrier to
infect cattle, and the relative amount of such contaminated
material which might have been fed to cattle compared with the
amount of animal (sheep and cattle) carcasses which had been
used in cattle feed, and the biochemical evidence for
similarities/differences between human TSEs and BSE.
29. Members suggested that since prion infections are known to alter
their properties to adapt to new host species, it might be
impossible to establish the origin of BSE from the biochemical
characteristics of prion strains. Currently it is not possible to
predict the ability or likelihood of prion infections to cross species
barriers based on a comparison of the biochemical properties of
prion protein strains in two different species.
30. Dr Mike Simmons (National Assembly of Wales) asked whether it
was more likely that BSE was originally derived from a scrapie
strain or a human TSE. Members noted the possible origin of
BSE from scrapie had been investigated very carefully but it had
not been possible to determine whether or not BSE was originally
derived from a scrapie strain. Dr Danny Matthews (VLA) noted
that when sheep are infected with BSE by the oral route, on
second passage in sheep no reduction in incubation period was
observed. Therefore, it would appear that there is no significant
species barrier for BSE infection from cattle to susceptible sheep.
It was possible that there is also no species barrier for BSE
transmission from sheep to cattle, but this was not known. It was
also possible that BSE may have existed in sheep in the past but
had not been detected. Members noted that, although BSE was
known to be biochemically different from known scrapie strains, it
was also different from sCJD and other prion strains. It was
therefore not possible to establish biochemically whether BSE
originated from CJD, scrapie or other known prion strains.
31. Members noted that, although little information was available on
the relative amounts of human remains that could have
contaminated animal feed in the past, in all probability only a
small amount of human remains could reasonably have entered
feed. In comparison, the quantities of animal remains that
entered animal feed would have been very much larger.
Furthermore, although the size of the species barrier between
cattle and humans was unknown, it was likely that some barrier
existed. Taking both of these factors into account it seemed
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©SEAC 2005
much more likely that the BSE epidemic originated from a
disease in cattle or sheep rather than in humans.
32. A member pointed out that bone material from the Indian subcontinent
was also exported to other countries, for example,
Australia, yet this had not caused an outbreak of BSE in these
countries. A member asked if this material was fed to cattle in
India and, if so, why there was not a similar epidemic of BSE in
that country. Professor Colchester responded that, as cattle feed
was prepared and used on a local level, isolated cases of BSE
might have occurred but such localised use would not result in an
epidemic. Since there was no rigorous surveillance of BSE in
cattle in India, isolated cases would not be detected. Dr
Matthews informed the committee that, although there is a
rendering industry in India, meat and bone meal would be fed
mainly to poultry and pigs, but not cattle for religious reasons.
33. Members noted that Professor Colchester's work had highlighted
the complex nature of production and movement of meat and
bone meal and also the possibility of contamination of feed with
human remains. Mr Burke explained that, although animal byproducts
from India were imported into the UK in the past and
may have been contaminated with human remains, control
measures implemented across the EU would now prevent the
importation of such material for either feed or fertiliser. There are
no EU approved rendering plants in India permitted to produce
meat and bone meal for use in fertiliser in the EU. Professor
Colchester asked for clarification about the controls on exports of
such materials from India to the EU as well as about controls on
imports reaching the UK. Mr Burke explained that exports to the
EU were checked at border inspection posts, but the controls are
rather complex and it would be better if Professor Colchester had
a copy of his report. The Chair said this would be helpful.
34. The Chair asked the committee to comment on the areas of
research to test the hypothesis suggested in the paper. A
number were interesting scientifically but the committee should
consider whether they might be important in terms of Government
policy.
35. The committee agreed that examination of the transmission
characteristics of human TSEs in transgenic mice expressing
forms of the human and bovine prion protein gene, or a human
CJD to cattle experiment, while potentially interesting, are unlikely
to inform TSE controls and are therefore not essential to conduct.
A member informed the committee that a number of experiments
14
©SEAC 2005
to test the transmissibility of BSE, vCJD, sheep scrapie and
sheep BSE in transgenic mice were underway to address
different questions, and may inform the above question. These
studies were using transgenic mice expressing human and
bovine forms of the prion protein that had been produced in
identical ways. Professor Colchester suggested that experiments
in transgenic mice might be less clear than studies that examined
transmissibility of human TSEs into cattle directly. Dr
Stephenson reminded the committee that experimental feeding of
human TSE material to animals was previously considered by
SEAC to be unethical.
36. Members noted that investigations of historic production of animal
feed were extremely difficult to undertake and had probably been
investigated as much as possible. Although it was important to
investigate possible feed related origins of BARB cases, further
investigation of feed manufacture processes in the 1960s and
1970s would not be worthwhile. Appropriate controls now appear
to be in place. The committee considered that the other areas of
research suggested in the paper were not within SEAC's remit.
37. In summary, SEAC:
• was grateful that the hypothesis was raised and for the
thoughtful and professional way in which Professor
Colchester had raised the hypothesis with the committee,
• considered the hypothesis plausible but for a number of
reasons considered that it was not the most likely origin of
BSE,
• was reassured that control measures were in place to
prevent possible transmission via the route identified in the
hypothesis,
• considered that although a number of interesting areas of
research had been identified, these were unlikely to affect
policy, and that it was also unlikely that the hypothesis could
be experimentally verified,
• agreed to produce a statement on the hypothesis.
ITEM 6 – SEAC EPIDEMIOLOGY SUBGROUP REPORT
38. Professor Graham Medley (Chair of SEAC Epidemiology
Subgroup) updated the committee on the Subgroup's second
meeting on 13th September 2005 which continued to address the
SEAC request to evaluate the nature and profile of the vCJD
epidemic. The Subgroup had reviewed the available data on the
prevalence of vCJD infection in the UK population and modelling
15
©SEAC 2005
studies, making extrapolations in areas where data gaps exist.
The importance of data acquisition in removing uncertainty about
the distribution of infection in the population had been highlighted.
Whilst modelling methods are useful to explore hypotheses on,
for example, the influence of age and genotype on infection,
because the disease incubation period and the level of infection
are unknown, any number of hypotheses were plausible. The
validity of hypotheses could only be tested with further data. A
position statement including a table of options for further data
collection would be prepared with the aim of presenting it at
SEAC 90. The Subgroup would meet early next year when
further modelling work was completed.
39. The Chair asked whether the modelling work underway was
sufficient to allow the Subgroup to address the questions SEAC
had asked the Subgroup to consider. It was explained that
modelling work was useful to provide quantification of
uncertainties around the epidemic but it was crucial that more
data were collected to remove these uncertainties and improve
understanding of the epidemic.
ITEM 7 – BSE DVD
40. The Chair explained that during the SEAC 88 discussion on
differential diagnosis of BSE, members expressed an interest in
viewing the DVD supplied to veterinary surgeons on the clinical
diagnosis of BSE in cattle.
41. Mr Burke informed the committee that the DVD had been
produced by a clinical neurologist at VLA and circulated to a
number of bodies including the State Veterinary Service, Meat
Hygiene Service and organisations representing veterinary
surgeons. The committee was shown extracts covering a number
of diagnostic tests for BSE and differential diagnosis of BSE from
other diseases with similar clinical signs.
42. Members welcomed the development of the DVD and noted it
would be very useful in maintaining knowledge of the clinical
symptoms of BSE, particularly amongst individuals who had not
had practical experience of the disease at the height of the
epidemic.
ITEM 8 – ANY OTHER BUSINESS
43. There was no other business.
http://www.seac.gov.uk/minutes/draft89.pdf
1
SEAC 90/2
CJD UPDATE
There is no discussion paper for agenda item 90/2, however Professor
Ironside will refer to the following papers during his presentation:
Polymenidou et al. (2005) Coexistence of multiple PrPSc types in individuals
with Creutzfeldt-Jacob disease. The Lancet neurology online, 31 October
2005.
Yull et al. (2006) Detection of Type 1 of the Prion Protein in Variant
Creutzfeldt-Jacob Disease. American Journal of Pathology 168, No.1,
January 2006 in Press.
http://www.seac.gov.uk/papers/90-2.pdf
1
SEAC 90/3
EVOLUTION OF THE SHEEP PRION PROTEIN GENE
ISSUE
1. To consider a recent paper on molecular evolution of the sheep
prion protein gene1.
BACKGROUND
2. The susceptibility of sheep to scrapie is known to be influenced by
polymorphisms in the prion protein gene (PRNP) especially at
codons 136, 154 and 171. Fifteen genotypes resulting from
variation at these codons have been identified. The genotypes
occur at widely differing frequencies in different breeds of sheep.
3. The National Scrapie Plan (NSP) for Great Britain consists of a
breeding programme to increase the number of sheep that
genetically are naturally resistant to transmissible spongiform
encephalopathies (TSEs). Its primary aims are to protect animal
health by reducing and eventually eradicating scrapie and to
protect public health from the theoretical risk of BSE (if it is present
and being masked by scrapie) by increasing levels of genetic
resistance to TSEs. The breeding programme consists of different
schemes and initiatives, based on various considerations including
the relative resistance of sheep carrying the ARR allele to scrapie.
4. The NSP implements a recommendation from the SEAC Sheep
Subgroup for a long-term control and eradication programme for
scrapie. At its most recent meeting in July 2004 the Subgroup
concluded that the underlying strategy of the NSP to breed for
scrapie resistance remains appropriate. However, it was
considered that the basis for the strategy should be continue to be
kept under review in the light of emerging scientific findings with
respect to the possible detection of scrapie infections in animals of
genotypes currently thought to be most resistant to infection.
1 Slate (2005) Molecular evolution of the sheep prion protein gene. Proc. R. Soc. B. 272,
2337-2344.
2
5. At SEAC 88, SEAC was informed about a range of studies on
atypical scrapie in sheep. The committee agreed that, now that a
number of issues around atypical scrapie are becoming clearer,
the SEAC Sheep Subgroup should consider the emerging scientific
information in more depth and the possible implications for the
NSP. The Subgroup will meet in January 2006.
SLATE PAPER
6. A paper by Jon Slate (see Annex 1) investigated the evolutionary
selection pressures acting on ruminant PRNP using a theoretical
approach of molecular evolution analyses of ruminant PRNP
sequence data. On the basis of these analyses, the author
concluded that PRNP in sheep has evolved by balancing selection
rather than positive selection. In other words, the natural evolution
of sheep PRNP has resulted in variation in the coding sequence to
include genotypes that are relatively susceptible to scrapie
because variation in the gene is favourable.
7. The author proposes a number of possible hypotheses for the
variation in sheep PRNP:
(i) susceptible genotypes confer some advantage(s) to sheep in
the absence of scrapie thereby maintaining PRNP variation over
time.
(ii) heterozygote genotypes are advantageous because they confer
relative resistance to scrapie compared with homozygous
genotypes.
(iii) relative susceptibility to scrapie is determined by the
compatibility of PRNP genotype of the host and the scrapie strain
such that incompatibility leads to a barrier to infection. Thus,
variation in PRNP could be maintained by exposure over time to
scrapie strains with different compatibilities, and therefore infection
efficiencies, with sheep genotypes.
(iv) variation in an untranslated region linked to PRNP influences
the expression levels of prion protein and therefore, susceptibility
to scrapie, which helps to maintain variation in the coding region.
8. The author suggests that hypotheses (ii) and (iii) appear to be the
most likely. This because there is evidence from humans and
sheep that heterozygote genotypes are more resistant to TSEs. In
addition, there is evidence that conversion of normal prion protein
to an abnormal form is most efficient when the genotype of the
3
host from which infection is transmitted and the recipient host is the
same.
9. The author notes that the aim of the NSP breeding programme is
to induce positive selection of a single relatively resistant genotype
to scrapie infection. Since this results in depletion in genetic
variation, it runs counter to the natural evolution of PRNP in sheep
that appears to favour variation. One possible implication is that
the NSP may produce a genetically uniform population of sheep
that could be susceptible to rare scrapie strain(s). In view of this,
the author recommends that further investigations of the role of
PRNP variation on resistance to rare scrapie strains and on fitness
and production traits be conducted. In addition, it would be
prudent to preserve existing PRNP variation, as frozen semen and
in managed populations.
INDEPENDENT REVIEWS OF THE SLATE PAPER
10. Due to the specialist nature of the molecular evolution approach
and analyses undertaken, the paper by Slate was sent to two
independent genetics experts. The experts were asked to review
the paper and to comment on the methodology used and the
implications for the NSP. The reviews have been anonymised and
are given at Annex 2.
ADVICE SOUGHT FROM THE COMMITTEE
11. The committee is requested to comment on the findings of the
Slate paper and the possible implications for the NSP.
4
SEAC 90/3 ANNEX 1
Slate (2005) Molecular evolution of the sheep prion protein gene.
Proc. R Soc B. 272, 2337-2344.
5
SEAC 90/3 ANNEX 2
Independent expert reviews of the paper by Slate
http://www.seac.gov.uk/papers/90-3.pdf
Lancet Neurology 2005; 4:805-814
DOI:10.1016/S1474-4422(05)70225-8
Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease
Magdalini Polymenidou a, Katharina Stoeck a, Markus Glatzel a b, Martin Vey c, Anne Bellon c and Adriano Aguzzi a
Summary
Background
The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.
Methods
We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.
Findings
We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.
Interpretation
The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.
Affiliations
a Institute of Neuropathology, University Hospital Zurich, Switzerland
b Present address: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
c ZLB Behring, Marburg, Germany
Correspondence to: Dr Adriano Aguzzi, Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
http://www.thelancet.com/journals/laneur/article/PIIS1474442205702258/abstract
what i been saying for years, that the diagnostic criteria differentiating between the nvCJD (i.e. 'the chosen ones') and the sCJD (i.e. 'the forgotten ones') has been terribly flawed from the beginning. ....TSS