BSEvCJD: The European Ongoing Story

1
BSE/vCJD The European On-going Story

• Prof J Ralph Blanchfield, MBE
• Past President
• Institute of Food Science Technology
• President 2006-2008
• International Academy of Food Science
  Technology
• IUFoST Governing Council Member 2003-2008
• Food science, food technology and food law
  consultant
• E-mail jralphb_at_easynet.co.uk Web
  www.jralphb.co.uk
• (updated 25 Sepember 2009)

2
BSE/vCJD The European On-going Story

• ? Containment of risks of ?
• a fatal cattle disease and
• a fatal human disease
• caused by entities which appear not to obey the
  rules of microbiology or toxicology
• with incubation periods 3-5 years in cattle,
  6-30 years or more in humans
• with clinical signs developing only very late in
  the incubation period and
• no ante mortem test

3
Institute of Food Science Technology

• the UK-based professional qualifying body of food
  scientists and technologists
• democratic, not-for-profit, self-governing,
  self-funding
• totally independent of government, of industry,
  and of any lobbying groups or special interest
  groups

4
Institute of Food Science Technology

• professional members elected on academic
  qualifications and relevant experience, and
  signed undertaking to comply with the Institute's
  ethical Code of Professional Conduct

5
Institute of Food Science Technology

• The first of its four purposes is
• to serve the public interest by furthering the
  application of science and technology to all
  aspects of the supply of safe, wholesome,
  nutritious and attractive food, nationally and
  internationally.

6
Institute of Food Science TechnologyWhy
concerned with BSE?

• New disease affecting major food source -
• Rapid UK escalation to epidemic proportion
• Not veterinarians, not neurologists, not
  pathologists, not geneticists, not molecular
  biologists, not epidemiologists, not BSE
  researchers
• Experts study small parts of picture close-up
• Role of food scientists -
• to stand back and observe whole picture.

7
BSE

• Jigsaw many missing pieces
• Every successive update of the IFST Information
  Statement on BSE has emphazised
•  
• "While that sums up the present state of
  knowledge, scientists always have to keep open
  minds. They have to act on existing knowledge
  while recognizing that further research will
  bring new information and knowledge, which may in
  turn lead to revised conclusions. We welcome the
  devotion of substantial extra resources to
  research in this field."

8
BSE

• Origin?

Scrapie in rendered meat and bone meal (MBM) feed
becoming changed when passaged through
cows? Or Originating from a one-in-a-million case
of sporadic BSE infection in a cow which was
rendered and recycled? Or (latest speculation,
in Lancet 3 Sept 05) Originating from bonemeal
imported from Indian sub-continent containing
human remains
9
BSE

• Origin?

Probably never be able to prove which. R
Capobianco et al (PLoS Pathogens, March 9 2007)
have proposed that the atypical form of
spongiform encephalopathy termed BASE, is caused
by a prion strain distinct from that of classical
BSE. They show that it converts into the
classical BSE strain on serial transmission to
inbred mouse lines. Accordingly BASE may be the
origin of BSE, following conversion of the causal
agent in an intermediate host. These findings may
have major implications with respect to the
origin of BSE . Role of contributory factors?
10
BSE

• Whichever origin -

• Rendered MBM was the vehicle.
• Role of John Wilesmith
• Wilesmith J W et al (1988) "Bovine spongiform
  encephalopathy epidemiological studies on the
  origin", Veterinary Record , 123, 638.
• Wilesmith J W et al (1991) " Bovine spongiform
  encephalopathy epidemiological studies on the
  origin", Veterinary Record , 128, 200-203.

11
BSE

• Rendered MBM was also the vector
• Key factor in subsequent development of the
  epidemic was the use of MBM as cattle feed, as
  demonstrated when its prohibition led to
  successive year-by-year reductions in confirmed
  new cases.

12
BSE
13
BSE
14
BSE
15
BSE
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
BSE

• Incidence Rest of World
• 2000 452 cases
• 2001 987 cases (Detwiler Effect?)
• 2002 864 cases
• 2003 643 cases
• 2004 524 cases
• 2005 225 cases
• 2006 139 cases
• 2007 73 cases
• 2008 57 cases
• 2009 10 cases (to 7 Setember 2009)
• Improved surveillance efforts
• Passive versus active surveillance
• 2001 increase due to active testing

20
BSE

• Incidence Great Britain
• Passive surveillance
• 1988 to 2007 179,180 cases
• 2000 1,311 cases
• 2001 781 cases
• 2002 445 cases
• 2003 173 cases
• 2004 82 cases
• 2005 39 cases
• 2006 15 cases
• 2007 7 cases
• Active surveillance 1,849
• (2001 - 18 September 2009)

21
BSE

• Active surveillance testing
• Active surveillance has been possible on a large
  scale through development of rapid tests. So far
  a total of 12 rapid tests based on different
  detection principles are approved for BSE
  monitoring in cattle in Europe 1 Western blot,
  10 ELISA, and 1 Strip-based test. All are post
  mortem tests that use brain or spinal cord tissue
  of the slaughtered animal.

22
BSE

• Occurrence of 17 cases in Canada
• Between 20 May 2003 and 20 February 2009, there
  have been seventeen cases of BSE in Canada.
• Completed investigation reports on the first
  eight are at http//www.inspection.gc.ca/english/a
  nima/heasan/disemala/bseesb/comenqe.shtml

23
BSE

• Occurrence of three cases in USA
• On 23 December 2003 USDA reported its first BSE
  case in Washington State. By 6 January 2004
  investigation established by DNA that the cow,
  born in 1997, originated from a dairy farm in
  Alberta, Canada.
• A second case,finally confirmed in June 2005 was
  a 12 year old cow born and bred in South-east
  Texas. A third case, a cow in Alabama, was
  confirmed on 13 March 2006.
• Investigations are ongoing in both USA and
  Canada. Meanwhile USA is practising enhanced
  measures and controls. Full details and updates
  may be accessed at
• http//www.aphis.usda.gov/lpa/issues/bse/bse.html
• http//www.fda.gov/oc/opacom/hottopics/bse.html
• http//www.cdc.gov/ncidod/diseases/cjd/cjd.htm

24
BSE

• Prion protein
• designated PrP or sometimes PrPC
• small glycosylated protein molecule found mainly
  in the brain cell membrane
• ?-helix structure

25
BSE

• Infective agent Prion (Pree-on)
• Misfolded protein molecule that causes normally
  folded prion protein molecules to misfold.
• Separate lines of research provide strong
  evidence for the prion hypothesis.

26
BSE

• Infective agent Prion (Pree-on)
• Concept J S Griffith (1967)
• Formalized S B Prusiner (1982)
• Does not obey conventional rules of microbiology
  or of toxicology
• Replicates with no DNA or RNA
• Misfolded prion protein molecule that causes
  normally folded prion protein molecules to
  misfold
• ?-helix ? ?sheet structure (PrPsc)
• Largely protease-resistant (PrPres)
• Resistant to heat, irradiation, most practicable
  chemical treatments

27
BSE

• Infective agent Prion (Pree-on)
• A study by Aguzzis group in Zurich now gives
  concrete evidence that the abnormal-normal prion
  interaction does in fact occur.
• Meier, P et al. (2003). Misfolded soluble
  dimeric prion protein binds PrPSc in vivo and
  antagonizes prion disease. Cell, 113, 49 60.

28
BSE

• Infective agent Prion (Pree-on)
• A study by Prusinerss group in San Fransisco
  now provides compelling evidence that prions
• are infectious proteins and demonstrates that
  artificially-produced prions can trigger
  development of a BSE-like neurological disorder
  in mice and damage brain tissue without the
  presence of viral DNA or RNA.
• Legname G et al (2004), Synthetic Mammalian
  Prions, Science, 305, (5684), 673-676.

29
BSE

• Infective agent Prion (Pree-on)
• Collinges group (2004) have characterised two
  distinct prion strains derived from BSE
• transmissions to inbred mice. These data indicate
  a crucial involvement of the host
• genome in modulating prion strain selection and
  propagation in mice. It is possible that
• multiple disease phenotypes may also be possible
  in BSE prion infection in humans and other
  animals.
• Lloyd SE et al, (2004), J Gen Virol, 85,
  2471-2478.

30
BSE

• Infective agent Prion (Pree-on)
• Studies by two independent research teams have
  shown that synthesised yeast protein Sup35
  clumped at different temperatures had structural
  differences and acted as different prion strains
  when put into yeast cells.
• King C-H and Diaz-Avalos R (2004). Protein-only
  transmission of three yeast prion strains,
  Nature 428, 319 323.
• Tanaka M et al (2004). Conformational variations
  in an infectious protein determine prion strain
  differences, Nature 428, 323 328.

31
BSE

• Infective agent Prion (cont)
• Five alternative treatments have been proposed
  for decontaminating prion infectivity on
  surfaces, including a phenolic disinfectant an
  alkaline cleaner the combination of an enzymatic
  cleaner and vaporised hydrogen peroxide (VHP) a
  mixture of two proteolytic enzmes and a
  detergent and radio-frequency gas plasma
  treatment.
• The first two appear to be proprietary
  disinfectants already marketed by STERIS.

32
BSE

• Infective agent Prion (cont)
• Radio-frequency (RF) gas-plasma treatment was
  investigated as a method of removing both the
  protein debris and TSE infectivity.
  Stainless-steel spheres contaminated with the
  263K strain of scrapie and a variety of used
  surgical instruments, which had been cleaned by a
  hospital sterile-services department, were
  examined both before and after treatment by RF
  gas plasma.

33
BSE

• Infective agent Prion (cont)
• In vivo testing showed that RF gas-plasma
  treatment of scrapie-infected spheres eliminated
  transmission of infectivity. The infectivity of
  the TSE agent adsorbed on metal spheres could be
  removed effectively by gas-plasma cleaning with
  argon/oxygen mixtures. This treatment can
  effectively remove stubborn residual
  contamination on surgical instruments.
• Baxter HC et al (2005), J Gen Virol 86,2393-2399

34
BSE

• Infective agent Prion (cont)
• Langeveld J et al (2003) Journal of Infectious
  Diseases, 1 December 2003 have shown that, when
  brain tissues from cows with BSE and sheep with
  scrapie are treated with a bacterial enzyme
  keratinase, the enzyme fully degraded the prion,
  rendering it undetectable.

35
BSE

• Infective agent Prion (cont)
• Prusiners group have reported in PNAS that they
  have genetically altered a strain of mice so that
  the animals made a mutated form of prion protein
  which prevented the animals from becoming ill
  when injected with infective prions. This raises
  the possibility of breeding cattle that are
  protected from BSE.

36
BSE

• Infective agent Prion (cont)
• In March 2005 LipidViro Tech, Inc. have announced
  pre-clinical research results demonstrating the
  ability to substantially inactivate infective
  prion proteins in bovine serum utilising patented
  equipment to deliver a precise, measured dose of
  ozone, allowing accurate targeting of the
  threshold which produces prion inactivation while
  maintaining the biological integrity of the
  treated fluid. Prion infectivity was reduced in
  bovine serum below the limit of detection in both
  cell and Western Blot assays. This ongoing
  research has been submitted for presentation at
  the Meeting of the International Union of
  Microbiological Societies, San Francisco, July
  2005. If confirmed these findings could be of
  value in treating bovine sera for pharmaceutical
  use and in treating blood.

37
BSE
Source SCI Biotechnology Group
38
BSE

• PrPsc model structure based on electron
  crystallography
• Source Wille et al (2002), PNAS, 99, 10, 1073

39
BSE

• Infectivity of bovine materials?
• Brain, spinal cord,
• Retina (?)
• Dorsal root and the trigeminal ganglia
• Bone marrow slightly infectious
• Distal ilium of calves (experimentally induced)
• Muscle? Milk? Blood? Not detectable by current
  methods.
• BUT

40
BSE

• Infectivity of bovine materials?
• In January 2005 Aguzzis group has shown in mice
  suffering from any of five inflammatory diseases
  of kidney, pancreas or liver. that infective
  prions may spread further in the body to those
  tissues. In all cases,
• chronic lymphocytic inflammation enabled prion
  accumulation in otherwise prion-free organs.
• Heikenwalder et al., Chronic Lymphocytic
  Inflammation Specifies the Organ Tropism of
  Prions, Science 2005 0 11064601

41
BSE

• Infectivity of bovine materials?
• Then in October 2005 Aguzzis group found that
  scrapie-infected mice with kidney inflammation
  accumulated and replicated prions in their
  kidneys and excreted prions in their urine and
  these prions infected other mice with scrapie
  when injected. Further research will be carried
  out to investigate the possible implications for
  humans.
• Aguzzi et al, Science doi 101126/science.1117196

42
BSE

• Infectivity of bovine materials?
• No infectivity yet detected in blood of BSE
  infected cattle
• but
• BSE transmitted to one of six scrapie-free sheep
  by blood transfusion from apparently still
  healthy scrapie-free sheep fed orally with brain
  of BSE infected cattle.
• Houston F et al (2000) Transmission of SE by
  blood transfusion in sheep, Lancet, 356,
  999-1000.
• Hunter, N et al (2002), Journal of General
  Virology 83, 2897-905.

43
BSE

• Infectivity of bovine materials?
• Further work resulted in a second transmission of
  BSE and four new cases of transmission of natural
  scrapie. Positive transmissions occurred with
  blood taken at pre-clinical and clinical stages
  of infection. These results confirmed the risks
  of TSE infection via blood products and suggest
  that the measures taken to restrict the use of
  blood in the UK have been fully justified.
• Hunter, N et al (2002), Journal of General
  Virology 83, 2897-905.

44
BSE

• The early UK containment controls (1988)
• to slaughter and destroy animals clinically
  diagnosed on the farm or elsewhere
• to prohibit the feeding of material containing
  animal protein derived from ruminants to cattle
  and other ruminants  
• to prohibit Specified Bovine Offals (SBOs) from
  the food or feed chain
•  

45
BSE
46
BSE

• UK health controls since 1996 ?
• Enhanced and strictly enforced ban on mammalian
  MBM for all farm animals, with recall of all
  existing stocks of MBM.
• Exclusion of SRMs from the food or feed chain
  (SRM from 1995 includes vertebral column and
  dorsal root ganglia).
• Over Thirty Months Scheme (OTMS) in which cattle
  aged over thirty months are slaughtered in
  designated abattoirs when they came to market and
  incinerated or rendered. To December 2001,
  5,410,716 cattle have been disposed of under the
  OTMS.
• Offspring cull, of offspring born after 1 August
  1996 to dams in which BSE was confirmed.
• Compulsory Cattle Passport traceability system.

47
BSE

• UK health controls since 1996 (cont)
• On 2 December 2004 , following advice from SEAC
  and the Food Standards Agency, the UK Government
  agreed to phase out the OTMS, replacing it from
  2005 by a vigorous and extensive testing regime
  of all cattle.
• On 15 August 2005, at the Food Standards Agency
  Board agreed its advice to Ministers that an
  effective system to test cattle aged over 30
  months (OTM) for BSE before they enter the food
  chain has now been developed. On 15 September
  2005, the UK Government announced that it is to
  replace the Over Thirty Months (OTM) Rule with
  BSE testing, Ministers also agreed to a number of
  pre-conditions set by the Food Standards Agency
  to ensure continued consumer protection during
  implementation.

48
BSE

• Born after the real ban (BARB)
• From 1 August 1996 to 31 December 2007
• UK 178 cases
• Rest of EU (since 1 Jan 1996) 298 cases
• Possible causes
• Inadequate practice/enforcement of controls?
• Maternal/vertical transmission?
• Contamination in calf feed?
• Unknown cause?

49
BSE

• Born after the real ban (BARB)
• DEFRA asked Prof William Hill to review its work
  on cases of BSE in cattle born since 1 August
  1996.
• Prof Hill issued his report in June 2005. It can
  be found on the DEFRA Website http//www.defra.gov
  .uk/animalh/bse/index.html

50
BSE

• Born after the real ban (BARB)
• Prof Hills principal conclusions are
• a) There is no strong reason to believe that BSE
  in BARBs cases is a different disease from that
  in animals born before the reinforced feed ban.
• b) The diagnostic tests used in active
  surveillance appear to be effective, but only
  when the animal is in the last few months of
  incubating the disease.
• c) Obtaining hard evidence on the crucial
  hypothesis on the identity of BSE in BARBs and
  previous cases is highly desirable and the
  relevance of atypical molecular forms of BSE
  found by active surveillance in other countries
  needs to be resolved.
• d) The efficacy and interpretation of the tests
  used in active surveillance of animals for BSE
  should be kept under review.

51
BSE

• BSE controls across the EU
• Essentially similar to the UK controls post-1996,
  plus post-mortem testing of
• suspect cattle over 30 months from January 2001,
• all over 30 months cattle, from 1 July 2001,
• some categories of over 24 months cattle from 1
  July 2001.
• tests mostly being carried out by the Prionics or
  Bio-Rad methods .

52
BSE

• Vertical or maternal transmission?
• Supposedly 10 during last six months of
  incubation, by a dubious 1996 assumption based on
  estimation from a flawed experiment started in
  1989 for another purpose.
• More recently reported research (Wrathall et al,
  2002) appears to provide no support for vertical
  transmisssion

53
BSE

• BSE risk by countries or regions
• EU Scientific Steering Committee (SSC) assessed
  countries in four Categories
• Category I Highly unlikely to present a BSE risk
• Category II Unlikely, but a BSE risk cannot be
  excluded
• Category III Likely to present a BSE risk, even
  if not confirmed, or presenting a low level of
  confirmed BSE risk
• Category IV BSE risk confirmed at a high level
• Note Assessment of risk of BSE being present,
• NOT of level of risk to human health
•  

54
BSE

• BSE risk by countries or regions
• Change proposed in BSE assessment 
• On 22 November 2006,the European Food Safety
  Authoritys (EFSA) Panel on Biological Hazards
  (BIOHAZ) launched a public consultation on a
  revision of the methodology for Geographical
  BSE-Risk (GBR) assessment. The update takes
  account of new scientific knowledge on BSE and
  recent trends in BSE prevalence based on the most
  recent surveillance data. By allowing a more
  accurate assessment of geographical BSE risk, the
  revised methodology will assist risk managers in
  making decisions to protect consumers which are
  commensurate with the risk identified.

55
BSE

• BSE risk by countries or regions
• In December 2008 the EU provided updated lists of
  
• Countries with negligible BSE risk
• Countries with a controlled BSE risk
• Commission Decision 2008/829/EC
• http//www.fsai.ie/legislation/legislation_update/
  2008/0810_euupdate/Dec2008_829.pdf

56
BASE

• During 2004 a few atypical cases have been
  described in France, Italy, Belgium, Denmark, The
  Netherlands and Japan, showing prion
  immunopositive amyloid plaques, as opposed to the
  lack of amyloid deposition in typical BSE cases,
  and by a different pattern of regional
  distribution and topology of brain prion
  accumulation.
• This new form has been named bovine amyloidotic
  spongiform encephalopathy (BASE).

57
BASE

• Biacabe et al have shown the existence of an
  atypical molecular phenotype among cattle
  diagnosed with BSE in France. Following western
  blot analysis, three cases showed unusual
  features of the electrophoretic profiles of the
  protease-resistant prion protein (PrPres)
  accumulating in the brain. The PrPres patterns
  were similar in these three atypical cases,
  showing a higher molecular mass of unglycosylated
  PrPres and strong labelling by P4 monoclonal
  antibody compared to 55 typical BSE cases. This
  finding suggests either some phenotypic
  modifications of PrPres following infection by
  the BSE agent or the existence of alternative
  origins of such diseases in cattle.
• Biacabe A G et al (2004). Distinct molecular
  phenotypes in bovine prion diseases. EMBO Rep 5,
  110-115.

58
BASE

• Similarly, C Casalone et al provide evidence of a
  second cattle TSE. The disorder was
  pathologically characterized by the presence of
  PrP-immunopositive amyloid plaques, as opposed to
  the lack of amyloid deposition in typical BSE
  cases, and by a different pattern of regional
  distribution and topology of brain PrPSc
  accumulation. In addition, Western blot analysis
  showed a PrPSc type with predominance of the low
  molecular mass glycoform and a protease-resistant
  fragment of lower molecular mass than BSE-PrPSc.
  Strikingly, the molecular signature of this
  previously undescribed bovine PrPSc was similar
  to that encountered in a distinct subtype of
  sporadic Creutzfeldt-Jakob disease.
• Casalone C et al (2004). Identification of a
  second bovine amyloidotic spongiform
  encephalopathymolecular similarities with
  sporadic Creutzfeldt-Jakob disease.. Proc Natl
  Acad Sci USA, 101 306570.

59
BASE

• Strikingly, the molecular signature of this
  previously undescribed bovine prion was similar
  to that encountered in a distinct subtype of
  sporadic Creutzfeldt-Jakob disease.
• More recently, two of the US cases of BSE have
  been reported to have shown these atypical
  characteristcs

60
BSE

• Production of cattle lacking prion protein
• In December 2006 Richt et al report the
  generation and characterization of PrPC-deficient
  cattle produced by a sequential gene-targeting
  system6. At over 20 months of age, the cattle are
  clinically, physiologically, histopathologically,
  immunologically and reproductively normal. Brain
  tissue homogenates are resistant to prion
  propagation in vitro as assessed by protein
  misfolding cyclic amplification. PrPC-deficient
  cattle may be a useful model for prion research
  and could provide industrial bovine products free
  of prion proteins.
• Richt et al, Nature Biotechnology, published
  online 31 December 2006 doi10.1038/nbt1271
• http//www.nature.com/nbt/journal/vaop/ncurrent/ab
  s/nbt1271.html

61
BSE

• BSE and sheep?
• In sheep but masked by scrapie?
• Serious concern since 1996 laboratory
  transmission
• August 1996 similar measures to protect human
  health against BSE in cattle were applied to
  sheep (and goats) in case BSE was present.
• No evidence of presence in Europe BUT.
• If present, far more tissues infected than in
  cattle
• If present and behaves in sheep like scrapie,
  both vertical and horizontal transmission,
  infection of pastures
• Until 2005, no rapid test to distinguish BSE from
  scrapie in sheep
• Full extent of scrapie in EU flocks is unknown

62
BSE

• BSE and sheep? (cont)
• From 1 April 2002, extensive testing for TSEs
  across the EU (560,000 a year, focussing on sheep
  aged over 18 months).
• Extension of the current list of SRMs
• New provisions on culling of scrapie-infected
  flocks
• More use of geno-typing of sheep breeds
• Proposal on identification and traceability
• September 2001 - UK Government contingency plan
  if BSE found in sheep. Worst case scenario"
  could include destruction of the whole 40 million
  national flock.
• June 2002 UK Food Standards Agency proposal to
  ban sheep intestines.

63
BSE

• BSE and sheep? (cont)
• DEFRA scrapie surveillance survey showed that TSE
  status could not be determined for 28 out of
  29,201 abattoir sheep) due to inconclusive
  analytical results. The 28 sheep tested positive
  by the Bio-Rad Platelia assay but negative by
  immunohistochemistry (an OIE approved TSE test).
  An Expert Panel called by DEFRA and FSA reported
  its conclusions and research recommendations to
  SEAC, which were accepted.
• (Report of SEAC 80th meeting, 26 November 2003)

64
BSE

• BSE and sheep? (cont)
• On 2 June 2004 DEFRA issues consultation document
  on Contingency plan for the emergence of
  naturally occurring BSE in sheep.
• http//www.defra.gov.uk/corporate/consult/bseinshe
  ep/index.htm
• In October 2005, Le Dur et al reported the
  discovery of a growing number of so-called
  atypical scrapie cases. A substantial proportion
  involved sheep with PrP genotypes known until now
  to confer natural resistance to conventional
  scrapie. Both Nor98 and discordant cases,
  including three sheep homozygous for the
  resistant PrPARR allele (A136R154R171),
  efficiently transmitted the disease to transgenic
  mice expressing ovine PrP, and they shared unique
  biological and biochemical features upon
  propagation in mice.

65
BSE

• BSE and sheep? (cont)
• On 9 March 2006 the EU Commission issued
  Questions and Answers on TSEs in Sheep
• Through the required monitoring programme for
  small ruminants laid down in EU legislation,
  three sheep (two in France, one in Cyprus) were
  found positive for TSE. These required further
  tests to ensure that the TSE present is not BSE.
  In the case of these sheep, the initial
  rule-out tests identified unusual profiles and
  while some data suggested that the samples may
  not be BSE in sheep, there was insufficient
  evidence to definitively rule out the presence of
  BSE. This means that further rule-out tests are
  required. The definitive test is a mouse
  bio-assay, which the Community Reference
  Laboratory (CRL) will now carry out on tissues
  from the suspected sheep.
• http//europa.eu.int/rapid/pressReleasesAction.do?
  referenceMEMO/06/114fo_at_òúrmatHTMLaged0langua
  geEN

66
BSE

• BSE and sheep? (cont)
• 4 April 2005 -The UK Veterinary Laboratories
  Agency (VLA) has developed a new Discriminatory
  Diagnostic Kit to distinguish between BSE and
  Scrapie in sheep, which has been authorised for
  use, and involves protein extraction and western
  blotting technology to differentiate between BSE
  and scrapie in sheep. It is a modified version of
  the Prionics - Check technique and provides a
  cleaner, more defined signal of the abnormal
  prion protein (PrPsc) profile, for analysis.
• A homogenised sample of central nervous system
  tissue from cattle or sheep is exposed to the
  enzyme, proteinase K, and PrPsc can be
  distinguished from the normal prion protein
  (PrPc) by protease resistance and molecular size.
  This double antibody detection method has been
  validated to show there are different molecular
  weight fragment sizes, differential antibody
  affinity and glycoform ratio differences between
  BSE and scrapie in sheep.

67
BSE

• BSE and sheep? (cont)
• Scientists from the Veterinary Laboratories
  Agency have revealed that two ewes fed 5mg of
  BSE-infected material had lambs that died of BSE
  after showing signs of infection in their
  tonsils, 546 days after birth. Their mothers had
  shown no outward signs of the disease at lambing,
  one showing them 73 days after lambing, and the
  other 198 days after.
• It is still not certain that the lambs were
  infected while in the uterus, or shortly before
  or after lambing. The disease may have spread
  through the birthing fluids or in some other way.
  The evidence so far suggests this is far more
  likely than the lambs catching the disease from
  other apparently unaffected sheep.
• Bellworthy SJ et al (2005), Natural transmission
  of BSE between sheep within an experimental
  flock,Vet Record, 157. 206.

68
BSE

• BSE and sheep? (cont)
• Statement of the Scientific Panel on Biological
  Hazards related to report of the EU TSE Community
  Reference Laboratory on the recent TSE cases in
  sheep.
• Last updated 17 March 2006
• The result does not fit the criteria for
  BSE-like by this test, nor does it match
  those for classical scrapie isolates. It also
  does not share the properties of atypical
  scrapie, as defined in the EFSA Opinion.

69
BSE

• BSE and sheep? (cont)
• Atypical scrapie has now been identified in the
  British sheep flock. On 15 June 2006, the UK Food
  Standards Agency updated its advice to the public
  because it did not know whether atypical scrapie
  could affect humans. While it is not advising
  people to stop eating sheep or goat meat, or
  their dairy products, it says that consumers can
  reduce the risk by avoiding meat from older sheep
  (mutton) but points out to the EU that new
  labelling provisions are needed for the public to
  be able to identify products containing mutton.

70
BSE

• BSE and sheep? (cont)
• On 17 November 2006 a UK Defra Information
  Bulletin stated that atypical scrapie had been
  detected in a sheep from a research flock all the
  founder animals of which were imported from New
  Zealand, a country considered to be free of TSEs.
  The flock is managed under strict bio-security
  conditions to ensure that the animals do not come
  into contact with other sheep. All animals that
  die or are culled in the flock are routinely
  tested for the presence of TSEs and as result of
  this routine testing one of the animals has
  tested positive for atypical scrapie. As the
  origin is not clear, independent scientific
  investigation will include ensuring that the
  bio-security on the farm was not compromised and
  that there was no possibility of cross
  contamination of the sample.

71
BSE

• BSE and goats?
• On 12 November 2004 the French General
  Directorate for Food (DGAL) reported that a goat
  was found, when slaughtered in 2002, to exhibit a
  TSE molecularly and biologically compatible with
  BSE. On 28 January 2005 BSE was confirmed. The
  goat was born before the Europe wide ban on MBM.
• Over 140,000 goats have been tested for BSE
  throughout the EU, with only this one case
  discovered. The rest of the infected animal's
  herd of 600 was tested, all with negative
  results. The EU Commission intends increased
  testing of goats.
• EFSA has advised that based on current
  scientific knowledge, goat milk and derived
  products are unlikely to present any risk of TSE
  contamination if the milk comes from healthy
  animals and is assessing whether restrictions
  are necessary on French goat meat.

72
BSE

• BSE and goats?
• In the UK, all sheep and goat TSE positive cases
  are tested by molecular methods that are capable
  of differentiating between classical scrapie,
  atypical scrapie and experimental BSE. Cases
  where the presence of BSE is ruled out and which
  are confirmed as classical or atypical scrapie
  are not routinely subjected to mouse bioassay. If
  the presence of BSE cannot be excluded, the
  sample is subjected to mouse bioassay.
• In each of the six cases of TSE detected in goats
  in the UK in the past three years, both BSE and
  atypical scrapie have been ruled out they have
  all been confirmed as classical scrapie.

73
BSE

• Transmissible to humans?
• March 1996 UK Government announcement of assumed
  causal connection.
• October 1996 First scientific evidence
  consistent with transmissibility of BSE
  infectivity to at least some humans (possibly to
  all humans but at varying incubation rates).
• Subsequent findings increased likelihood of
  causal connection.

74
BASE

• Transmissible to humans?
• In a paper given at the Prion 2008 Conference in
  Madrid in October 2008, Baron V et al reported
  the ransmission of atypical BE to non-human
  primates (lemurs). Only one of the four lemurs
  challenged with (H-type) BSE died without
  clinical signs after 19 months post inoculation
  (pmi), wheras all four lemurs inoculated with
  L-type BSE died at 19mpi (2 males) and 22mpi (2
  females), have shown blindness, tremor. abnormal
  posure, uncoordinated movements and balance loss.
• http//www.neuroprion.org/resources/pdf_docs/confe
  rences/prion2008/abstract-book-prion2008.pdf

75
BASE

• Transmissible to humans?
• In December 2008 a study showed the transmission
  of atypical bovine prions to mice transgenic for
  human prion protein, with no significant
  transmission barrier. Extrapolation of the data
  raises the theoretical possibility that the
  zoonotic risk associated with BSE-L prions might
  be higher than that associated with classical
  BSE.
• Béringue V et al, Emerg. Infect. Dis., 2008 Dec
  Epub ahead of print

76
BSE/vCJD

• Current UK incidence of vCJD
• As at 7 September 2009 UK - Deaths
• From definite vCJD (confirmed) 116
• From probable vCJD (without 7neuropathological
  confirmation) 49
• From probable vCJD (neuropathological
  confirmation pending) 0
• Total deaths from definite or probable vCJD
  (as above) 165
• Alive probable vCJD cases still alive 4
• Total number of definite or probable vCJD
  (dead and alive) 169

77
BSE/vCJD

• Current UK incidence of vCJD?
• (per million population aged 10 yrs )

78
BSE/vCJD

• Current incidence of vCJD
• As at 25 September 2009
• Deaths outside UK
• France 24
• Ireland 4
• Italy 1
• Hong Kong 1
• USA (1 British born, 1 Saudi born) 3
• Canada (spent some time in the UK)
  1
• Italy (alive, confirmed by brain scan / tonsil
  biopsy) 1
• Spain 4
• Japan (visited UK during 1989) 1
• The Netherlands 2
• Portugal 1
• Saudi Arabia 1

79
BSE/vCJD

• The role of MRM?
• Attention focused on MRM as a possible source of
  high titre infectivity in the food chain,
  particularly prior to 1995 when the use of spinal
  column for MRM was banned. Current EU measures
  prohibit MRM from any bovine or ovine bones.

80
BSE/vCJD

• The role of MRM?
• A research report prepared for the Food Standards
  Agency, issued 10 October 2002, on Sources of
  bse infectivity attempted retrospectively to
  estimate the uses of MRM in various meat products
  prior to 1996.
• http//www.food.gov.uk/multimedia/pdfs/sources_bse
  _infect.pdf

81
BSE/vCJD

• Susceptibility to vCJD
• Assuming causal link between consumption of BSE
  infectivity and vCJD, and millions exposed from
  1985 to 1996, why still only ca 170 cases by
  early 2005?
• In vitro research Raymond et al (1997) found
  that host prion protein that is
  methionine/methionine homozygous at codon 129 is
  converted to prions more rapidly than host prion
  protein valine/valine homozygous at codon 129 (no
  evidence about heterozygous met/val). All of the
  victims reported prior to July 2004 have been
  met/met homozygous at codon 129, i.e. suggesting
  that met/met has a shorter incubation period,
  than val/val or met/val.

82
BSE/vCJD

• Susceptibility to vCJD (cont)
• Wadsworth et al have reported that in transgenic
  mice expressing human PrP, human PrP 129 valine
  appears not to be a compatible substrate for the
  type of prion (type 4) seen in vCJD. These
  animal models suggest that human infection with
  BSE-derived prions may not be restricted to a
  single disease phenotype, but may result in
  sporadic CJD-like or novel phenotypes in addition
  to vCJD, with the type of disease experienced
  depending on the genotype of the host source of
  the infection, and the genotype of the recipient.
• (Wadsworth JD et al (2004). Science 2004 Nov 11
  2004)

83
vCJD

• Asante et al have shown that transgenic mice
  expressing human PrP methionine 129, inoculated
  with either BSE or vCJD prions, may develop the
  neuropathological and molecular phenotype of
  vCJD, consistent with these diseases being caused
  by the same prion strain. Surprisingly, however,
  BSE transmission to these transgenic mice, in
  addition to producing a vCJD-like phenotype, can
  also result in a distinct molecular phenotype
  that is indistinguishable from that of sporadic
  CJD with PrPSc type 2. These data suggest that
  more than one SE-derived prion strain might
  infect humans it is therefore possible that some
  patients with a phenotype consistent with
  sporadic CJD may have a disease arising from BSE
  exposure.
• Asante et al (2002). EMBO Journal, 21 ( 23),
  6358-6366.

84
vCJD

• First CJD case of valine homozygosity at codon
  129
• In a paper describing the histopathologic and
  molecular investigation in a young British woman
  with atypical sporadic CJD and valine
  homozygosity at PRNP codon 129. autopsy findings
  were atypical of sporadic CJD, with marked gray
  and white matter degeneration and widespread
  prion protein (PrP) deposition. Lymphoreticular
  tissue was not available for analysis. Molecular
  analysis of PrPSc from cerebellar tissue
  demonstrated a novel PrPSc type similar to that
  seen in vCJD (PrPSc type 4). Further studies will
  be required to characterize the prion strain seen
  in this patient and to investigate its etiologic
  relationship with BSE.
• Mead s et al Arch Neurol. 200764(12)1780-1784.
  

85
vCJD

• Aguzzis group in Zurich 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.
• Polymenidou et al (2005), Coexistence of
  multiple PrPSc types in individuals with
  Creutzfeldt-Jakob disease, Lancet Neurology,
  (4)805-814

86
BSE/vCJD

• Susceptibility to vCJD (cont)
• However, codon 129 may not be the only
  significant location. Collinge et al (2001) have
  shown that other genes are likely to play an
  important role in susceptibility to infection.
  Two different strains of mice with known
  differences in incubation periods for disease
  were used in the study and the mice given a
  thorough analysis of their whole genome, which
  allowed the three genes to be located that are
  involved in susceptibility to prion disease in
  mice. As the mouse and human genomes are so
  similar it is almost certain that corresponding
  genes in humans will be found which have the same
  role to play,

87
BSE/vCJD

• Susceptibility to vCJD (cont)
• A genome-wide association study of the risk of
  vCJD with follow-up analyses of the genetic
  control of the clinical phenotype of prion
  disease and analysis candidate gene expression in
  a mouse cellular model of prion infection. Showed
  that although the main contribution to disease
  risk was conferred by PRNP polymorphic codon 129,
  another nearby SNP conferred increased risk of
  vCJD. In addition to PRNP, one technically
  validated SNP association upstream of RARB (the
  gene that encodes retinoic acid receptor beta)
  had nominal genome-wide significance.
• Mead S et al (2009), The Lancet Neurology, (8)1,
  57 66
• Possible conclusion?

88
BSE/vCJD

• Susceptibility to vCJD (cont)
• Possible conclusion?
• There could up to three variably-susceptible
  genetic groups and at least three sub-groups in
  each. All the reported victims to early July
  2004, all met/met at codon 129, could be in the
  most susceptible genetic sub-group of the most
  susceptible group.
• This wave shows signs of declining but there
  may be several further waves to come.

89
vCJDJanuary 1994 December 2004
90
BSE/vCJD

• Incidence of vCJD?

91
BSE/vCJD

• Incidence of vCJD?
• (age vs calendar year)

92
BSE/vCJD

• Estimated influence of age on a) risk for
  infection with the variant Creutzfeldt-Jakob
  disease (vCJD) agent and b) risk for death from
  vCJD after infection
• (Barchetti, P (2003). EID serial online 9 (12))

93
vCJDJanuary 1994 June 2006
94
BSE/vCJD

• Susceptibility to vCJD (cont)
• Following a case in December 2003 of vCJD
  possibly acquired by a 1999 blood transfusion, a
  second case of possible transmission of vCJD from
  person to person via a 1999 blood tranfusion was
  reported Peden, AH et al, (2004), The Lancet,
  264, 527-29. A patient in the UK received a
• blood transfusion in 1999 from a donor who later
  went on to develop vCJD. The patient died of
  causes unrelated to vCJD but a post mortem
• revealed the presence of vCJD infectivity in the
  patient's spleen. This was the first instance of
  vCJD in a person in the codon 129 heterozygous
  (met/val) group.

95
BSE/vCJD

• Susceptibility to vCJD (cont)
• On 18 December 2008 it was reported that an
  individual with methionine/valine heterozygosity
  had been diagnosed on a clinical basis as vCJD.
  Prof Higgins, Chairman of SEAC, estimates that
  the number of met/val victims could be probably
  between 50 and 350.

96
BSE/vCJD

• Susceptibility to vCJD (cont)
• This could possibly signal the beginning of a new
  wave of heterozygous met/val cases.
• It also highlights the possibilities of
  iatrogenic person-to-person transmission of vCJD
  from persons silently incubating the disease to
  others via earlier blood transfusions or surgical
  instruments.

97
BSE/vCJD

• Susceptibility to vCJD (cont)
• In February 2006 a third case was reported. The
  patient developed symptoms of vCJD about 8 years
  after receiving a blood transfusion from a donor
  who developed symptoms of vCJD about 20 months
  after donating this blood. The patient who was at
  the at the National Prion Clinic and has now died
  was one of 25 living persons known to have
  received a blood transfusion in the UK from a
  donor who later developed vCJD. All have
  previously been informed of their potential
  exposure to vCJD and asked to take certain
  precautions to reduce the chance of passing on
  vCJD on to other people via healthcare
  procedures, such as surgery.

98
BSE/vCJD

• Susceptibility to vCJD (cont)
• This was confirmed by a case study published
• in December 2006 The patient, who has since
  passed away, is the first to have been diagnosed
  whilst still alive. At the age of 23, the patient
  was given a blood transfusion from a donor who
  later developed vCJD. Seven and a half years
  later he was referred to the NHS National Prion
  Clinic
• where his symptoms were confirmed to be caused by
  vCJD.
• The Lancet 2006 3682061-2067
• http//www.mrc.ac.uk/consumption/groups/public/doc
  uments/content/mrc003431.pdf

99
BSE/vCJD

• Susceptibility to vCJD (cont)
• Following a statement by the UK Secretary of
  State for Health on 9 September 2004, to reduce
  the risk of onward patient-to-patient
  transmission of vCJD, warning letters were sent
  during the week commencing 21 September 2004 to
  selected groups of patients (and their healthcare
  professionals) about the results of the risk
  assessment, informing them that, because they
  have received certain batches of plasma products
  in the past, which were derived from blood
  donated from someone who has later gone on to
  develop vCJD, they could be at a small increased
  risk of carrying the vCJD agent.
•  

100
BSE/vCJD

• Susceptibility to vCJD (cont)
• People who may be affected are
• Some people with haemophilia and other bleeding
  disorders. All of these people (around 6,000)
  will receive letters about the background to this
  exercise. The number who may be affected directly
  is estimated to be around 4,000 people.
• A small group of people suffering from primary
  immunodeficiency, estimated to number around 50
  people.
• A small number of people who have been treated
  with large quantities of particular plasma
  products for a range of conditions (e.g.
  secondary immunodeficiency).
•  

101
BSE/vCJD

• Transmission by blood
• The first two reported cases could have acquired
  infectivity by other means but statistical
  analysis suggests it is more probable it was
  acquired via (non-leucodepleted) blood donated in
  1997 by a person who subsequently developed vCJD
  (there are 13 other persons known to have
  received blood from that donor).

102
BSE/vCJD

• Transmission by blood
• In February 2009 evidence of abnormal prion
  protein infection has been found at post mortem
  in the spleen of a person with haemophilia. The
  patient, who was over 70 years old, died of a
  condition unrelated to vCJD and had shown no
  symptoms of vCJD or any other neurological
  condition prior to his death. Patients with
  bleeding disorders are being made aware of this
  preliminary information which is being further
  investigated. It is known that the patient had
  been treated with several batches of UK sourced
  clotting factors before 1999, when measures to
  improve the safety of blood in relation to vCJD
  were introduced. The patient's treatment had
  included one batch of Factor VIII that was
  manufactured using plasma from a donor who went
  on to develop symptoms of vCJD six months after
  donating the plasma in 1996.

103
BSE/vCJD

• Transmission by blood
• Nov 1997 - evidence that pathogenesis of vCJD may
  involve lymphoreticular tissues possibly
  involving circulating lymphocytes, led to UK
  leucodepletion of blood for transfusions and
  purchase of blood supplies from USA.

104
BSE/vCJD

• Transmission by blood
• However, in August 2004 research was published
  showing that leucodepletion removed only 42 of
  the initial TSE infectivity from whole blood.
  While further work was needed to identify the
  location of the residual infectivity, it was
  presumed that it is plasma associated.
• Gregori L, (2004). Effectiveness of
  leucoreduction for removal of infectivity of
  transmissible spongiform encephalopathies from
  blood,The Lancet, 264, 529-31.

105
BSE/vCJD

• Transmission by blood
• On 17 October 2005 research studies demonstrating
  the effectiveness of prion filtration technology
  to safeguard the blood supply were presented at
  the American Association of Blood Banks Annual
  Meeting in Seattle. 99.9 prion removal
  efficiency was claimed for the Pall Leukotrap
  Affinity Prion Reduction Filter System. A new
  study conducted by the American Red Cross and the
  Eastern Virginia Medical School, Norfolk Va.,
  et.al., found that red blood cells filtered
  through the system retain their therapeutic value
  and quality after 42 days of storage.

106
BSE/vCJD

• Transmission by blood
• In December 2006, Rohwer et al reported
  identifying a resin, called L13, that binds to
  both the normal and disease-causing forms of
  prion protein. They tested the resin using
  hamster blood spiked with scrapie. They then used
  this blood to transfuse hamsters. Around half of
  the animals injected with untreated blood
  developed disease, but the nearly 200 hamsters
  injected with blood filtered with L13 remained
  disease-free.
• Nature News, published on-line, 22 December 2006
  doi10.1038/news061218-13

107
BSE/vCJD

• Iatrogenic transmission
• Bishop et al (2006) have modeled in mice
  iatrogenic spread to enable a comparison of
  transmission efficiencies of vCJD and BSE and an
  assessment of the effect of the codon-129
• polymorphism on human susceptibility.
• BSE was transmitted to the bovine line but did
  not transmit to the human lines. By contrast,
  vCJD was transmitted to all three human lines
  with different pathological characteristics for
  each genotype and a gradation of transmission
  efficiency from MM to MV to VV.
• Lancet Neurology, DOI10.1016/S1474-4422(06)
  70413-6
• .

108
vCJD

• How many future cases of vCJD?
• Short-term forecast by CJDSU
• At July 2006, extrapolating the best fitting
  CJDSU model (the quadratic model) gives an
  estimate of one or 2 deaths in the following 12
  months (95 prediction interval 0 to 3), however
  with 5 cases currently alive a prediction of one
  or 2 deaths is likely to be a slight
  underestimate. It is important to note that
  although a peak has been passed, it is possible
  that there will be future peaks, possibly in
  other genetic groups.  There is also the
  possibility of ongoing person to person spread.

109
vCJD

• How many future cases of vCJD?
• No such thing as the incubation period
• Unknown dates of infection of individuals.
• Age-based susceptibility?
• Dose-response relationship?
• Three main populations (codon 129) with
  differing rates.
• Unknown number of possible genetic
  sub-populations?
• Secondary transmission via blood, surgical
  instruments
• Long-term forecast ?

110
vCJD

• Hilton et al (2004) tested samples from 16 703
  patients (14 964 appendectomies, 1739
  tonsillectomies), approximately 60 of whom were
  from the age group 20-29 years at operation (25
  of samples containing inadequate amounts of
  lymphoid tissue were excluded from final
  analyses), suggests a prevalence of vCJD among UK
  people aged 20-29  of 237 per million.. Three
  appendicectomy samples showed lymphoreticular
  accumulation of prion protein, giving a
  estimated prevalence of 3/12,674 or 237 per
  million (95 CI 49-692 per million). The pattern
  of lymphoreticular accumulation in two of these
  samples was dissimilar from that seen in known
  cases of vCJD. The margin of error for this
  figure is high and the authors stress the need
  for large scale screening of tonsil tissue to
  obtain precise data.
• Hilton DA et al (2004) Prevalence of
  lymphoreticular prion protein
• accumulation in UK tissue samples,Journal of
  Pathology, 202.

111
vCJD

• Comment
• Extrapolation from 3 (of which 2 are problematic)
  in 12,674 to the whole population is an
  unwarranted assumption.
• Moreover, we do not know at what stage in the
  long but variable incubation period, infective
  prions become detectable in the tonsils or
  appendix.
• Tonsils removed from 100,000 patients, mostly
  children or teenagers, over the next three years
  may provide a better basis.

112
vCJD

• In April 2008, SEAC noted the progress of the
  National Anonymous Tonsil Archive (NATA) and of
  discussions around a proposed post mortem tissue
  archive. These would provide data to estimate the
  prevalence of subclinical vCJD (vCJD infections
  that have yet to develop, or may never develop,
  into clinical disease). Approximately 55,000 NATA
  samples had been screened by the end of March
  2008. Although none was positive for abnormal
  prion protein (PrPvCJD), some testing remains to
  be done on some samples.

113
BSE/vCJD

• Aguzzi's group in Zurich engineered mice to
  produce a soluble protein that would stick to the
  scrapie prion, so the team could retrieve the
  prion protein for testing. The engineered mice
  turned out to take twice as long as normal to
  develop the disease. Aguzzi now hopes to
  mass-produce the protein so he can test it on
  macaque monkeys that have been exposed to BSE.
• (presentation at European Life Science
  Organisation conference reported in New
  Scientist, 4 October 2003)

114
BSE/vCJD

• On 8 January 2003 the EU issued Questions and
  Answers on BSE What is the current state of play
  on BSE in the EU?
• http//www.europa.eu.int/rapid/start/cgi/guesten.k
  sh?p_action.gettxtgtdocMEMO/03/30RAPIDlgEN
  display

115
BSE/vCJD

• O Koperek et al have demonstrated
  disease-associated prion protein deposits in
  intracranial vessel walls, in sporadic and
  variant Creutzfeldt-Jakob disease. They conclude
  that mobile cells in vessel walls like dendritic
  and monocyte/macrophage lineage cells may be
  involved in spread of disease-associated prion
  protein and possibly also of infectivity.
• O Koperek et al (2002). Disease-associated prion
  protein in vessel walls, American Journal of
  Pathology. 161,1979-1984)

116
BSE/vCJD

• G Zanusso et al have demonstrated that PrPSc is
  deposited in the neuroepithelium of the olfactory
  mucosa in patients with sporadic CJD, indicating
  that olfactory biopsy may provide diagnostic
  information in living patients. They conclude
  that the olfactory pathway may represent a route
  of infection and a means of spreading prions.
• (NB This has not yet been shown with vCJD)
• G Zanusso et al (2003)NEJM, 348(8),711-719.

117
BSE/vCJD

• G Mallucci and J Collinge suggest that new
  insights into the mechanisms of neurotoxicity in
  prion diseases support the concept that PrPSc
  itself is not directly neurotoxic. They suggest
  that neuronal prion propagation results in the
  production of a toxic intermediate or depletion
  of a key constituent. Prevention of the formation
  of such a species rather than PrPSc
  accumulation itself is a clear target for prion
  therapeutics.
• Mallucci, G and Collinge, J (2004) Update on
  Creutzfeldt-Jakob disease. Current Opinion in
  Neurology, 17(6),641-647, Dec 2004.

118
BSE/vCJD

• H Yull et al (NCJDSU) have shown that the PrPSc
  that accumulates in the brain in vCJD also
  contains a minority type 1 component. This
  minority type 1 PrPSc was found in all 21 cases
  of vCJD tested, irrespective of brain region
  examined, and was also present in the vCJD
  tonsil.
• The quantitative balance between PrPSc types was
  maintained when vCJD was transmitted to wild-type
  mice and was also found in BSE cattle brain,
  indicating
• that the agent rather than the host specifies
  their
• relative representation. These results indicate
  that PrPSc
• molecular typing is based on quantitative rather
  than
• qualitative phenomena and point to a complex
  relationship
• between prion protein biochemistry, disease
  phenotype
• and agent strain.
• (Am J Pathol 2006, 168151-157 DOI
  10.2353/ajpath.2006.050766)

119
BSE/vCJD

• What makes a good prion?
• The Cold Spring Harbor Laboratory/Wellcome Trust
  Conference on Prion Biology took place between 7
  and 11 September 2005 in Hinxton, UK, and was
  organized by A. Aguzzi, B. Chesebro, M. Tuite and
  R. Wickner.
• EMBO reports 7, 3, 254258 (2006)
• doi10.1038/sj.embor.7400642
• AOP Published online 17 February 2006
• http//www.nature.com/embor/journal/v7/n3/pdf/7400
  642.pdf
• (see next slide for I ndividual References)

120
BSE/vCJD

• References
• Aguzzi A , Polymenidou M (2004) Mammalian prion
  biology one century of evolving concepts. Cell
  116 313327 Article PubMed ISI ChemPort
  
• Chien P , Weissman JS , DePace AH (2004) Emerging
  principles of conformation-based prion
  inheritance. Ann Rev Biochem 73 617656
  Article PubMed ISI ChemPort
• Dobson CM (2004) In the footsteps of alchemists.
  Science 304 12591262 Article PubMed ISI
  ChemPort
• Shorter J , Lindquist S (2005) Prions as adaptive
  conduits of memory and inheritance. Nat Rev Genet
  6 435450 Article PubMed ISI ChemPort
• Weissmann C (2005) Birth of a prion spontaneous
  generation revisited. Cell 122 165168 Article
  PubMed ISI ChemPort

121
BSE/vCJD

• Main knowledge gaps?
• There is no treatment or cure for BSE or vCJD