Transcript Prion-related diseases: issues, problems, recommendations

Presentation layout
1.
2.
Introductory remarks
New Infectious Disease Paradigm
Prion-related diseases:
•
•
•
3.
TSEs
Prions
Human prion disease
hypothesis
EU medico-scientific
TSE Epidemiology
•
•
4.
•
Human
Animal
EU TSE Legislative Framework
Food and feed products
William P. Charteris
•
chronology of EU consumer health protection measures (1988-2005)
•
•
key EU TSE protection measures
The Consultant’s Consultant™
EU TSE Legislative Road Map
•
•
6.
7.
www.billcharteris.com
summary of EU TSE protection measures
Blood products
•
5.
and regulatory issues,
problems, and recommendations
Proposed changes to EU TSE protection measures
(2005-2014)
Nov. 7th, 2005.
Personal recommendations
Concluding remarks
Addendum
Introductory remarks
1.
BSE epidemic (1986-2014)
•
•
•
•
•
2.
1.6 million infected animals entered the human food chain
huge number of animals destroyed
EU, CH, JP, CA, USA
total estimated losses: €100 billion
significant decline in disease incidence since 2002
nvCJD epidemic (1996-2010)
•
•
•
•
3.
Table 2: Probable and definitive mortality from nvCJD in the UK
(as of October 5 2005)
not more than 500 fatalities; < 200 lives more likely
UK, IE, FR, PT
compensation: £125,000 per victim
significant decline in disease incidence since 2000
Year
Risk assessment and management
Table 1: Prevalence
of BSE in the EU and UK
•
bovine
•
•
•
Parameter
ovine
caprine
cervid
Incidence of BSE [2004]
Reduction since 2002
Incidence of BSE in healthy slaughtered animals
[2004]

a new infectious
disease
paradigm
Reduction
since
2003
Incidence ofBSE in high
risk
animals
[2004]
in the face of incomplete knowledge
Reduction since 2003
4.
Risk communication

undermined public confidence
Source: EU TSE Annual Report 2004
Number of cases
EU25
UK
865
40%
166
39%
520
35%
343
30%
151
43%
243
49%
nvCJD
sCJD
iCJD
fCJD
GSS
Total
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
3
10
10
18
15
28
20
17
18
9
3
28
32
45
37
53
35
40
60
63
62
50
58
72
77
52
41
5
1
2
4
1
4
4
6
3
6
1
4
0
5
2
1
0
3
5
3
4
2
2
4
3
2
2
3
4
4
3
2
0
0
1
2
3
3
4
1
2
0
1
2
1
2
1
1
33
36
53
46
61
47
60
81
89
85
82
87
94
106
67
48
All
151
805
49
46
24
1,075
Source: UK Department of Health
The New Infectious Disease Paradigm
Transmissible spongiform encephalopathies
sheep
1.
Characteristics
•
•
•
•
2.
very rare, uniformly fatal neurodegenerative diseases
Table 3: Human and animal prion disease
long incubation period
multi-focal neuropathology
Mode of transmission
Prion disease
toxic gain of function of an aberrant form of a constitutive protein
Human Animal
Classification of prion-related diseases
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•
•
3.
infectious
infectious
sporadic
genetic
villi
genetic
fCJD
GSS
FFI
sporadic
sCJD
Pathogenesis
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•
•
4.
penetration and peripheral replication
translocation and neuroinvasion
neurodegeneration
Transmissibility barriers (R/M)
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•
inter-species transmission barrier
intra-species transmission barrier
•
strain transmission barrier
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adaptation
nvCJD
iCJD
kuru
BSE
Scrapie
cow
TME
CWD
CJD - Creutzfeldt-Jakob
human
nv - new variant
i - iatrogenic
f - familial
s - sporadic
GSS - Gerstmann-Straüssler-Scheinker Syndrome
FFI - Fatal Familiar Insomnia
BSE – bovine spongiform encephalopathy
TME – transmissible mink encephalopathy
CWD – chronic wasting disease
The New Infectious Disease Paradigm
Prions
1.
Structural types
•
native or constitutive [PrPc]
•
non-toxic proteins/peptides characterized by:
•
foreign or pathogenic [PrPres]
•
amyloid proteins/peptides characterized by:
•
•
•
•
•
2.
(b) high β sheet content
(d) birefringence on Congo Red staining
toxic amyloid, inactive amyloid, active amyloid, and self-activating enzyme
stable interchangeable conformers of each another [PrPc + PrPres -> 2 PrPres]
PrPc is a ubiquitously expressed, GPI-anchored membrane bound glycoprotein
theTable
precise nature
of its physiological
role remains
a mystery proteins and peptides
4: Examples
of human
amyloid
it has dual neurological and immunological functions
it is likely that PrPc represents a new type of pattern recognition receptor
Protein
Disorder
its likely evolutionary origin - a horizontally transferred gene from an early RNA virus
Genetics
Aβ
peptides
Alzheimer’s disease
chromosomally
encoded:
Transthyretin
Senile systemic amyloidosis
• Serum
PrPc is
encoded by
chromosome
20 at 20pter-p12
amyloid
A PRNP on human
Secondary
systemic
amyloidosis
•
SNP polymorphism at codon 129 on human PRNP
(infections and chronic inflammatory conditions)
•
MV heterozygote individuals have increased resistance to disease
•
MM homozygotes individuals have increased susceptibility to disease
Amylin (IAPP)
Type II diabetes
Transmissibility
to humans
α -synuclein
Parkinson’s disease
•
bovines:
confirmed
Superoxide dismutase
Amyotrophic amyloidosis
•
the mean nvCJD incubation period following consumption of an infectious dose of BSE-infected
β 2-microglobulin
beef by MM homozygote is 16.7Hemodialysis-related
years (95% CI, 8–30 years) amyloidosis
Huntingtin
Huntington’s
disease
•
sheep, goats, deer, etc.: not confirmed
PrP
Transmissible spongiform encephalopathies
Ig light chain
Primary systemic amyloidosis
•
4.
(a) filamentous morphology
(c) relative protease resistance
(b) relative protease sensitivity
Function
•
•
•
•
•
3.
(a) high a-helix content
The New Infectious Disease Paradigm
Human Prion Disease Hypothesis
1.
Background
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•
2.
The cause of the original case or cases of BSE remains an enigma
Sheep scrapie or a previously undetected sporadic form of BSE
have long been considered as candidates, but no convincing
evidence to support these proposals has come to light
New Theory
•
3.
A new theory has been presented, with three related hypotheses:
•
that BSE was acquired from a human TSE
•
that the route of infection was oral, through animal feed
containing imported mammalian raw materials contaminated
with human remains
•
that the origin was the Indian subcontinent, from which large
amounts of mammalian material were imported during the
relevant time period. Human remains are known to be
incorporated into meal made locally, and may still be entering
exported material!
Research requirements
•
Further investigations are needed regarding:
•
the sources of animal by-products used in animal feed
manufacture
•
the transmissibility of human TSEs to cattle
Colchester, A. C., and N. T. Colchester. 2005. The origin of bovine spongiform
encephalopathy: the human prion disease hypothesis. Lancet 366:856-61.
TSE Epidemiology
Human
Characteristics of nvCJD epidemic
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Figure 1: UK nvCJD mortality (1990 – October 5 2005)
Zoonosis with age-dependent susceptibility
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•
•
•
•
dietary exposure
individual susceptibility (genetics, etc.)
Mean incubation period is 15 years
Mean age at death is 29 years
Started - 1994; Peaked - 2001; End - 2010
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•
•
exposure before 1986
exposure after 1989 SBO ban [90% effective]
An epidemic of relatively moderate size
•
•
30
not more than 500 lives; < 200 lives more likely
UK, FR, IE, IT, USA, CA affected
25
UK nvCJD mortality
1.
20
15
Table 5: Summary of nvCJD cases in the UK (1990 – October 5 2005)
2.
Unresolved issues
Details
• StatusDifferential
diagnosis at autopsy
•
Alive
•
Number
10
diminishing number of referrals
Number of definite/probable nvCJD cases still alive
6
Evolution of epidemic in homozygous individuals
5 ban
bimodal
distribution
to MRM
not included
in the 1989 SBO
Deaths
from due
definite
nvCJD
(confirmed)
from in
probable
nvCJDindividuals
(without neuropathology confirmation)
EvolutionDeaths
of epidemic
heterozygous
Deaths
from
probable
nvCJD
(neuropathology confirmation pending)
•
60% of the population
•
• All
0
•
Secondary
transmission
(blood,
bone,
medical
devices,
etc.)
Total
number of
probable
and
confirmed
nvCJD
cases (alive and
low level
endemicity in humans and animals
deceased)
Source: UK Department of Health 2005
108
42
1
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
•
Deceased
Year
Source: www.cjd.ed.ac.uk/figures.htm
157
Animal
1.
Characteristics of bovine epidemic
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Unknown cause
•
•
•
•
dietary exposure
individual susceptibility (genetics, etc.)
Mean incubation period is 5 years
Started -1986; Peak - 1992; End - 2014
•
•
•
30,000
20,000
10,000
0
Year
exposure before 1986
exposure after 1989 SBO ban [90% effective]
Source: EC TSE Annual Report 2004
An epidemic of large size
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•
•
•
40,000
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
TSE Epidemiology
BSE positive cases
Figure 2: Evolution of BSE in the UK
188,809,000 infected bovines [EU25: 1988-2004]
1.6 million entered the human food chain
Figure 3: Evolution of BSE in other countries affected
number of risk animals destroyed
total estimated losses: 100 billion euro
350
Sheep
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Goats
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•
3.
2,332 TSE cases a population of 89,838,000 [EU25: 2004] 250
CY (52%), FR (20%), UK (14%)
200
Inter-species transmission [1998-2004]
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•
FR
DE
398 TSE cases in a population of 12,370,000 [EU25: 2004]
150
CY (89%), FR (7%), GR (1%)
Unresolved issues
•
IE
CH
JP
100
50
bovine->ovine: not shown by bio-assay [3,506 tests]
0
bovine->caprine: 1 confirmed FR case by bio-assay [57 tests]
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
•
BSE-positive cases
300
Characteristics of ovine and caprine ‘epidemics’
2.
Year
Source: EC TSE Annual Report 2004
EU TSE Regulatory Framework
Food & Feed Products
1.
Background
Table 6: Selected chronology of EU consumer health protection measures (1989 – 2005)
Year
Regulatory Measure
1989
1990
Restrictions on the dispatch of certain live cattle from the UK
Compulsory notification of BSE
Restrictions on the dispatch of certain bovine tissues and organs from the UK
Restrictions on the dispatch of bovine embryos from the UK
Ban on the use of mammalian-derived proteins for feeding ruminants
Rendering systems for processing ruminant waste into MBM (inactivation of BSE agents)
Total ban on dispatch of live cattle and all cattle products from the UK (UK embargo)
Eradication programmes for BSE in the UK and Portugal
Prohibition of the use of SRM (mainly brain, eyes and spinal cord)
Restrictions on trade in MBM
Epidemiological surveillance for all animal TSEs
Total ban on dispatch of live cattle and all cattle products from Portugal (Portugal embargo)
Conditions for the production of MBM and tallow (Repeals D 96/449/EC)
Temporary ban on use of MBM
Prohibition of the use of dead animals in the production of animal feed
Prevention, control and eradication of certain TSE
Establishment of breeding programmes for resistance to TSEs in sheep
Requirements for the import of cervid products from Canada and the United States
Systematic BSE-scrapie discriminatory tests for all confirmed TSE cases in small ruminants
Increased TSE monitoring in goats
Prohibition of products derived from bovine animals born or reared in the UK before 1 August
1996
1992
1994
1996
1997
1998
1999
2000
2001
2003
2004
2005
EU TSE Regulatory Framework
Food & Feed Products
2.
Protective measures
Table 7: EU TSE Protective Measures
Measure
Details
Country restrictions
DEC 98/256 (UK embargo Decision)
1996-2005: UK Over-Thirty-Months (OTM) Rule
2006: permanent exclusion of cattle born before 1 August 1996 from the food and feed chain
\ some exceptions like the use of fish meal for non-ruminants
these tissues must be removed from the food and feed chains
\ prohibition for use in food and feed such as tallow, gelatine, collagen, and dicalcium phosphate
1994-2000: partial ban on the feeding of mammalian MBM to cattle, sheep and goats was introduced in July 1994
2001: total EU wide ban on the use of processed animal protein in feeds for any food animals
Joint Research Centre, Ispra, Italy
culling of epidemiologically linked ‘birth’ and ‘feed’ cohorts to bovine TSE cases
whole or partial (sensitive genotypes) culling if TSE is detected in sheep, including atypical cases
whole herd culling of goats if TSE is detected
a minimal sheep breeding programme became mandatory for flocks of high genetic merit on 1 April 2005
Country categorisation according to BSE risk has as its objective the definition of trade rules to protect animal and
public health in importing countries. The conditions for such trade are already laid down in the current
recommendations of the Terrestrial Animal Health Code of the World Organisation for Animal Health (OIE Code)
bovine passive monitoring up to July 2001; active monitoring thereafter
\ all risk animals over 24 months of age and all healthy slaughtered animals above 30 months of age (≈ 10 million p.
passive monitoring up to 2002; active monitoring thereafter
\ risk animals and healthy slaughtered animals over 18 months of age
\\ minimum of 10,000 sheep and 10,000 goats per Member State
extended monitoring of all healthy slaughtered goats since 2005
Specified Risk Material
Feed ban
Prion inactivation research
Disease eradication
Breeding for resistance
Country categorisation
and trade rules
Monitoring & Age of Testing
Source: COM (2005) 0322 FINAL
EU TSE Regulatory Framework
Blood and blood products
1.
Background
•
high therapeutic value but communicable disease transmission risks to patients
Table 8: Key EU Blood Regulatory Measures
Year
Regulatory document
1998
2001
REC 1998/10 ohe use of human red blood cells for the preparation of oxygen-carrying substances
Parliamentary questions - Written question E-0096/01
BSE: blood donations
REC 2001/4 on the prevention of the possible transmission of variant Creutzfeldt-Jakob Disease
Parliamentary questions - Written question E-1079/01
Commercial action for the storage of umbilical cord blood for obtaining stem cells
DIR 2002/98 on the quality and safety of blood and blood components
Parliamentary questions - Written question P-0590/02
Europeanisation of Italian law 107/90 on the production of blood derivatives
REC 2002\11 on the hospital's and clinician's role in the optimal use of blood and blood products
Council of Europe Guide to the preparation, use and quality assurance of blood components
Draft Technical Requirements for blood and blood components
Opinion of the Scientific Committee on Medicinal Products and Medical Devices on the impact of
REC 2003\11 on the introduction of pathogen inactivation procedures for blood components
Precautionary measures against WNV transmission by blood
Precautionary measures against nvCJD transmission by blood
DIR 2004/33 on certain technical requirements for blood and blood components
Dir 2005 0061 on blood traceability + adverse events
Dir 2005 0062 on quality system for blood establishments
2002
2003
2004
2005
EU TSE Regulatory Framework
Blood and blood products
2.
Protective measures
•
DIR 2004/0033 on technical requirements for the collection, testing, processing,
storage, and distribution of human blood and blood components
•
•
•
•
•
•
3.
permanent deferral criteria for persons who have a family history which places them at risk of
developing a TSE, or persons who have received a corneal or dura mater graft, or who have
been treated with medicines made from pituitary glands;
temporary deferral criteria for blood donors who have inter alia received a blood transfusion,
a tissue or cell transplant of human origin, or undergone major surgery;
other deferral for particular epidemiological situations. These deferrals are to be notified by
the competent authority to the Commission with a view to Community Action.
DIR 2002/0098 on quality and safety standards for blood and blood components
DIR 2005/0061 on blood traceability + adverse events
DIR 2005/0062 on quality system for blood establishments
Additional measures
•
other patient groups ‘potentially at-risk of nvCJD for public health purposes’:
•
•
•
•
certain patients who have been operated on with instruments previously used for healthcare
interventions on a patient with nvCJD
recipients of blood from donors who later developed nvCJD
patients who have been treated with plasma products that may have been contaminated with
nvCJD infection
new patient group (UK and Ireland):
•
‘donors to nvCJD cases’ (about 100) [UK and Ireland only]
EU TSE Regulatory Road Map
2005 to 2014
1.
Background
•
•
2.
Declining nvCJD and BSE epidemics
Emerging risks incl. avian influenza, SARS, etc.
Strategic goals
Table 9: Strategic goals of the EU TSE Regulatory Road Map (2005-2014)
Strategic
goal
1
2
3
4
5
6
7
1
2
Details
Short to medium term – 2005 to 2009
To ensure and maintain the current level of consumer protection by continuing to assure the safe
removal of SRM but modify list/age based on new & evolving scientific opinion
A relaxation of certain measures of the current total feed ban when certain conditions are met
To reduce the numbers of tests of bovine animals and at the same time continue to measure the
effectiveness of the measures in place with a better targeting of the surveillance activity
Simplification of the categorisation criteria and conclusion of the categorisation of the countries
before 1 July 2007
Review and relaxation of the eradication measures for small ruminants taking into account the
new diagnostic tools available but ensuring the current level of consumer protection
To stop the immediate culling of the bovine cohort
To discuss the lifting of the additional restrictions on exports of beef and beef products from the
UK if the preset conditions are complied with
Short to medium term – 2009 to 2014
To modify measures in line with current technology and new evolving scientific knowledge
Scenario analysis
EU TSE Regulatory Road Map
Personal recommendations
1.
Risk assessment
•
subpopulation susceptibility to nvCJD
heterozygous individuals
prion transmissibility
•
human to animal (bovine, ovine, caprine, etc.)
•
animal to animal (bovine-caprine, etc.)
•
animal to human (cervids, etc.)
age-dependent susceptibility to nvCJD
•
maturation of gastrointestinal epithelial barrier function
•
•
•
2.
Risk management
•
true nature of the prion-related diseases
a genetic/somatic disorder more like cancer than an infectious disease
appropriateness and efficacy of protective measures
•
surveillance, quarantine, and slaughter?
reinforce transmissibility barriers
•
absolute prohibition on at-risk blood, tissue, and organs donors
•
absolute prohibition on occult cannibalism
•
temporary ban on inter-species recycling
•
•
•
3.
Risk communication
•
•
•
4.
true nature and impact of both epidemics
likelihood of associated epidemics
memorialize nvCJD victims
Global assistance
•
proactive provision of risk-based support services
Concluding remarks
1.
Global risk and the global need for action


2.
there is a global risk of TSE due to trade in live animals and certain
animal-tissue containing products (incl. meat and meat products
and animal feed)
it is essential that countries should not wait until their first case of
TSE before acting
Risk assessment



3.
countries without known TSE cases must conduct risk assessments
and may require surveillance systems for both human and animal
TSEs
the global risk assessment must include information about global
trade practices with the aim of identifying potentially high risk
activities
there are some hypothesized risks in trade in live animals, meat and
meat products, and animal feed
Risk management


4.
policies to minimize human exposure to TSE have been introduced
(and evaluated) in many countries
extensive international experience has accrued regarding the most
significant measures to be adopted to reduce the risk of TSE
Risk communication


one of the largest problems has been the difficulties in
communicating risks in the face of incomplete knowledge
the process of development of public policy through iterative
processes has undermined public confidence.
Addendum
1.
Presentation details


2.
Other important presentation details


3.
prepared using MS PowerPoint 2003 with custom animation settings on each slide
speaker notes are available for each slide
a narrated version of the presentation has been prepared with Articulate Presenter
the narrated presentation can be viewed on-line at the following URL:

www.imperialconsulting.net/ass01for705c1x/index.html
Assignment details: ASSIGNMENT 1 FOR 705C1X
Prepare a 15 minute presentation comprising 12 PowerPoint slides (excluding references) and speaker notes (100 words max.) on a regulatory
issue of current concern. The presentation should be directed at the management board of your company or the management
group of your ministry or equivalent. It should concisely and precisely lay out the main issues and problems and make
recommendations for action.
Prion-related diseases:
Issues, problems, and recommendations
Submitted
by
William P. Charteris
[Student Registration Number 32491904] PG Dip Eur Food Regul Aff DL