Prion-related diseases:EU medico-scientific and regulatory issues,

problems, and recommendations

William P. Charteriswww.billcharteris.com

The Consultant’s Consultant™

Nov. 7th, 2005.

Presentation layout

1. Introductory remarks2. New Infectious Disease Paradigm

• TSEs• Prions• Human prion disease hypothesis

3. TSE Epidemiology• Human• Animal

4. EU TSE Legislative Framework• Food and feed products

• chronology of EU consumer health protection measures (1988-2005)• summary of EU TSE protection measures

• Blood products• key EU TSE protection measures

5. EU TSE Legislative Road Map• Proposed changes to EU TSE protection measures (2005-2014)• Personal recommendations

6. Concluding remarks7. Addendum

Introductory remarks

1. BSE epidemic (1986-2014)• 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

2. nvCJD epidemic (1996-2010)• 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

3. Risk assessment and management• bovine• ovine• caprine• cervid

4. Risk communication a new infectious disease paradigm in the face of incomplete knowledge undermined public confidence

Table 1: Prevalence of BSE in the EU and UK

ParameterEU25 UK

Incidence of BSE [2004] 865 343Reduction since 2002 40% 30%

Incidence of BSE in healthy slaughtered animals [2004]

166 151

Reduction since 2003 39% 43%Incidence of BSE in high risk animals [2004] 520 243

Reduction since 2003 35% 49%

Source: EU TSE Annual Report 2004

Number of cases

Table 2: Probable and definitive mortality from nvCJD in the UK(as of October 5 2005)

Year nvCJD sCJD iCJD fCJD GSS Total

1990 28 5 0 0 331991 32 1 3 0 361992 45 2 5 1 531993 37 4 3 2 461994 53 1 4 3 611995 3 35 4 2 3 471996 10 40 4 2 4 601997 10 60 6 4 1 811998 18 63 3 3 2 891999 15 62 6 2 0 852000 28 50 1 2 1 822001 20 58 4 3 2 872002 17 72 0 4 1 942003 18 77 5 4 2 1062004 9 52 2 3 1 672005 3 41 1 2 1 48

All 151 805 49 46 24 1,075

Source: UK Department of Health

The New Infectious Disease ParadigmTransmissible spongiform encephalopathies

1. Characteristics• very rare, uniformly fatal neurodegenerative diseases• long incubation period• multi-focal neuropathology• toxic gain of function of an aberrant form of a constitutive protein

2. Classification of prion-related diseases• infectious• sporadic• genetic

3. Pathogenesis• penetration and peripheral replication• translocation and neuroinvasion• neurodegeneration

4. Transmissibility barriers (R/M)• inter-species transmission barrier• intra-species transmission barrier

• strain transmission barrier• adaptation

sheep

cow

human

villi

Table 3: Human and animal prion disease

Mode of transmissionHuman Animal

infectious nvCJD BSEiCJD Scrapiekuru TME

CWD

genetic fCJDGSSFFI

sporadic sCJD

CJD - Creutzfeldt-Jakobnv - new variant

i - iatrogenicf - familial

s - sporadicGSS - Gerstmann-Straüssler-Scheinker SyndromeFFI - Fatal Familiar InsomniaBSE – bovine spongiform encephalopathyTME – transmissible mink encephalopathyCWD – chronic wasting disease

Prion disease

The New Infectious Disease Paradigm Prions

1. Structural types• native or constitutive [PrPc]

• non-toxic proteins/peptides characterized by:• (a) high -helix content (b) relative protease sensitivity

• foreign or pathogenic [PrPres]• amyloid proteins/peptides characterized by:

• (a) filamentous morphology (b) high β sheet content• (c) relative protease resistance (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]

2. Function• PrPc is a ubiquitously expressed, GPI-anchored membrane bound glycoprotein• the precise nature of its physiological role remains a mystery• it has dual neurological and immunological functions• it is likely that PrPc represents a new type of pattern recognition receptor• its likely evolutionary origin - a horizontally transferred gene from an early RNA virus

3. Genetics• chromosomally encoded:

• PrPc is encoded by PRNP on human chromosome 20 at 20pter-p12• SNP polymorphism at codon 129 on human PRNP

• MV heterozygote individuals have increased resistance to disease• MM homozygotes individuals have increased susceptibility to disease

4. Transmissibility to humans• bovines: confirmed

• the mean nvCJD incubation period following consumption of an infectious dose of BSE-infected beef by MM homozygote is 16.7 years (95% CI, 8–30 years)

• sheep, goats, deer, etc.: not confirmed

Table 4: Examples of human amyloid proteins and peptides

Protein Disorder

Aβ peptides Alzheimer’s diseaseTransthyretin Senile systemic amyloidosis

Secondary systemic amyloidosis (infections and chronic inflammatory conditions)

Amylin (IAPP) Type II diabetesα-synuclein Parkinson’s diseaseSuperoxide dismutase Amyotrophic amyloidosisβ2-microglobulin Hemodialysis-related amyloidosisHuntingtin Huntington’s diseasePrP Transmissible spongiform encephalopathiesIg light chain Primary systemic amyloidosis

Serum amyloid A

The New Infectious Disease Paradigm Human Prion Disease Hypothesis

1. Background• 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

2. New Theory• 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!

3. 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 EpidemiologyHuman

1. Characteristics of nvCJD epidemic• Zoonosis with age-dependent susceptibility

• 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

• exposure before 1986• exposure after 1989 SBO ban [90% effective]

• An epidemic of relatively moderate size• not more than 500 lives; < 200 lives more likely

• UK, FR, IE, IT, USA, CA affected

2. Unresolved issues• Differential diagnosis at autopsy

• diminishing number of referrals

• Evolution of epidemic in homozygous individuals• bimodal distribution due to MRM not included in the 1989 SBO ban

• Evolution of epidemic in heterozygous individuals• 60% of the population

• Secondary transmission (blood, bone, medical devices, etc.)• low level endemicity in humans and animals

Figure 1: UK nvCJD mortality (1990 – October 5 2005)

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Source: www.cjd.ed.ac.uk/figures.htm

Table 5: Summary of nvCJD cases in the UK (1990 – October 5 2005)

Status Details Number

Alive Number of definite/probable nvCJD cases still alive 6

Deceased Deaths from definite nvCJD (confirmed) 108Deaths from probable nvCJD (without neuropathology confirmation) 42Deaths from probable nvCJD (neuropathology confirmation pending) 1

All Total number of probable and confirmed nvCJD cases (alive and deceased)

157

Source: UK Department of Health 2005

TSE EpidemiologyAnimal

1. Characteristics of bovine epidemic• Unknown cause

• dietary exposure• individual susceptibility (genetics, etc.)

• Mean incubation period is 5 years• Started -1986; Peak - 1992; End - 2014

• exposure before 1986• exposure after 1989 SBO ban [90% effective]

• An epidemic of large size• 188,809,000 infected bovines [EU25: 1988-2004]• 1.6 million entered the human food chain• number of risk animals destroyed• total estimated losses: 100 billion euro

2. Characteristics of ovine and caprine ‘epidemics’• Sheep

• 2,332 TSE cases a population of 89,838,000 [EU25: 2004]• CY (52%), FR (20%), UK (14%)

• Goats• 398 TSE cases in a population of 12,370,000 [EU25: 2004]• CY (89%), FR (7%), GR (1%)

3. Unresolved issues• Inter-species transmission [1998-2004]

• bovine->ovine: not shown by bio-assay [3,506 tests]• bovine->caprine: 1 confirmed FR case by bio-assay [57 tests]

Figure 2: Evolution of BSE in the UK

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Source: EC TSE Annual Report 2004

Figure 3: Evolution of BSE in other countries affected

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Source: EC TSE Annual Report 2004

EU TSE Regulatory FrameworkFood & Feed Products

1. Background

Table 6: Selected chronology of EU consumer health protection measures (1989 – 2005)

Year Regulatory Measure

1989 Restrictions on the dispatch of certain live cattle from the UK1990 Compulsory notification of BSE

Restrictions on the dispatch of certain bovine tissues and organs from the UK1992 Restrictions on the dispatch of bovine embryos from the UK1994 Ban on the use of mammalian-derived proteins for feeding ruminants

Rendering systems for processing ruminant waste into MBM (inactivation of BSE agents)1996 Total ban on dispatch of live cattle and all cattle products from the UK (UK embargo)

Eradication programmes for BSE in the UK and Portugal1997 Prohibition of the use of SRM (mainly brain, eyes and spinal cord)

Restrictions on trade in MBM1998 Epidemiological surveillance for all animal TSEs

Total ban on dispatch of live cattle and all cattle products from Portugal (Portugal embargo)1999 Conditions for the production of MBM and tallow (Repeals D 96/449/EC)2000 Temporary ban on use of MBM

Prohibition of the use of dead animals in the production of animal feed2001 Prevention, control and eradication of certain TSE2003 Establishment of breeding programmes for resistance to TSEs in sheep2004 Requirements for the import of cervid products from Canada and the United States2005 Systematic BSE-scrapie discriminatory tests for all confirmed TSE cases in small ruminants

Increased TSE monitoring in goatsProhibition of products derived from bovine animals born or reared in the UK before 1 August 1996

EU TSE Regulatory FrameworkFood & 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) Rule2006: 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

Specified Risk Material 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

Feed ban 1994-2000: partial ban on the feeding of mammalian MBM to cattle, sheep and goats was introduced in July 19942001: total EU wide ban on the use of processed animal protein in feeds for any food animals

Prion inactivation research Joint Research Centre, Ispra, ItalyDisease eradication 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 caseswhole herd culling of goats if TSE is detected

Breeding for resistance a minimal sheep breeding programme became mandatory for flocks of high genetic merit on 1 April 2005Country categorisation Country categorisation according to BSE risk has as its objective the definition of trade rules to protect animal and and trade rules 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)Monitoring & Age of Testing 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.a.)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 Stateextended monitoring of all healthy slaughtered goats since 2005

Source: COM (2005) 0322 FINAL

EU TSE Regulatory FrameworkBlood 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 REC 1998/10 ohe use of human red blood cells for the preparation of oxygen-carrying substancesParliamentary questions - Written question E-0096/01BSE: blood donationsREC 2001/4 on the prevention of the possible transmission of variant Creutzfeldt-Jakob Disease Parliamentary questions - Written question E-1079/01Commercial action for the storage of umbilical cord blood for obtaining stem cells

2002 DIR 2002/98 on the quality and safety of blood and blood componentsParliamentary questions - Written question P-0590/02Europeanisation of Italian law 107/90 on the production of blood derivativesREC 2002\11 on the hospital's and clinician's role in the optimal use of blood and blood products

2003 Council of Europe Guide to the preparation, use and quality assurance of blood componentsDraft Technical Requirements for blood and blood componentsOpinion 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

2004 Precautionary measures against WNV transmission by bloodPrecautionary measures against nvCJD transmission by bloodDIR 2004/33 on certain technical requirements for blood and blood components

2005 Dir 2005 0061 on blood traceability + adverse eventsDir 2005 0062 on quality system for blood establishments

2001

EU TSE Regulatory FrameworkBlood 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• 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

3. 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 Map2005 to 2014

1. Background• Declining nvCJD and BSE epidemics• Emerging risks incl. avian influenza, SARS, etc.

2. Strategic goalsTable 9: Strategic goals of the EU TSE Regulatory Road Map (2005-2014)

Strategic goal

Details

Short to medium term – 2005 to 20091 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 opinion2 A relaxation of certain measures of the current total feed ban when certain conditions are met3 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 activity4 Simplification of the categorisation criteria and conclusion of the categorisation of the countries

before 1 July 20075 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 protection6 To stop the immediate culling of the bovine cohort7 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 20141 To modify measures in line with current technology and new evolving scientific knowledge2 Scenario analysis

EU TSE Regulatory Road MapPersonal 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• true nature and impact of both epidemics• likelihood of associated epidemics• memorialize nvCJD victims

4. Global assistance• proactive provision of risk-based support services

Concluding remarks

1. Global risk and the global need for action 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

2. Risk assessment 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

3. Risk management 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

4. 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 prepared using MS PowerPoint 2003 with custom animation settings on each slide speaker notes are available for each slide

2. Other important presentation details 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

3. 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