1. Prion-related diseases: EU medico-scientific and regulatory issues, problems, and recommendations William P. Charteris www.billcharteris.com The Consultant’s Consultant™ Nov. 7 th, 2005. Presentation layout 1.Introductory remarks 2.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 remarks 7.Addendum

2. 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

3. The New Infectious Disease Paradigm Transmissible 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

4. The New Infectious Disease Paradigm Prions 1.Structural types native or constitutive [PrP c ] non-toxic proteins/peptides characterized by: (a) high  -helix content(b) relative protease sensitivity foreign or pathogenic [PrP res ] 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 [PrP c + PrP res -> 2 PrP res ] 2.Function PrP c 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 PrP c 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: PrP c is encoded by PRNP on human chromosome 20 at 20pter-p12human chromosome 20 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

5. 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.

6. TSE Epidemiology Human 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

7. TSE Epidemiology Animal 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]

8. EU TSE Regulatory Framework Food & Feed Products 1.Background

9. EU TSE Regulatory Framework Food & Feed Products 2.Protective measures

10. EU TSE Regulatory Framework Blood and blood products 1.Background high therapeutic value but communicable disease transmission risks to patients

11. 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 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]

12. EU TSE Regulatory Road Map 2005 to 2014 1.Background Declining nvCJD and BSE epidemics Emerging risks incl. avian influenza, SARS, etc. 2.Strategic goals

13. 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 true nature and impact of both epidemics likelihood of associated epidemics memorialize nvCJD victims 4.Global assistance proactive provision of risk-based support services

14. 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.

15. 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 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