WHO Guidelines on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies World Health Organization 2006 Proceedings of a Consultation Convened by WHO Geneva 14-16 September 2005 Summary

1
WHO Guidelines on Tissue Infectivity Distribution
in Transmissible Spongiform EncephalopathiesWorl
d Health Organization 2006Proceedings of a
Consultation Convened by WHOGeneva 14-16
September 2005Summary

• David M. Asher, MD
• ltdavid.asher_at_fda.hhs.govgt
• Laboratory of Bacterial, Parasitic
  Unconventional Agents
• Division of Emerging Transfusion-Transmitted
  Diseases
• Office of Blood Research Review
• Center for Biologics Evaluation Research
• US Food Drug Administration

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WHO Guidelines on Tissue Infectivity Distribution
in Transmissible Spongiform Encephalopathieshttp
//www.who.int/bloodproducts/TSEREPORT-LoRes.pdfWo
rld Health Organization 2006Proceedings of WHO
ConsultationGeneva 14-16 September 2005

• Quality and Safety of Plasma Derivatives
• and Related Substances
• Department of Medicines Policy and Standards
• Health Technology and Pharmaceuticals Cluster
• World Health Organization
• -------------------------?------------------------
  -
• WHO Secretariat
• A Padilla (project leader)
• S Groth
• L Rago
• D Wood
• FX Meslin
• N Dhingra

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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Goals of
Consultation

• Revise WHO 2003 Consultation advice on TSE safety
  of medicinal products, especially biological
  products
• Vaccines, etc., prepared with ruminant-derived
  materials
• Products derived from human blood (components,
  plasma derivatives)
• Other human cells and tissues and products
  derived from them
• Review scientific information on TSEs relevant to
  safety of medicinal products
• Compare TSE risk assessments for various
  countries
• Provide general advice to national regulatory
  authorities with limited resources about TSE
  risks associated with medical products and
  suggest approaches to assess and, if indicated,
  attempt to reduce risk
• Special goal
• Summarize and evaluate reliability of available
  information about distribution of infectivity and
  disease-related prion protein in tissues and body
  fluids of TSEs of humans and ruminants

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WHO TSE Consultation14-16 September 2005 Report
Issued 2006

• Executive summary
• Recent scientific developments
• Epidemiology, clinical features, Dx criteria of
  CJD
• BSE and scrapie
• Risk of transmission of CJD/vCJD by human blood,
  blood products
• Recommendations
• Tissue infectivity
• Reducing risk to humans from biological and
  pharmaceutical products made with
  ruminant-derived materials
• Tissue source
• Tissue removal/processing
• Production vaccines, recDNA (from banked cells),
  other
• Reducing risk to humans from biological and
  pharmaceutical products made with human-derived
  materials
• Risk of transmitting vCJD by blood, blood
  products
• Risk assessment
• Risk reduction product retrieval/market
  withdrawal, donor deferral, plasma products, c.
• Risk from HCT/Ps
• Conclusions
• Annexes
• TSE infectivity (selected) humans, BSE cattle,
  scrapie sheep/goats

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26 Countries with BSE in Native Cattleyr first
reported approx. total cases reported to OIE
thro 07 Sept 2006

• UK 1986 (gt184,431) 1202 01 1144 02 611 03
  343 04 225 05 gt61 06
• Ireland 1989 (1579)
• Switzerland 1990 (461)
• France 1991 (971)
• Portugal 1994 (990)
• Belgium 1997 (131)
• Netherlands 1997 (80)
• Luxembourg 1997 (1)
• Liechtenstein 1998 (3)
• Denmark 2000 (14)
• Germany 2000 (389)
• Spain 2000 (654)
• Italy 2000 (132)

• Greece 2001 (1)
• Czech Repub 2001 (24)
• Slovakia 2001 (23)
• Japan 2001 (28)
• Slovenia 2001 (6)
• Finland 2001 (1)
• Austria 2001 (5)
• Poland 2002 (48)
• Israel 2002 (1)
• Canada 2003 (1UK8)
• USA 2004 (1 Canada2)
• Croatia 2006 (1)
• Sweden 2006 (1)

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Total Reported UK Exports of MBM 1986
1995(unconfirmed review by UK authorities of
export records)
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Unique Pathology of vCJD (Chazot G al. Lancet
19963471181. Will RG al. Lancet
1996347921-5. Hill AF al. Lancet
1999353183-9)
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BSE and vCJD deaths in UK

Feed ban
Transfusion Cases Reported 12/03 7/04
2/06
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vCJD Non-UK cases 34 (Aug 2006 UK 162) mod
from R. Knight/CJD SU Edinburgh

• FRANCE 20 (3?UK)
• ITALY 1
• NETHERLANDS 2
• PORTUGAL 1
• SPAIN 1
• REPUBLIC of IRELAND 2
• REPUBLIC of IRELAND 2
• USA 2
• CANADA 1
• JAPAN 1
• SAUDI ARABIA (origin uncertain) 1

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gt 360 Iatrogenic Transmissions of CJD/vCJD
byClasses of FDA-regulated Medical Products of
Human Origin

• RBC the only new class of medical product
  CJD-implicated past 10 yr

Product Cases Incubn Average Incubn Range
Cornea ? 3 ? 16 mo (excluding outlier) 13, 18, 320 mo
Dura mater gt 168 12 yr 1.3-22 yr
Pit hormones Growth Gonadotropin gt 180 4 12 yr 13 yr 5-39 yr 12-16 yr
Neurosurgical instruments (includes electrode) 6 (? 7) 19 mo 15 28 mo
RBC (UK vCJD) 3 gt 6 yr 7.8 yr, 6.5 yr, (gt 5 yr)
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WHO Consultation Suggested NomenclaturePrPTSE
for All Abnormal Forms of Prion Protein
(PrP)Associated with Transmissible Spongiform
Encephalopathies

• PrPTSE ?
• PrPSc scrapie-type PrP, or
• PrPres proteinase-K-resistant PrP, or
• PrPd disease-associated PrP
• 
  Solubility in Detergent-Salt

Soluble Sedimented
PK-sensitive PrPC PrPsen sPrPSc
PK-resistant ? rPrPSc PrPres PrPd
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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Selected
Highlights

• When feasible, tissues or body fluids of
  ruminant origin should be avoided in the
  preparation of biological and pharmaceutical
  products. When bovine materials must be used,
  they should be obtained from sources assessed to
  have negligible risk from the infectious agent of
  BSE.
• Most bovine tissues, including bovine muscle,
  used to manufacture biologicals, if carefully
  selected by taking into account the geographical
  distribution of BSE and collected according to
  guidelines, have little risk of contamination
  with BSE agent
• No country except UK and Ireland has reported
  more than 1500 BSE cases.
• Recent findings of disease-associated proteins in
  muscles of sheep with scrapie ( not known to
  infect humans) and the recognition of BSE itself
  in a goat, reinforce the need for manufacturers
  of biologicals to maintain precautionary safety
  measures

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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Selected
Highlights

• In naturally affected cattle, BSE infectivity,
  detected by assay in mice, has been demonstrated
  only in brain, spinal cord and retina and in
  a pool of nictitating membranes but not in pools
  of lymph nodes or spleen.
• Recently infectivity was detected in some
  peripheral nerves and a solitary muscle, of a
  single case of BSE in a German cow
• In cattle experimentally exposed by the oral
  route, BSE infectivity has been detected by mouse
  assay in the distal ileum through much of the
  disease course from six months post exposure and
  in the CNS and sensory ganglia of the
  peripheral nervous system from late in the
  incubation period.
• Infectivity has also been found in palatine
  tonsil, at a single time point only by assay in
  cattle and not by the mouse assay.
• BSE has been experimentally transmitted via the
  oral route to sheep and goats.
• There is recent evidence that one goat and
  perhaps another has been naturally infected with
  BSE.

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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Selected
Highlights

• Under specific experimental conditions, the
  brains of some TSE-affected rodents may be
  infectious by bioassay while PrPTSE remains
  undetected.
• Immunoassays have detected PrPTSE in the brains
  of BSE-infected cattle at least three months
  before onset of clinical illness.
• However, no immunological method has yet been
  validated to be sufficiently sensitive to detect
  PrPTSE in the blood of infected animals or
  humans, though promising initial results have
  been reported by several groups of investigators
  
• Transfusion experiments have not been conducted
  in cattle however, studies using small
  amounts of blood components or spleens of cattle
  with BSE assayed in mice and cattle injected by
  the most effective routes failed to detect
  infectivity.
• A conservative regulatory approach would assume
  that bovine serum might potentially contain TSE
  infectivitypresumably in small amounts.

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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Selected
Highlights

• Ruminant blood and blood derivatives, such as
  fetal calf serum in cell cultures media and
  bovine serum albumin stabilizers have not
  been identified as a source of infection, and
  properly collected fetal bovine serum has a
  negligible risk.
• However, blood of sheep with experimental BSE or
  natural scrapie can be infectious and, because
  scrapie and BSE agents behave similarly in sheep
  and goats, the blood of small ruminants should
  either be avoided in preparing biologicals or
  selected very carefully from sources known to be
  free of TSEs.
• There is a continuing need to ensure that all
  national regulatory authorities with limited
  resources have ready access to reliable and
  up-to-date information when assessing TSE risks
  and evaluating medicinal product safety.

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Proceedings of a Consultation Convened by
WHOGeneva 14-16 September 2005Results of
National Risk Assessments for vCJD and Blood

• UK (M Turner, P Bennett)
• Labile components 1/120,000 transfusions may be
  from donors incubating vCJD, butif strict
  indications for transfusion observedbenefits
  clearly exceed risk
• Plasma-derived products minimal risk
• Surgical/dental instruments, HCT/Ps highly
  uncertain risk
• France (J-H Trouvin) Independent assessment
  yielded results very similar to those for UK (for
  both labile components and plasma-derived
  products)
• Australia (A Farrugia) FVIII has highest risk
  among PDs
• Canada (S ElSaadany) Due to uncertainties, risk
  communication is difficult
• Germany (J Löwer)
• Under realistic conditions for Germany, vCJD
  should not become an endemic infection maintained
  only by blood transfusion.
• Deferring transfused donors only slightly reduces
  vCJD risk in Germany.
• German conclusions should not be applied to
  countries with different BSE/vCJD risks.
• USA (D Scott) Due to uncertainties in
  assumptions, risk assessments to date allow no
  confident predictions regarding probability of
  vCJD infections and clinical illnesses in
  individuals exposed to various blood components
  and plasma derivatives.

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WHO TSE Consultation Report Annex 1TSE
Infectivity and PrPTSE Detected in Human and
Animal Tissues, Other Materials(WHO tables
converted to tile table by OA Maximova, CBER, FDA)

• IA. High Infectivity
• CNS tissues with high titers of infectivity in
  late stages of all TSEs
• Certain tissues anatomically associated with CNS
• IB. Lower Infectivity
• Peripheral tissues with infectivity and/or PrPTSE
  in at least one TSE
• IC. No Detected Infectivity
• 
  Table Entries

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Table IA High-infectivity Tissues CNS tissues
with high titres of infectivity in TSEs
and Certain tissues anatomically associated with
CNS
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Table IB Lower-infectivity Tissues Peripheral
tissues testing positive for infectivity and/or
PrPTSE in at least one form of TSE
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Table IB Lower-infectivity Tissues
(Cont.) Peripheral tissues testing positive for
infectivity and/or PrPTSE in at least one form of
TSE
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Six Candidate PrPTSE Blood Screening Tests Early
Results WHO TSE Consultation Sept 2005
No Test Description Model Sens (/total) Spec (F/total) Spike LOD
1 Palindromic peptide binding to PrPTSE (no PK) Scr sheep 52/52 0/45 1 ID50/ml
Scr hamster 43/43 0/23
BSE cow 36/40 1/40
CJD mouse 5/5
CJD monkey 8/8 0/4
CJD human 14/14 0/53

• Sensitivity results with samples from known
  infected animals or human CJD cases
• Specificity results with samples from
  uninfected animals or negligible-CJD-risk pts
• Spike LOD determined from last brain or spleen
  dilution detected and known infect titer

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Six Candidate PrPTSE Blood Screening TestsEarly
ResultsWHO TSE Consultation Sept 2005
No Test Description Model Sens (/total) Spec (F/total) Spike LOD
2 Conc PrPTSE, PK, ppt w/ streptomycin capture w/calix arene, detect w/ sandwich ELISA CJD human 7/10 0/500
3 Peptides on mag beads bind to PrPTSE, no PK, detect w/ sandwich ELISA Scr sheep 3/8 3 ID50/ml
4 PMCA ampl of PrPTSE by repeated addns of nl tissue extracts, sonications, PK, Western blot Scr hamster 20 da pi 100 da pi 3/6 16/18 0/12
5 Proprietary ligand on mag bead, no PK, elute, denature, ELISA Scr sheep 2/3 0/26 100 ID50/ml
6 Capt w/ IgM mAb to PrPTSE, sand ELISA or FACS Scr sheep BSE cow 6/6 3/12 0/16 0/10

• Sensitivity results with samples from known
  infected animals or human CJD cases
• Specificity results with samples from
  uninfected animals or negligible-CJD-risk pts
• Spike LOD determined from last brain or spleen
  dilution detected and known infect titer

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Table IC Tissues with No Detected Infectivity
Tissues examined for infectivity and/or PrPTSE
with negative results
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Limitationsof Negative TSE Infectivity and
PrPTSE Studies

• Small numbers of human cases and animals studied
• Small numbers of bioassays attempted
• Small volumes of materials sampled
• Limits of detection usually unknown
• Bioassay animal species some relatively
  insensitive
• PrPTSE assays some relatively insensitive
• Very limited numbers of infected animals studied
  during incubation periods
• Infected humans rarely if ever identified and
  studied before onset of overt disease
• Uncertain relevance of TSE models to each other

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WHO Guidelines on Tissue Infectivity Distribution
in TSEsPartial Credits

• Consultation Chairman
• WG van Aken, Netherlands
• Draft Report
• DM Asher, USA
• J-P Deslys, France
• E Griffiths, Canada
• A Padilla, WHO
• R Bradley UK
• M Pocchiari, Italy
• RG Rohwer, USA
• J-H Trouvin, France
• GAH Wells, UK
• RG Will, UK
• Annex 1 Working Group
• P Brown, USA (chairman)
• R Bradley, GAH Wells, UK (animal TSEs)