# Presentation: 498122

## 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

**David M. Asher, MD**
**<david.asher@fda.hhs.gov>**
**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**

## WHO Guidelines on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathieshttp://www.who.int/bloodproducts/TSEREPORT-LoRes.pdfWorld Health Organization 2006Proceedings of WHO ConsultationGeneva 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**

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Goals 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**

## WHO TSE Consultation14-16 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**
_**Summary of presentations**_

## 26 Countries with BSE in Native Cattle[yr first reported & approx. total cases reported to OIE thro’ 07 Sept 2006]

**UK**** ****1986 ****(>184,431) [1202 ’01;**** ****1144 ’02; 611 ’03; 343 ’04; 225 ’05; >61 ’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 (1UK+8)**
**USA ****2004 (1 Canada+2)**
**Croatia ****2006**** ****(1)**
**Sweden**** 2006 (1)**

**Notes:**
In 22 countries with BSE affecting native cattle, the vast majority of cases—more than 182,000—have occurred in the UK.

## Total Reported UK Exports of MBM 1986 –1995(unconfirmed review by UK authorities of export records)

**Total Reported UK Exports of MBM 1986 –1995****(****unconfirmed review by UK authorities of export records)**

## Slide 7

## Slide 8

## Unique Pathology of vCJD (Chazot G & al. Lancet 1996;347:1181. Will RG & al. Lancet 1996:347:921-5. Hill AF & al. Lancet 1999;353:183-9)

## BSE and vCJD deaths in UK

|  |
| --- |

- Feed ban

**Transfusion Cases Reported**
**12/03  7/04                2/06**

## 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****	****	****	****	****	****	****    **
**	****	****	****	**
**Probably acquired in UK**** **** ******** ****Probably non-UK origin**

## > 360 Iatrogenic Transmissions of CJD/vCJD byClasses of FDA-regulated Medical Products of Human Origin

**RBC: the only **_**new**_** class of medical product CJD-implicated past 10 yr**

| 
Product | 
Cases | Incub’n
Average | Incub’n
Range |
| --- | --- | --- | --- |
| Cornea |  3 | ? 16 mo
(excluding outlier) | 13, 18, 320 mo |
| Dura mater | > 168 | 12 yr | 1.3-22 yr |
| Pit hormones
 Growth
 Gonadotropin | 
> 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 | > 6 yr | 7.8 yr, 6.5 yr,
(> 5 yr) |

## WHO Consultation Suggested Nomenclature:PrPTSE for All Abnormal Forms of Prion Protein (PrP)Associated with Transmissible Spongiform Encephalopathies 

_**PrP**__**TSE**_** ******
**PrP****Sc****  scrapie-type PrP, or**
**PrP****res**** proteinase-K-resistant PrP, or**
**PrP****d****    disease-associated PrP**
**                                               **_**Solubility**_** **_**in**_** **_**Detergent-Salt**_

|  | Soluble | Sedimented |
| --- | --- | --- |
| PK-sensitive | PrPC
PrPsen | sPrPSc |
| PK-resistant | ? | rPrPSc
PrPres
PrPd |

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Selected Highlights

**... ****[W]hen 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 ...**

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Selected 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.**
**[T]here is recent evidence that one goat [and perhaps another] has been naturally infected with BSE.**

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Selected Highlights

** ****[U]nder specific experimental conditions, the brains of some TSE-affected rodents may be infectious by bioassay while PrP****TSE**** remains undetected.**
**[I]mmunoassays have detected PrP****TSE**** 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 PrP****TSE**** 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, s]tudies 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 infectivity—presumably in small amounts.**

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Selected 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. **

## Proceedings of a Consultation Convened by WHOGeneva 14-16 September 2005Results 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, but—if strict indications for transfusion observed—benefits 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.**

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

**WHO TSE Consultation Report: Annex 1****TSE Infectivity and PrP****TSE**** 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 PrP****TSE**** in at least one TSE**
**IC. **_**No**_** **_**Detected**_** **_**Infectivity**_
**                                                                           ****Table Entries**

## Table IA: High-infectivity Tissues 

**CNS tissues with high titres of infectivity in TSEs and**
**Certain tissues anatomically associated with CNS**

## Table IB: Lower-infectivity Tissues

_**Table IB: Lower-infectivity Tissues**_
**Peripheral tissues testing positive for infectivity**
**and/or PrP****TSE**** in at least one form of TSE**

## Table IB: Lower-infectivity Tissues (Cont.)

_**Table IB: Lower-infectivity Tissues **__**(Cont.)**_
**Peripheral tissues testing positive for infectivity**
**and/or PrP****TSE**** in at least one form of TSE**

## Six Candidate PrPTSE Blood Screening Tests: Early Results WHO TSE Consultation Sept 2005

**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 **

| 
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 |  |

## Six Candidate PrPTSE Blood Screening Tests:Early ResultsWHO TSE Consultation Sept 2005

**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**

| 
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 add’ns 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 |  |

## Table IC: Tissues with No Detected Infectivity 

_**Table IC: Tissues with No Detected Infectivity**_** **
**Tissues examined for infectivity and/or PrP****TSE**** with negative results**

## Limitationsof 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**
**PrP****TSE**** 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**

## WHO Guidelines on Tissue Infectivity Distribution in TSEsPartial 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)**