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From: TSS ()
Subject: Re: TSE ADVISORY COMMITTEE DECEMBER 15, 2006 [TSS SUBMISSION PART II]
Date: November 30, 2006 at 11:47 am PST

In Reply to: TSE ADVISORY COMMITTEE DECEMBER 15, 2006 [TSS SUBMISSION] posted by TSS on November 30, 2006 at 9:05 am:


----- Original Message -----
From: Terry S. Singeltary Sr.
To: Terry S. Singeltary Sr. ; FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Thursday, November 30, 2006 1:47 PM
Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION PART II]



SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE

Draft minutes of the 94th meeting held on 21st September 2006

Approval of draft open minutes from SEAC 94

snip...

ITEM 5 – CJD UPDATE

16. Dr Richard Knight (NCJDSU) provided an update on the

epidemiology of cases of sporadic CJD (sCJD) and vCJD in the UK

and elsewhere. Between May 1990 and June 2006, 845 cases of

sCJD had been identified in the UK with a mean age at onset of 66

(range 15-94) years and mean age of death of 67 (range 20-95)

years. There is no significant gender difference in sCJD incidence.

There had been a trend towards an increasing number of cases

over time to almost 80 cases per year in 2003. This phenomenon

had also been observed in other countries and was considered to

be a result of better ascertainment. Fewer cases were identified in

the UK in 2004 compared to 2003 and 2005 but this finding may

not be significant. The genotype distribution of sCJD cases was

64% methionine (M) M, 18% M valine (V) and 18% VV at codon

129 of the prion protein gene.

17. The total number of definite and probable vCJD cases in the UK up

to September 2006 was 162, with six cases still alive. Two of

these are considered to have been infected by blood transfusion

rather than a dietary route. No statistically significant gender

difference had been observed in vCJD cases. The age distribution

of vCJD had not altered over the course of the UK epidemic, with

the median age of death of 28 (range 12-72) years. The median

duration of clinical vCJD was 14 (range 6-40) months. Statistical

analysis of the UK incidence of deaths from vCJD suggested the

epidemic had peaked in 2000 with 28 deaths. All 141 vCJD cases

tested to date are of the MM genotype. Elsewhere in the world up

to September 2006, 34 vCJD cases have been reported with 20 in

France, four in the Republic of Ireland (RoI), two in the USA, two in

the Netherlands and single cases in Italy, Canada, Japan, Saudi

Arabia, Spain and Portugal. The clinical, pathological and prion

protein gene PrP codon 129 genotype of all these cases is similar

to that of UK cases. Infection was likely to have occurred in the UK

in two RoI cases, both USA cases, one French case and the

Japanese and Canadian cases.

18. Dr Knight explained that evidence from experiments to compare

BSE transmission to bovinised and humanised mice suggested a

significant barrier to transmission of BSE between cattle and

humans. There appears to much less of a barrier between

humans, suggesting that secondary transfer from human to human

may be relatively efficient. This is borne out by the three recent

blood transfusion associated cases of vCJD. However, although

all clinical cases of vCJD that have been genotyped are of the MM

genotype, there is evidence that cases of non-MM genotypes

should be expected. Infected individuals of non-MM genotypes

may have longer incubation periods, subclinical infections and, or a

different clinico-pathological phenotype. Experiments on the

transmission of vCJD to humanised mice of the MM, MV or VV

genotype suggested that susceptibility to vCJD was highest in MM,

lower in MV and lowest in VV18. Mice of MM and MV genotypes

showed similar rates of brain involvement, however differences in

neuropathology were observed between the three genotypes. The

incubation period was shortest in MM mice and a higher rate of

subclinical disease was found in MV and VV mice.

19. Dr Knight explained that data from the UK appendix and tonsil

study19 provided further evidence for the existence of subclinical

vCJD infections. In this survey, three out of 12 674 samples had

tested positive for abnormal prion protein (PrPSc), indicating a

prevalence of 237 (95% confidence interval 49-692) cases per

million. An extrapolation of these data suggest 3 808 (95%

confidence interval 785-11 128) people could be infected out of

approximately 16 million in the 10 to 30 year old age group.

However, the actual number of clinical cases of vCJD observed in

the 10 to 30 age group was 102, and in decline. The discrepancy

in observed and predicted cases in the 10 to 30 year age group

could be due to subclinical infections. Whether these individuals

will eventually develop vCJD clinical disease, with a longer

incubation period, is unknown. Importantly, two out of the three

positive appendix samples were VV, a much higher proportion than

the 11% of VV individuals in the UK population. If it is assumed

that the third positive appendix is non-VV, statistical analysis

indicates a prevalence ratio of VV to non-VV of 18:1. If the third

positive appendix is MM, then the VV:MM prevalence ratio is 8:1.

This suggests that, although VV may have the longest incubation

period, it may be most susceptible genotype. However, this

18 Bishop et al. (2006) Predicting susceptibility and incubation time of human-to-human

transmission of vCJD. Lancet Neurol. 5, 374-375

19 Hilton et al. (2004) Prevalence of lymphoreticular prion protein accumulation in UK tissue

samples. J. Pathol. 203, 733-739.

seemed counterintuitive and not consistent with data from

humanised mice, thus there may be an important unidentified

factor involved. Although the downward trend in vCJD clinical

cases is reassuring, it is possible that subclinical infections may be

more widespread. Further peaks in vCJD cases could occur,

however the timescale in which these peaks could occur is

uncertain. It is therefore very important to ascertain the prevalence

of subclinical infection in the UK population.

20. Dr Knight explained that three blood transfusion associated vCJD

cases had been identified through the Transfusion Medicine and

Epidemiological review (TMER)20. The first case (MM), developed

vCJD 6.5 years after receiving non-leucodepleted red blood cells

(RBC) from a donor, who themselves developed vCJD 3.3 years

after donation21. The second case (MM), developed vCJD 7.8

years after receiving non-leucodepleted RBC from a donor, who

themselves developed vCJD 1.8 years after donation. The third

case22(MV) died of a non-neurological illness five years after

receiving non-leucodepleted RBC from a donor, who themselves

developed vCJD 1.5 years after donation. PrPSc was detected in

the spleen of this recipient, with no other clinical or

neuropathological evidence of vCJD infection. Statistical analysis

indicated that the chances of the three recipients having developed

vCJD through consuming BSE infected meat was one in a

thousand million, therefore it could be concluded that transmission

had occurred via blood transfusion.

21. The TMER also identified 66 individuals who received blood from

donors who later developed vCJD. Out of these individuals, 42

recipients have died and of those still alive, seven have survived

over 10 years after receiving the donation, without developing

vCJD. There were 25 blood donations from 11 individuals that

subsequently developed vCJD that were used for plasma

fractionation, however no cases of vCJD have occurred in

recipients of plasma.

22. In the reverse TMER study, seven vCJD cases were identified as

having received blood from 121 identified donors, two of which

were known vCJD cases. If these two cases are excluded,

together with a third case, because of the small amount of time

between the onset of disease and the timing of the transfusion,

20 Hewitt et al. (2006) Creutzfeld-Jakob disease and blood transfusion: results of the UK

Transfusion Medicine Epidemiological Review Study. Vox Sang. 91, 221-230.

21 Llewelyn et al. (2004) Possible transmission of variant Creutzfeld Jakob disease by blood

transfusion. Lancet 363, 417-421.

22 Peden et al. (2004) Preclinical vCJD after blood transfusion in a PRNP codon 129

heterozygous patient. Lancet 364, 527-529.

four cases remain. One of these recipients received two

transfusions in the same year and developed clinical vCJD four or

five years post transfusion. In a second recipient of two blood

transfusions, the onset of vCJD was 17 years after the first

transfusion and between six and seven years after the second

transfusion. The two other recipients each received one

transfusion with the onset of vCJD at around six and 14 years

following transfusion.

23. The Chair noted that although the incidence of clinical vCJD was

reducing, recent evidence suggested that there may be a

substantial number of subclinical carriers that could potentially give

rise to secondary transmissions. Therefore it was very important to

know the prevalence of subclinical vCJD.

24. A member asked how the incidence of vCJD and BSE compare in

other countries, relative to that of the UK. Dr Knight indicated that

the numbers of BSE and vCJD cases in some countries correlate

poorly. In addition, in some countries the historic incidence of BSE

is not well known or uncertain and numbers of vCJD cases are too

small to make meaningful comparisons.

25. A member noted that the genotype of the PrPSc positive samples

from the appendix and tonsil survey raised many questions. These

include whether individuals of the VV genotype were protected

from clinical disease, whether PrPSc resided in the appendix rather

than in the brain in these individuals and whether these individuals

were themselves infectious. Further studies were needed to

answer these questions. A member noted that the susceptibility to

vCJD could not be equated with incubation time and asked

whether transmission studies using the PrPSc positive appendix

material were underway. Dr Knight was not aware if transmission

studies had begun on this material.

26. A member asked if the genotype of the transfused patients

surviving for 10 years after receiving vCJD infected blood was

known. Dr Knight indicated this was not known and agreed these

are important data.

27. Regarding the possible barrier to transmission of BSE from cattle

to humans, a member noted that this could be due to inefficient

entry or inefficient replication of the BSE agent in humans and

these possibilities are under investigation.

28. Members agreed it was important to continue surveillance to be

able to detect the onset of secondary epidemics of vCJD. It was

noted that there may be periods of a number of years with few or

no cases of vCJD, before an increase in cases may be observed.

snip...

39. Dr Gleadle explained that FSA will continue to develop the

contingency policy, should BSE be found in sheep. The current

policy involves a graduated response, with increasing levels of

control proposed depending on the number of unrelated cases of

BSE in sheep that might be identified. FSA would be asking for

advice from SEAC on the criteria for determining whether cases of

BSE are related, should more than one case of BSE be identified

in the national sheep flock, and on the appropriate level of

surveillance should BSE be found in sheep. SEAC would also be

consulted on the emerging science and contingency plans under

development in relation to atypical scrapie. FSA would continue to

maintain a watching brief on chronic wasting disease in deer and

may wish SEAC to comment on its project examining the

transmissibility of BSE to deer.

snip...

NCJDSU

42. Dr Knight explained that NCJDSU is considering how it may

identify new cases of human illness should they arise from

exposure to atypical scrapie or TSE cases in cattle that appear

different from BSE and to examine whether, as has been

suggested by some, there are links between sCJD and atypical

scrapie. He noted that the possibility of vCJD infection in

individuals of non-MM genotypes and that these individuals may

present with a different clinical phenotype, were particular areas of

uncertainty in relation to the vCJD epidemic. As the incubation

period of human TSEs was long, continued surveillance was very

important to identify new types of TSE and to identify potential

routes of secondary transmission. Evaluation of the sensitivity and

specificity of ante mortem blood tests for subclinical vCJD and the

appropriate use of blood samples from vCJD cases was also of

importance. It is likely that very large numbers of false positive

results would arise from blood tests and it would be very important

to consider the implications and handling of the results, prior to the

introduction of blood testing.

Discussion

43. The Chair explained that Professor John Collinge (National Prion

Unit [NPU]) had been invited to contribute to the horizon scanning

session, however he was unable to attend. However, Professor

Collinge had personally informed the Chair that the NPU had

partially characterised a number of mouse and human genes that

appear to modify the incubation period and susceptibility to TSEs.

Thus, it was possible that the clinical cases of vCJD identified to

date were in individuals from a group that are genetically the most

susceptible to this disease and further, possibly larger, numbers of

cases might appear in the future in other genetic groups. A

member noted that the prion protein gene is the major gene

influencing susceptibility to TSEs. Although other genes may

modify susceptibility to infection, they may have relatively small,

but possibly, additive effects. Professor Collinge had suggested

that some of the genes identified had substantial effects on the

susceptibility to infection. Members considered it important to

review these data when published. Dr Knight noted that EU

funded projects were examining the existence of such modifier

genes, using large numbers of subjects.

snip...

ITEM 9 – EVALUATION CRITERIA FOR ANTE MORTEM

DIAGNOSTIC TESTS FOR SUBCLINICAL vCJD (SEAC 94/3)

56. The Chair explained that the UK blood services and DH requested

SEAC’s advice on the scientific criteria by which ante mortem

diagnostic tests for subclinical vCJD could be validated. A position

statement would be produced based on the committee’s

consideration.

57. Dr John Stephenson (DH) presented an overview of DH research

related to the development and evaluation of ante mortem tests for

vCJD, prototype tests developed by commercial companies and

the work of DH advisory committees that had considered issues

related to diagnostic tests for vCJD. The available information on

prototype tests was limited for reasons of commercial sensitivity,

however most, if not all, appear to be based on the detection of

PrPSc. DH had set up a CJD Tissue Management Group to

oversee the collection and allocation of human tissues with which

to evaluate tests. However a new group was being convened with

a wider remit that included the allocation of blood samples and

oversight of the vCJD tissue resource centre at the National

Institute of Biological Standards and Controls (NIBSC). A

Subgroup of the Committee of Microbiological Safety of Blood

Tissues and Organs had provided advice on the preparative work

required, should a screening test for subclinical vCJD become

available. The Subgroup concluded that, unless a test was

developed with very high specificity, large numbers of false positive

results would be obtained leading to an unnecessary shortage of

blood, therefore a reliable confirmatory test was required.

Establishment of a panel of blood samples from cohorts of UK and

USA blood donors to evaluate diagnostic tests was also

recommended. The HPA Expert Advisory Group on a Testing

Strategy for NATA was considering the criteria for screening tests

for tonsil samples. The UK blood services have also convened the

Prion Assay Working Group to provide guidance on the suitability

of diagnostic tests for use within the blood services. The ethical

implications of screening tests for subclinical vCJD had been

considered by the HPA, together with the Nuffield Council for

Bioethics and a report was due for release.

58. Dr Roger Eglin (National Blood Service) presented an overview of

the performance requirements for screening tests for subclinical

vCJD for use in the blood services. It was considered that a

screening test must be CE marked23 and meet an, as yet

undefined, Common Technical Specification (CTS) for an Annex

IIA assay, as specified in the In Vitro Diagnostic Medical Devices

(IVD) Directive 98/79/EC. Initially a test should have a sensitivity

of at least one infectious dose (ID)/mL and a specificity that gave

an initial reactive result rate of below 0.3% and for a repeat

reactive result rate of below 0.15%. A panel of blood samples is

being prepared from 5 000 UK and 5 000 USA blood donors

separated into plasma, red cells and white cells to assess the

specificity of blood tests. It was envisaged that one or two other

tests would be performed on reactive samples from a screening

test to confirm the presence of PrPSc, with repeat positive results

resulting in deferral of the blood donor. Reactive samples from the

screening test could be confirmed by the secondary or tertiary test,

as the tests would all use a different mechanism(s) to capture the

analyte.

59. Dr Philip Minor (NIBSC) presented an overview of the samples

available for use in evaluation of tests for subclinical vCJD. These

include dilution series of brain and spleen from vCJD cases and

classical scrapie infected sheep, blood spiked with brain or spleen

from vCJD cases or healthy individuals and blood samples from

classical scrapie infected and healthy sheep. It was proposed that

large numbers of blood samples from classical scrapie endemic

and classical scrapie free flocks, UK and non UK blood donors and

importantly blood from vCJD cases be collected to assess and

compare the performance of diagnostic tests. In addition, panels

of blood collected from mice and sheep through the TSE

incubation period, from individuals classified as ‘at risk of vCJD for

public health purposes’ and from haemophiliacs would also be

useful to assess the time in the incubation period when blood

become infectious and detectable by tests.

60. Dr Minor noted that, at present, the performance of tests was not

specified and they could be freely marketed. However, should

diagnostic tests for subclinical vCJD be included in Annex IIA of

the IVD Directive 98/79/EC, all such tests would have to comply

with a CTS.

23 CE (Conformité Européene) mark is a declaration by the manufacturer that a product meets

all the necessary requirements of the relevant EU legislation.

61. Dr John Parry (HPA) provided an overview of the issues arising

from the evaluation, validation and implementation of blood tests in

relation to the human immunodeficiency virus.

62. Members agreed that it was very important that diagnostic tests for

subclinical vCJD be included in Annex IIA of the IVD Directive

98/79/EC, to ensure proper evaluation against a CTS.

63. A member noted that all the diagnostic tests were based on the

major assumption that PrPSc is a good marker of the infectious

agent, however PrPSc does not always correlate with TSE

infectivity. As a better marker has not been identified, PrPSc is

currently the most appropriate marker, although this assumption

should be reviewed in light of any data that may become available.

It must be recognised that PrPSc levels are a non quantitative

measure of infectivity. As the relationship between PrPSc and the

infectious agent is unclear, tests that recognise different parts of

the PrPSc molecule may produce conflicting results, possibly

making it difficult to identify suitable confirmatory tests. Therefore,

it would be very important in the evaluation of screening and

confirmatory blood tests that blood from vCJD cases be tested, as

blood from animal models or blood spiked with vCJD brain or

spleen may not reflect the response from tests when applied to the

detection of the vCJD agent in blood. Preliminary evaluation of the

specificity and sensitivity of tests could be achieved by using

spiked blood or blood from animal models, however final

evaluation of tests must include blood from vCJD cases.

64. A member queried whether there was any evidence that PrPSc is in

a different form in blood than in spleen or brain. Dr Minor

responded that there were no such data, however some tests were

able to detect both PrPSc in the brain and spleen, providing some

assurance that the test may detect the form of PrPSc in blood. A

member suggested that PrPSc may be in a more soluble form in

blood compared with the form in spleen or brain, thus it was

important to collect blood from preclinical and clinical vCJD

patients for use in the assessment of the efficacy of blood tests

and to assess the point in the incubation period when blood

becomes infectious. Blood collected from individuals “at risk of

vCJD for public health purposes” would provide a valuable source

of blood from potentially preclinical vCJD cases. This issue was

being considered by CGAG.

65. Members agreed that independent evaluation of tests using the

same panels of blood was very important. Dr Eglin noted that the

blood services have a Kit Evaluation Group which independently

evaluates test kits, using staff trained by the companies in the use

of their products.

66. A member noted that two key considerations for the applicability of

a blood test were the volume of material required and the

reproducibility of a concentration step, should it be required. Dr

Minor responded that tests vary in the volume of sample required

and the requirement for sample concentration. However

manufacturers recognise the difficulty a concentration step poses

to the blood services.

67. It was noted that work with the vCJD agent requires a category 3

containment facility. Dr Eglin responded that, as for the blood born

viruses, the screening is conducted on a largely negative

population and can be derogated to category 2 laboratory

conditions. However, further testing on reactive samples would be

undertaken in a category 3 laboratory.

68. A member asked whether any of the prototype diagnostic tests had

been assessed using blood from classical scrapie infected and

healthy sheep. Dr Minor explained that some companies had

obtained these samples and had been able to correctly identify

blood from infected animals. It was important that the same panels

of blood samples be sent to manufacturers to ensure a consistent

approach. However, stocks of these samples may be insufficient

to evaluate the number of diagnostic tests that may become

available.

69. A member asked about the collection of blood from vCJD patients

and whether there were sufficient samples available to evaluate

tests. Dr Knight explained that relatively small amounts of blood

had been collected and this had been fractionated into plasma, red

cells and white cells. Dr Minor suggested there was insufficient

blood from vCJD patients to conduct proper evaluations with the

required number of replicate tests. A member suggested collection

of larger volumes of ante mortem blood from vCJD cases. It was

also suggested that blood collected at post mortem from vCJD

cases would be a source of large quantities of blood. Dr Knight

explained that not all vCJD cases underwent autopsy and many

were performed up to two days after death when significant

autolysis may have occurred. Furthermore, it is difficult to obtain

large volumes of blood post mortem. It was suggested that blood

from familial cases of CJD be collected. Members noted that the

form of PrPSc may be different between familial CJD and vCJD and

that, unlike vCJD, familial cases of CJD did not express PrPSc

systemically. Members suggested that a non-human primate

model of vCJD could provide large volumes of blood.

70. The Chair considered it important that the volume of blood required

to evaluate diagnostic tests be calculated and that a mechanism to

acquire sufficient blood from vCJD patients was developed.

Replicate tests to evaluate the efficacy of tests could be conducted

using spiked blood samples and, or, blood from animal models.

However it is very important that the final evaluation is conducted

using blood from vCJD cases. Dr Stephenson noted that the CJD

Tissue Management Group was established to ensure that tissue

samples from vCJD cases were used appropriately. The Chair

noted that a number of research organisations had collected blood

from vCJD patients and these samples should be made available.

A Group was required to calculate the quantities of blood required

to evaluate tests, oversee the collection of samples, develop clear

performance criteria that must be fulfilled by manufacturers before

they receive these very valuable samples and to make decisions

about the supply of these samples to manufacturers. Dr

Stephenson responded that such a group was being convened at

NIBSC. Members considered it important there is coordination of

collection and supply of animal as well as human tissues.

71. The Chair suggested that risk assessments be conducted to

examine the required sensitivity and specificity for blood tests and

to examine scenarios of the effect of such tests on the blood

supply and transmission of vCJD.

72. Members noted that use of screening tests was not restricted to

the blood services and tests could be used for other purposes with

less stringent performance criteria. Use of tests for other purposes

may create a market that encourages commercial companies to

develop improved tests.

73. A member asked when an evaluated test might be available. Dr

Minor responded that a preliminary evaluation of tests could be

started relatively soon, however it was difficult to predict when a

fully evaluated and validated test may be implemented. Members

recommended that the ethical issues must be resolved prior to the

introduction of a blood test.

74. The Chair summarised the discussion, noting that:

• Until diagnostic tests for subclinical vCJD are included in

Annex IIA of the IVD Directive 98/79/EC and validated against

a defined CTS, the CE mark cannot be relied upon to indicate

a test had been properly evaluated and validated. In the

meantime, tests should be independently validated using

blinded samples.

• Preliminary evaluation of the specificity and sensitivity of tests

could be achieved using blood spiked with brain or spleen

from vCJD cases or blood from animal models. However, it is

very important that the final evaluation include testing of blood

from vCJD cases.

• It is critical to collect sufficient quantities of appropriate

tissues, to prepare panels of samples with which to evaluate

and validate tests and to manage this material appropriately.

Mechanisms need to be put in place to ensure these are

readily available for testing potential products, but that guard

against inappropriate use of a valuable resource.

• Risk assessments are required to establish the performance

requirements of blood tests and to examine scenarios of the

effect of introduction of such tests on the blood supply and

transmission of vCJD.

• The ethical issues around ante mortem testing for subclinical

vCJD need to be resolved prior to implementation of such

tests.

ITEM 10 – ANY OTHER BUSINESS

75. There was no other business.

snip...

http://www.seac.gov.uk/papers/95-1.pdf

13European Commission Scientific Committee on Emerging and Newly Identified Health Risks

(2006) Safety of Human-derived Products with regard to vCJD

http://ec.europa.eu/health/ph_risk/committees/04_scenihr/scenihr_cons_02_en.htm

14 http://www.food.gov.uk/aboutus/ourboard/boardmeetings/boardmeetings2006/boardmeeting130706/agenda13jul06

15 http://www.food.gov.uk/news/newsarchive/2006/aug/srmupdate0708

16 http://www.seac.gov.uk/statements/state260106.htm

Report from the SEAC Sheep Subgroup

Are the numbers of cases of vCJD in line with model predictions if the

only source of infection was cattle or is there evidence of an ovine

origin? Have vCJD cases from food borne sources stabilised or

declined?

20. There have, up to September 2006, been 162 definite and probable

cases of vCJD in the UK16. The Sheep Subgroup accepted the

data and conclusions on the human vCJD epidemic, presented at

SEAC 9417, that the number of vCJD cases is entirely consistent

with infection originating from BSE-infected cattle. Specifically, the

peak of the current wave of human cases mirrors the peak of

infected cattle entering the human food chain with a delay of

approximately eight years. However it was not possible to exclude

the possibility that another source of dietary infection was the

cause of a small proportion of the clinical vCJD cases. It would

only become apparent that there were non-bovine sources of

primary infection in the circumstance that a significant number of

vCJD cases arise in individuals who could only have been infected

after the introduction of the feed and SRM controls for cattle.

21. It was not possible to answer the question of whether vCJD cases

from food borne sources had stabilised or declined. The current

profile of clinical cases shows a peak in 2000, and a subsequent

decline. However, all these individuals are of the MM genotype and

further peaks of vCJD cases may well occur, with longer incubation

periods, in non-MM individuals still attributable to the original BSE

epidemic in cattle. It was noted that there were a number of cases

of vCJD worldwide, with no history of UK residence, whose source

of infection was not yet elucidated.

If BSE is present in the national sheep flock, what is the amount of BSE

infectivity that might be entering the food chain and from how many

sheep? How does this compare with the amount of infectivity that is

estimated to have entered the food chain historically due to bovine

and/or ovine BSE?

SEAC 95/2 Annex 1

DRAFT

Page 8

©SEAC 2006

22. The Sheep Subgroup noted that modelling12 showed that one BSE

infected sheep, close to the end of its incubation period, may

contribute 10 to 1000 times more infectious material to the food

chain than an infected cow. This is because thirty per cent of the

risk from a BSE infected sheep is likely to come from infectivity in

lymphatic and peripheral tissue that cannot be completely removed

from a carcass by removal of SRM under normal abattoir

conditions. This modelling indicated that although a maximum of

four flocks might currently harbour an ongoing BSE epidemic, the

annual human exposure from four flocks could be as much as

0.5% of the total exposure from cattle over the whole BSE

epidemic. This is, of course, a worst case scenario. Given that, to

date 162 definite and probable vCJD cases have arisen in the UK

ascribed to the bovine epidemic, extrapolation suggests that, in the

worst case, if BSE were in the UK sheep flock it might add a further

1 to 2 deaths per annum, assuming that these 162 cases

represented the total number of people infected through exposure

to cattle BSE. The most likely number is, however, zero.

23. From the modelling study12, small reductions in the risk of food

chain exposure from sheep could be achieved by strategies based

on tissue testing, a 12 month age restriction or expanded

definitions of high risk tissues. However, the most effective risk

reduction strategies would remain genotype based.

24. It was also noted that recent unpublished studies suggested that

the BSE agent, once passaged through ovine transgenic mice,

might become more virulent, transmitting more quickly with faster

incubation times and infecting a greater number of species.18 If this

result can be confirmed, extrapolation suggests that ovine BSE

may be more infectious to humans than bovine BSE. However, the

Subgroup has not seen the primary, unpublished, data and

therefore cannot comment on their reliability.

What reduction in risk to public health is delivered by

(i) an aim to produce small year on year increases in the percentage of

resistant and semi-resistant animals being eaten?

(ii) reduce the incidence of classical scrapie and BSE if present?

What studies are needed to inform on whether there is a risk to public

health from atypical scrapie? What data would lead the subgroup to

consider that atypical scrapie is a greater potential risk to public health

than BSE in sheep? How long are such studies likely to take? Can the

risks to consumers, if any, from BSE or atypical scrapie in sheep be

compared and if so, how?

33. No studies examining the human health risks of atypical scrapie

have been completed. Therefore, such a risk cannot yet be

excluded. Current risk reduction measures such as SRM and MBM

feeding bans reduce any risk, should it exist. The Subgroup

referred to its position statement which contained

recommendations for further studies6. The Subgroup noted that

experiments were under way to assess the transmissibility of

atypical scrapie in mice expressing human PrP genotypes. They

were encouraged by a recent report25, although the unpublished

data was not presented to the Subgroup, that atypical scrapie was

present in sheep samples from 1989, making it less likely that it is

a new and rapidly spreading infection or a risk to human health.

The Subgroup agreed that studies to assess the risk of atypical

scrapie relative to BSE and classical scrapie in mice would take

many years, and it needs to be recognised that results from the

mouse model alone may not necessarily inform whether or not

atypical scrapie is a human health risk.

34. On the transmissibility of atypical scrapie, which may have

implications for human health, it was suggested that relevant

25 Unpublished information from the Institute for Animal Health

departments should consider in advance their responses to results

which may emerge.

If the RGS continues, what are the risks associated with potentially

creating a sheep population that is susceptible to atypical scrapie?

What are the implications for a) human health and b) animal health?

35. The Subgroup agreed that the current RGS would likely be less

effective in reducing susceptibility to atypical scrapie in the national

flock than it is in reducing susceptibility to classical scrapie. It was

not yet clear how the RGS would alter susceptibility to atypical

scrapie in the national flock, and the present data are so scarce

that it is not possible to be certain whether the RGS would increase

or decrease prevalence26. It was agreed that further work was

needed to establish the prevalence of atypical scrapie within the

different genotypes and breeds, and modelling of these data could

inform on the expected impact of the RGS over the next 5 to 10

years on atypical scrapie prevalence.

36. The Subgroup was informed of preliminary and limited

epidemiological data27 indicating, on the basis of trading

associations, that atypical scrapie is unlikely to be spreading

quickly. Given a slow spread of disease, the Subgroup considered

that, since atypical scrapie cases were present in many European

countries, this is consistent with the hypothesis that it is not a new

disease but has been present for some considerable time. If

atypical scrapie has been present for 200 years, as has classical

scrapie, it was considered that the risks to human health would be

small. Data collected long term were needed to inform on this

aspect. To date, the earliest case of atypical scrapie in GB dates

back to 198925.

37. The RGS operates on a 3 codon screening system for codons 136,

154 and 171. The Subgroup recommended consideration of the

inclusion of codon 141 in any genotyping programme for sheep, to

take account of the importance of this allele regarding susceptibility

to atypical scrapie28.

38. There have been six clinical cases of atypical scrapie to October

2006 in the GB flock, but others may have gone undetected. The

26 Baylis M., Bishop S., Hope J. and Kao R., (2006) Analysis for the SEAC sheep subgroup

27 Data provided by Rowland Kao

28 Saunders G.C., Cawthraw S., Mountjoy S.J., Hope J. and Windl O. (2006) PrP genotypes

of atypical scrapie cases in Great Britain. J.Gen. Virol. 87, 3141-9

SEAC 95/2 Annex 1

DRAFT

Page 13

©SEAC 2006

full clinical phenotype is still undefined. It was noted that clinical

signs tend to appear in older animals than for classical scrapie.

The Subgroup considered the data insufficient to assess the

potential impact of atypical scrapie on animal health. Additional

research is needed here.

snip...full text ;

http://www.seac.gov.uk/papers/95-2.pdf

SRM controls at abattoirs and cutting plants

http://www.seac.gov.uk/papers/95-3.pdf

Report from the SEAC Epidemiology Subgroup

snip...

SEAC 95/4 ANNEX 1

Revised position statement of the SEAC Epidemiology Subgroup

B L A N K PAGE

2

© SEAC 2006

B L A N K PAGE

3

© SEAC 2006

http://www.seac.gov.uk/papers/95-4.pdf

Terry S. Singeltary Sr.

P.O. Box 42

Bacliff, Texas USA 77518

----- Original Message -----
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Wednesday, November 29, 2006 1:24 PM
Subject: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION]


November 29, 2006


Greetings FDA, DHH, Dr. Freas, and Dr. Harvey et al,

snip.....end...........TSS



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