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From: TSS ()
In Reply to: TSE ADVISORY COMMITTEE DECEMBER 15, 2006 [TSS SUBMISSION] posted by TSS on November 30, 2006 at 9:05 am:
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 ----- snip.....end...........TSS
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