Public summary of the meeting on
18th September 2001

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The Spongiform Encephalopathy Advisory Committee (SEAC) met in London on the 18 September 2001.

The meeting was the first that the Committee had conducted in public, and following advance publicity, Members were pleased to welcome over 100 audience members to the morning session.

vCJD update

An analysis of sporadic CJD cases was considered by the Committee. It showed a steady increase since the 1970s, which was considered largely to reflect increased case ascertainment in the elderly. The Committee was informed that the total number of cases of definite or probable variant Creutzfeldt Jakob Disease (vCJD) had risen to 106, of whom 5 were still alive. The Committee heard that a number of geographically associated case groupings were under evaluation by the National CJD Surveillance Unit. A greater incidence of vCJD cases in Northern Britain had been determined, with the mortality rate per million showing 0.51 in the North; 0.34 in the North West and 0.19 in the South East, in the period from 1 May 1995 to 31 August 2001. It was unknown whether the cause of these differences was due to variation in exposure to the vCJD agent, or some other factor such as differences in genetic susceptibility. No such geographical difference had been found for sporadic CJD.

The Committee noted an analysis from the Public Health Laboratory Service which continued to show a statistically significant rising trend of around 20-30% per annum to date in the number of reported cases of vCJD. The fact that no onsets of the disease had yet been recorded in the current year was not thought to be significant. The Committee reiterated that it was too early to accurately predict the ultimate number of vCJD cases. However they also noted the view from the Imperial College group that, within the modelling undertaken to look at possible ranges of case numbers, in forthcoming projections the upper bound seemed likely to reduce from previous forecasts, provided the current pattern of genetic susceptibility was maintained.

The Committee heard that a probable case of vCJD had recently been identified in France, which meant there were now 4 known French vCJD cases. They also noted that a Hong Kong resident, who had lived for substantial periods in the UK, had been recently identified as having vCJD.

Potential vCJD therapies

The Committee noted an announcement made on 17 September from the Department of Health which explained the arrangements underway to fast-track the design of a clinical trial to evaluate the effectiveness of quinacrine as a potential treatment for CJD. Some Members expressed their concern about the pace of developments and counselled against reaching premature conclusions about the potential effectiveness of new treatments. It was emphasised that a number of avenues of research were being explored to produce an effective treatment, and that effective and proper assessment through well-designed clinical trials would be essential. To that end, a trial steering committee was being established to oversee the trial of quinacrine, in line with Medical Research Council guidelines for good clinical practice. In addition, the Committee welcomed the news that a CJD therapy advisory committee was being set up by the Chief Medical Officer to evaluate a number of candidate therapies for CJD, and advise on ethical and practical aspects.

BSE update in the UK and Europe

Professor Roy Anderson from Imperial College updated Members on the current and projected status of the BSE epidemic in the UK and in other EU Member states. Professor Anderson began by outlining EU requirements for TSE surveillance. These had increased dramatically over the last few years. Currently all animals over thirty months of age are required to be tested using an approved diagnostic test before they can enter the human food chain. Because the UK implements the over thirty month rule (OTM rule), which prevents any OTM cattle (with limited exceptions) from entering the food chain, this country is not currently required to test all older cattle. However under EU regulations, the UK has introduced a large TSE surveillance programme. Although the foot and mouth (FMD) epidemic has limited tissue collection for surveillance purposes, the UK programme includes the examination of fallen stock, 50,000 cattle over thirty months of age and 18,000 sheep over 18 months old. Professor Anderson reiterated concerns about the sensitivity of the current diagnostic tests. Because it was not clear at what point in the incubation period the tests were able to detect infection in an animal, it was likely that current surveillance regimes may underestimate the overall level of BSE prevalence. Professor Anderson considered it was important that diagnostic tests are validated using tissue taken throughout the incubation period to ascertain their reliability at detecting abnormal prion in the pre-clinical phase.

Professor Anderson reported that the UK BSE epidemic continues to decline largely as predicted. Future predictions suggest that the tail of the epidemic will be long, and that the number of cases will be in the order of a few hundred in 2002, reducing to approximately 100 in 2003. Professor Anderson noted that the UK control measures, particularly the offspring and selective cull, had made a significant impact in reducing the tail of the epidemic.

In contrast to the UK epidemic, which had continued to decline since 1992, a number of other EU Member States had rising numbers of BSE cases. This was partially because of the introduction of the increased surveillance measures but also due to the later introduction of control measures. The sharp upward trend in the epidemic in certain EU Member States was a cause for concern. The Committee noted that this may have implications for the importation of meat from other Member States. This could also affect the choice of country from which to import cattle for breeding stock, notably as part of the restocking following FMD.

In regard to public health protection, Professor Anderson estimated that because the OTM rule prevents older animals from entering the food chain, less than 1 such animal in the late stages of the incubation period was estimated to enter the human food chain in 2001. Professor Anderson noted that in comparison to the years prior to 1996, the risk is almost unmeasurable, and suggested that there may be a case for relaxing the OTM rule upwards to either 48 or 60 months in the future.

BSE investigations- post Aug 1996

Members received a summary of investigations into the possible routes of BSE exposure in cattle with BSE born after 1 August 1996, the date when further measures to improve feed security were considered to be fully effective. To date there had been six such cases in the UK, 5 in GB and one in Northern Ireland. A protocol for investigation had been established and had been applied to each case. This examined all potential exposure routes including from the dam (maternal transmission), from other cattle in the herd, other contact animals (horizontal transmission), veterinary products, environmental exposure from manure or other animal waste by-products. Possible exposure via feed was also examined, including an assessment of possible exposure to old feed stocks that may have contained contaminated material, contamination of new feed during milling or transportation or adulteration with illegal feed products.

It was noted that because all analysis was carried out retrospectively, the investigations were difficult to conduct and were largely reliant on anecdotal evidence. Hence the route of transmission could not be definitively isolated, although there was reason to suspect that the animals were likely to have been exposed to contaminated feed in at least some of the cases.

The Committee noted that although contaminated feedstocks could not be ruled out as a possible exposure route, it was unlikely that maternal transmission was the route of exposure in at least 4 out of the 6 cases, given that the dam of the affected animal lived for a significant time after the offspring was born without displaying clinical signs. In view of this the Committee reviewed the evidence for maternal transmission. This was largely based on two studies; an experimental study which examined BSE incidence in a group of calves taken from known cases of BSE(1) (the 'cohort' study), and an epidemiological examination of the BSE case database for a correlation between affected cattle and their offspring(2). Both studies were consistent with a maternal transmission rate of 10% during the last 6 months of the incubation period. Members agreed that if any of the four cases in question had resulted from maternal transmission, the assumption that transmission risk was confined to the period close to disease onset was not valid. However both studies had involved a large number of animals and were statistically more rigorous than any conclusions from the small number of post August 1996 cases, where the route of exposure was not known.

Scrapie in sheep - how is scrapie maintained endemically in sheep flocks

The Committee considered a paper by Dr Hoinville of the Veterinary Laboratories Agency (VLA) on the mechanisms of transmission and maintenance of scrapie within flocks. The Committee noted that some experimental work was underway to investigate scrapie transmission. However they agreed that further research was important, particularly in view of the current drive to reduce scrapie incidence under the National Scrapie Plan (NSP). It was felt that insightful experimental design would be required to define the relative importance of proposed transmission mechanisms. This was likely to require a large resource allocation, but Members agreed that such work should be a high priority.

Members considered whether the NSP could be accelerated by restocking flocks culled because of Foot and Mouth Disease (FMD) with animals that were genetically resistant to scrapie. While it was recognised that this would be beneficial, currently there was not sufficient capacity to genotype all breeding animals prior to repopulation. It was also unlikely that sufficient numbers of sheep carrying resistant genotypes were available at the present time, particularly in certain breeds of sheep. However the NSP recognised the need to assess and improve the genetic make up within individual breeds, and proposals to address this were fundamental to the plan.

Members expressed their thanks to Dr Hoinville for the thoroughness and clarity of her report.

Review of the origin of BSE

Members welcomed Professor Gabriel Horn, who presented an outline of his group's examination and subsequent report on the origins of the BSE epidemic. Professor Horn explained that their investigations had suggested that it was plausible that BSE arose because a number of factors that, taken together, were unique to the UK and which may have allowed the causative agent to induce disease in the bovine food chain. These factors included a change in rendering procedures which may have resulted in a small but clinically significant increase in the degree of infectivity allowed to pass through rendering systems, and the relative high proportion of sheep to cattle rendered in the UK, of which some of the former would have been scrapie infected. Of particular note was the introduction of meat and bone meal (MBM) into calf starter rations in the mid 1970s. The review group noted that this appeared to have happened in the UK before the practice was introduced in other countries, and it was hypothesised that this may have been the critical to the establishment of BSE disease in cattle.

During discussions in the afternoon session, SEAC acknowledged that Professor Horn's remit had been almost impossible given the limited retrospective information available. However the Committee agreed that the report gave a persuasive account of the possible origins of the epidemic. Members felt that the novel hypothesis regarding the feeding of MBM in calf starter rations was particularly interesting, and may warrant a more exhaustive investigation of relevant literature and other information sources. Overall SEAC agreed that in view of the limited time scale available, Professor Horn's team had produced an excellent review for which they should be congratulated.

Question and Answer Session

Prior to closing the open session, the Committee conducted a question and answer session with members of the audience on the topics considered during the morning's discussions.

Outcome of the open meeting

The Committee's initial reaction was that the open session had been a positive experiment, and agreed to consider the outcome in more detail at a future meeting when feedback from both Committee Members and delegates had been received.

Report on the Working group on sheep brain pool experiments

Members considered a report from a SEAC working group which had been convened to examine an ongoing experiment to examine a pool of scrapie brains collected in the early 1990's for evidence of BSE. The working group were asked to consider whether the strain typing technique, based on the examination of characteristic incubation periods and brain pathology in a panel of mice, was able to distinguish BSE from known scrapie strains. They concluded that, in principle, if both the incubation period patterns and brain lesion profiles seen in the mouse panel, particularly on sub-passage within mice, were characteristic of patterns seen with a BSE-derived strain, it would present strong evidence that the agent was related to BSE.

Members agreed that the strain typing results from the scrapie brain pool (SBP) collected to date could not positively distinguish between scrapie and BSE but could be compatible with BSE having been in sheep at that time. However currently it was too early to draw definitive conclusions from the research. Members agreed to review the experiment later in the year as further results became available.

The working group had also considered a risk assessment to examine the possibility that the SBP may have been contaminated with bovine tissue at the time of collection. SEAC agreed that work to examine potential contamination should be carried forward, including DNA analysis of the original pool for evidence of bovine tissue.

Members received presentations from groups from Imperial College and DNV, who outlined their approaches to assessing the potential public health risk if BSE were ever found in sheep. These contingent risk assessments, commissioned by the FSA, would be used to make an assessment of the range of potential levels of infectivity in the sheep flock and also give an indication of the relative effectiveness of possible risk reduction strategies.

Members briefly considered current work to look for evidence of BSE in the current sheep flock. Currently, 183 individual scrapie brains are being tested in panels of mice. Experiments are incomplete, but to date, no signs characteristic of BSE have been seen.

Departmental R&D updates

The Committee welcomed the news that 32 full proposals had been submitted, following the Government's Joint Funders' March 2001 public call for proposals for a diagnostic test for TSEs.

vCJD pre-publication paper

An unpublished paper that argued vCJD was not a new disease was remitted for examination to the Committee's epidemiology sub-group.

All other items were deferred to a future meeting because of lack of time.

References

1. Donnelly, CA.; Ghani, AC.; Ferguson, NM.; Wilesmith, JW., and Anderson, RM. Analysis of the bovine spongiform encephalopathy maternal cohort study: Evidence for direct maternal transmission. Applied Statistics. 1997; 46(3):321-344.

2. Donnelly-C-A, Ferguson-N-M Ghani-A-C Wilesmith-J-W Anderson-R-M. Analysis of dam-calf pairs of BSE cases: confirmation of a maternal risk enhancement. PROCEEDINGS-OF-THE-ROYAL-SOCIETY-OF-LONDON-SERIES-BIOLOGICAL- SCIENCES, 1997, 264, 1388, Pp 1647-1656.

SEAC
December 2001

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