Bulletin No 85, June 1997
The Spongiform Encephalopathy Advisory Committee (SEAC) has considered the final results of MAFF's "cohort study" into maternal transmission of BSE in cattle. SEAC concluded that the results show some evidence of direct maternal transmission of BSE from dam to calf at a low level (less than 10 per cent), but that some variation in genetic susceptibility to feed-borne infection may also occur. SEAC has therefore recommended that further research be carried out on the mechanism of direct maternal transmission, and into genetic factors. It also recommends that the Government should take the findings into account in deciding its policy on culling.
SEAC submitted a statement of its conclusions to MAFF and Department of Health Ministers on 16 April 1997. The SEAC statement which incorporates a report from its subcommittee which describes the "cohort study" is given below.
SEAC has confirmed that it considers that the current measures to protect consumers are appropriate and that there is no evidence to suggest any risk from milk.
Interim results of the study were published in Bulletin No. 76 (August 1996).
SEAC STATEMENT ON MATERNAL TRANSMISSION OF BSE - 16 April 1997
1. On 29 July 1996, the Spongiform Encephalopathy Advisory Committee (SEAC) issued a statement on maternal transmission of BSE following its consideration of an interim report on a study conducted by the Epidemiology Department, Central Veterinary Laboratory, Weybridge to investigate the occurrence and incidence of dam to calf transmission of BSE (the cohort study).
2. SEAC established an Epidemiology Subcommittee to consider the final results from the cohort study. The Subcommittee was chaired by Professor Peter Smith (London School of Hygiene and Tropical Medicine), a member of SEAC. It included two further members of SEAC, Dr Richard H Kimberlin (SARDAS) and Professor Will Hueston (University of Maryland). The Subcommittee also included Professor Roy Anderson (Oxford University), Professor Robert Curnow (Reading University), Dr Peter Goodfellow (SmithKline Beecham Pharmaceuticals), Professor Dr. Ir. Aalt Dijkhuizen (Wageningen Agricultural University, the Netherlands), Professor Nicholas Day (Medical Research Council Biostatistics Unit), Dr John Williams (Roslin Institute), Dr Rosalind Ridley (Cambridge University) and Mr John Wilesmith (Central Veterinary Laboratory). The Subcommittee was assisted by Dr Sheila Gore (Medical Research Council Biostatistics Unit), Dr Neil Ferguson (Oxford University), Dr Christl Donnelly (Oxford University), Dr John Woolliams (Roslin Institute), and Ms Judith Ryan (Central Veterinary Laboratory). The Subcommittee met on four occasions, and submitted its final report on maternal transmission of BSE to SEAC on 11 April 1997.
3. At its meeting on 15 April 1997, SEAC considered and accepted in full the report from the Epidemiology Subcommittee which is reproduced at the end of this statement.
4. SEAC noted that the results of the cohort study were not inconsistent with those of the case control study published in 1995 by Hoinville and others of the Epidemiology Department, CVL. That study, which involved cases of BSE born after the ruminant feed ban, did not identify significant evidence of maternal transmission, but the statistical confidence interval included a risk of up to 13 per cent (Veterinary Record (1995) 136, 312-318).
5. The cohort study provides no information on the mechanism of direct maternal transmission of BSE. We recommend that further research should be undertaken to shed light on the mechanism. Some research has already been carried out into potential routes of transmission from dam to calf, by testing the infectivity of tissues from BSE-affected animals, including placenta, embryos, blood and milk: no evidence of infectivity has been found. However, given that the rate of transmission is probably low, some of these negative results may be due to the practical difficulties of detecting low levels, or a low prevalence, of infectivity. SEAC recognises that a low level of transmission would make research on mechanisms difficult, and that it would be complemented by a better understanding of the mechanisms of scrapie transmission in sheep.
6. Any cull based upon the slaughter of calves born to cows in which BSE has been confirmed will have only a small effect on the incidence of BSE and the duration of the epidemic. Nevertheless, Government should consider the possibilities for such a cull, and its effects.
7. SEAC noted that, in its statement of 29 July 1996, it had concluded that the evidence on maternal transmission did not call into question existing measures to protect public health. In the light of the Subcommittee's report, SEAC reconsidered the existing measures.
8. With respect to consumption of bovine products the measures currently in place to protect the consumer are considered appropriate. In particular, the Committee considered the possibility of milk being a vehicle of transmission. SEAC concludes that no evidence has been found to suggest that milk from any species affected by transmissible spongiform encephalopathies is infectious. This concurs with the opinion of the Scientific Veterinary Committee, which advises the European Commission.
9. With respect to occupational exposure, responsibility for assessing whether any amendments are needed to the existing Health and Safety Executive guidance rests with the Advisory Committee on Dangerous Pathogens.
EPIDEMIOLOGY SUBCOMMITTEE STATEMENT TO SEAC ON MATERNAL TRANSMISSION - 11 APRIL 1997
1. In July 1996 SEAC issued a statement on maternal transmission of BSE following an interim analysis of data from an ongoing study (called the "cohort study") being conducted by the Epidemiology Department, Central Veterinary Laboratory (CVL). The study was intended to determine whether maternal transmission occurred, and if so, to inform policy makers with respect to animal health implications.
2. The study involved over 300 "matched-pairs" of calves. One calf in each pair was the offspring of a confirmed case of BSE and the other an animal born in the same herd in the same calving season whose dam had reached the age of 6 years without developing clinical signs of BSE. The two groups of animals were born between August 1987 and November 1989, and were taken from their natal herds between July 1989 and February 1990, aged between 2 and 24 months. They were kept on one of three experimental farms until they reached the age of 7 years or were culled at an earlier age with BSE or another disease. All animals surviving to the age of 7 years were then slaughtered and their brains were examined pathologically for evidence of BSE.
3. The preliminary results of the study, when most but not all of the animals had been followed to the age of 7 years, suggested that the offspring of BSE cases had an incidence of BSE that was about 10 per cent greater than that of control animals, with statistical confidence limits (95 per cent) ranging from 5-15 per cent, the range reflecting the limited numbers of animals that developed BSE in the study.
4. By November 1996 the last of the animals in the study had reached the age of 7 years, and by January 1997 the last of their brains had been examined. As had been anticipated, the final results were not markedly different from those on which the interim analysis had been based in 1996. Of the 301 offspring of BSE cases, 42 (14 per cent) developed BSE. Among the 301 offspring of the "control" dams without BSE, 13 (4.3 per cent) developed BSE. The difference between the two risks was thus 9.6 per cent, and was highly statistically significant with a confidence interval ranging from 5.1 per cent to 14.2 per cent. A paper giving the results of the study will be published shortly in the Veterinary Record by the Epidemiology Department of CVL.
5. The cohort study was set up to investigate the occurrence of maternal transmission, but interpretation of the results was confounded by the likely exposure of some of the experimental animals to contaminated feed. The results could be explained by two hypotheses, acting alone or in combination, namely direct maternal transmission of infection or inherited genetic variation in susceptibility to BSE via contaminated feed. Although most of the animals involved in the study had been born after the ruminant feed ban in July 1988, feed-borne transmission is thought to have continued beyond that date. This is consistent with the observation that the BSE risk in both of the groups was greater among animals born before the introduction of the feed ban than among animals born later. However, the difference in risk between the two groups was also greater in those born earlier, and this would not be expected if direct maternal transmission was the sole route of infection of the calves in the study. Such an effect might be apparent if cattle vary in their susceptibility to contracting BSE from infected feed. It is possible that the offspring of BSE cases may inherit, from their dams, genes associated with increased susceptibility to disease and that at least some of the difference in BSE risk between the offspring of BSE affected and non-affected dams in the study may be due to inherited factors, rather than because of direct transmission of BSE from dam to calf.
6. The subcommittee has reviewed the evidence for variation in genetic susceptibility to BSE in cattle. There is variation in the risk of TSEs according to genotype in some species. For example, polymorphisms of the PrP gene are associated with substantial variation in susceptibility to infection with the scrapie (and in incubation period ) in sheep and mice and with differences in risk of CJD in humans. The subcommittee notes, however, that the limited research so far completed has failed to identify genetic factors as a major component in the epidemiology of BSE.
7. To assist the CVL Epidemiology Department in the interpretation of the results of the cohort study, independent analyses of the data were conducted by three additional groups with expertise in statistical analysis (based in the Wellcome Trust Centre for the Epidemiology of Infectious Disease, University of Oxford; the MRC Biostatistics Unit, Cambridge; and the Department of Applied Statistics, University of Reading). In so far as was possible, they tried to evaluate the contributions to the risk difference between the animals in the two groups from inherited differences in susceptibility to disease caused by infected feed and from direct transmission of BSE from dam to calf. In the absence of detailed information on the genetic make up of the animals in the study, the possible genetic contribution could only be assessed by statistical modelling.
8. The analyses by the three groups have been submitted for publication during the latter part of 1997. These analyses reached broadly the same conclusions. That there was a highly significant difference in risk between the two groups of animals was clear. The findings did not definitively establish direct maternal transmission as the sole explanation for the difference in risk. The statistical model which fitted the data best involved contributions from both direct maternal transmission and inherited susceptibility. The main evidence for direct maternal transmission is that the risk of BSE in the calf of an affected dam was greatest for calves born close to the onset of BSE in the dam. However, the power of the study to detect differences related to the time between BSE onset and the date of birth of a calf was limited by the design of the study which resulted in 83.4 per cent of the calves being born within the six months prior to onset of clinical disease in the dam.
9. Further investigation was necessary of the possible variation in the risk of BSE associated with the time between the birth of an animal and the onset of BSE in the dam. This was undertaken mainly by the group from the Wellcome Centre for the Epidemiology of Infectious Diseases, University of Oxford through analyses of data on all cases of BSE born after the ruminant feed ban, which are recorded on the BSE database held by the Epidemiology Department at the CVL. The findings will be submitted for publication shortly. Evidence was found that the subsequent BSE-risk was greatest in calves born after the date of BSE onset in the dam. For calves born before onset, the risk was lower, and diminished as the interval between birth and onset increased, and no risk was apparent more than two years before onset (see next paragraph). Thus, although possibly subject to some biases, these analyses also suggested that enhanced BSE-risk in the offspring of BSE dams involves a low level of direct maternal transmission in the late stages of the incubation period.
10. In view of the findings of the analyses that are summarised above, the subcommittee concludes that there is some evidence for direct maternal transmission of BSE at a low level, but some variation in genetic susceptibility to BSE following feed-borne exposure may occur. The risk of transmission of BSE from dam to calf is likely to be less than 10 per cent, and appears to be confined to animals born after the onset of BSE in the dam or up to two years beforehand. This level of transmission is not sufficient, by itself, to perpetuate BSE in the cattle population and is likely to have only a minor effect on the rate at which the incidence of BSE declines. It is inevitable that cases infected via animal feed will continue to appear in diminishing numbers for several years. Therefore, although the number of cases infected maternally will be small, they may represent an increasing proportion of the remaining cases detected.
11. Given the evidence that variation in genetic susceptibility may have contributed to the results of the cohort study, and of the importance of genetic factors in TSEs in other species, the subcommittee considers that further research is necessary to clarify whether or not variations in the PrP gene or other genes may be influencing the transmission of, or susceptibility to, BSE in cattle. Research should seek to identify polymorphisms of the PrP gene which may be associated with BSE susceptibility, including stored samples from the cohort study. There should also be a search for other genetic markers, outside the PrP gene, which may be associated with an increased BSE risk in cattle.
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