SEAC

Position Statement

New forms of Bovine Spongiform Encephalopathy

Issue

1. SEAC considered the implications of scientific research on recently identified novel forms of bovine spongiform encephalopathy (BSE).

Background

2. Very low numbers of cattle with abnormal prion proteins (PrPsc) with different biochemical properties from those normally associated with BSE have been detected in active surveillance programmes in a number of countries. SEAC considered (SEAC 97, May 2007) published and unpublished research relating to these putatively new forms of BSE.

Characterisation of cases

3. Different forms of BSE were initially identified and distinguished from classical BSE on the basis of their PrPsc profiles in biochemical tests. All BSE cases identified to date conform to one of three different PrPsc profiles on western blot tests. The European Union (EU) Community Reference Laboratory has suggested that cases be classified on the basis of these profiles as classical, L- or H-type BSE. The key distinguishing features in western blot tests are the lower concentration of the diglycosylated band and the slightly lower molecular mass of unglycosylated band of PrPsc in L-type BSE, and the higher molecular mass of the unglycosylated band in H-type BSE, compared with classical BSE. A western blot method to discriminate between the three types of BSE has been developed .

4. All the reported cases of L-4,5,6,7 and H-type7,9,8,9 BSE have been detected during active surveillance of healthy slaughtered animals or fallen stock. In the majority of cases, retrospective investigations indicated that these animals either showed no clinical signs of BSE or showed non-specific signs such as ataxia and recumbency. As these cases have been detected following active rather than passive surveillance, it has not been possible to observe the clinical signs associated with L- or H-type BSE in sufficient detail to assess whether there are differences in the clinical features between L-type, H-type and classical BSE. However, a significant distinction between classical BSE and L- and H-type BSEs is the age distribution of cases as L- and H-type BSE are found in older cattle with an age range of 5.5 to 19 years. One putative L-type BSE case was aged two years6, however the BSE typing of this case has not been verified. Around 85% of L- or H-type BSE cases have been found in animals more than 10 years old, which is much older than most cases of classical BSE.

5. Neuropathological investigations suggest that PrPsc may be more widely distributed, with a different brain distribution pattern for L- and H-type BSE, compared with classical BSE. However, these investigations are limited by the very low number of animals for which a complete brain has been available for analysis. There are no data on the peripheral distribution of PrPsc or infectivity of L- and H-type BSE or on the pathogenesis of these diseases. However, studies to assess the tissue distribution of infectivity and PrPsc in animals throughout the incubation period following intracerebral challenge are underway.

Prevalence

6. As there is no regulatory requirement to specify the type of BSE when notifying the EU or the World Organisation of Animal Health of BSE cases, it is not possible to accurately quantify the number of H- or L-type BSE cases that have occurred world-wide. Information presented to SEAC indicated that at least 37 cases of L- and H-type BSE have been identified world-wide to date. These cases are widely distributed geographically with L-type cases identified in a number of European countries and Japan, and H-type cases identified in a number of European countries and North America.

7. Due to the different approaches to surveillance between countries, proportions of animals tested and methods used, which do not necessarily include systematic molecular typing, these surveillance systems are not equally capable of detecting L- and H-type BSE. Furthermore, surveillance procedures, including the most appropriate brain region to sample, have not been optimised for the detection of L- and H-type BSE. Therefore, it is not possible to accurately assess and compare the prevalence of L- and H-type BSE in different countries. Origins and Causes

8. It is not known whether L- or H-type BSE are newly emerging forms of BSE or whether they have existed for some time and have only come to light following extensive active surveillance programmes in the EU and elsewhere, together with the introduction and development of new biochemical tests. Studies using historic frozen brain samples from cattle collected from passive surveillance during the early years of the UK BSE epidemic are underway to investigate whether L- and H-type BSE existed in the UK in the past. However, if the prevalence of these BSE types was low, these studies may not identify many, if any, cases.

9. Genetic analyses of a few L- and H-type BSE cases4,5,8,9 have not identified associations between the occurrence of such cases and known genetic polymorphisms in the prion protein gene. There are no mutations in the prion protein gene open reading frame in all, but one, sequenced case. However, the analyses conducted to date are limited by the small number of cases and controls analysed. Thus, a genetic cause of the disease cannot be ruled out.

10. No detailed epidemiological investigations have been conducted to investigate the possible causes for, or links between, L- and H-type BSE cases. No geographical clusters of L- and H-type BSE cases have been found to date. Therefore, it is not possible to rule out feed related, environmental or spontaneous causes for these types of cases.

Transmission studies

11. Transmission studies5,10,11 have demonstrated that both L- and H-type BSE are transmissible to other species by the intracerebral route. No studies have assessed the transmissibility by the oral route. Thus, the available information shows that it is possible for species other than cattle to develop these diseases upon infection. However, these data do not allow an assessment of the susceptibility to infection from the most likely natural route of exposure.

12. L-type BSE has been transmitted to wild-type, bovinised, ovinised and humanised mice as well as to cattle and a cynomolgus macaque by intracerebral inoculation. Incubation periods, clinical signs, neuropathology as well as the neurological distribution of PrPsc were distinct from classical BSE13,12. With the exception of transmissions to wild-type mice, primary transmissions resulted in clinical disease. Although primary transmission to wild-type mice did not result in clinical disease, secondary transmissions from some of these animals resulted in clinical disease. Sub-passage of L-type BSE in wild-type12 and ovinised mice13 suggests that L-type BSE may be converted to an infection of a similar phenotype to classical BSE. However, further experiments using serial sub-passages of infections in a range of species are required to more fully investigate whether L-type BSE may convert to a disease with a classical BSE phenotype.

13. H-type BSE has been transmitted to wild type, bovinised and ovinised mice by intracerebral inoculation with incubation periods, neuropathology and neurological distribution of PrPsc distinct from classical and L-type BSE.

14. Studies of intracerebral transmission of H-type BSE to cattle and cynomolgus macaques . To date, clinical disease has developed from one intracerebral inoculation of H-type BSE to cattle. Oral transmissions of L- and H-type to cynomolgus macaques are underway.

Human and animals health implications

15. There are too few data to enable an assessment of the natural transmissibility of L- and H-type BSE between cattle, or to sheep or goats. The present feed control measures which prevent feeding of mammalian meat and bone meal to ruminants would limit the spread of these forms of BSE to cattle, sheep and goats should they be transmissible to these species by the oral route.

16. Similarly, the lack of data on the oral transmissibility of L- or H-type BSE to humanised mice or non-human primates does not allow an assessment of the human health implications of ingestion of meat from animals infected with L- or H-type BSE. The differing clinical features of L-type and classical BSE in the cynomolgus macaque suggest that if L-type BSE were ever to be transmitted to humans, its clinical presentation may differ from that of vCJD. It is possible, therefore, that, if transmitted to humans, it could be identified by continuing surveillance of unusual neurological conditions in place in the UK.

Conclusions

17. L- and H-type BSE have not yet been fully characterised, however data from biochemical, neuropathological and transmission studies suggest that L- and H-type and classical BSE may be distinct strains of prion disease. In contrast to classical BSE, L- and H-type BSE infections are mostly detected in animals of older age with most of the infected animals identified to date over 10 years of age. Although L- and H-type BSE may be diseases that predominantly affect older cattle, it is possible that infections may occur at a young age and develop over a long period of time. The origins and possible routes of transmission, if transmissible under natural conditions, of L- and H-type BSE are not known. Due to the older age of the cases identified, wide geographical distribution and their apparent low number, it is possible they may have arisen spontaneously, however feed borne or environmental transmission cannot be ruled out.

18. As data on the oral transmissibility of L- and H-type BSE are lacking, it is not possible to fully assess the animal and human health implications. However, as the occurrence of L- and H-type BSE appears to be low, and due to the feed control measures in place, the risk of spread to other cattle, sheep and goats is likely to be very low assuming that, as with classical BSE, environmental transmission is negligible. For these reasons, and because of the BSE control measures in place to protect the food supply, assuming that the specific risk material controls are similarly effective for L- and H-type and classical BSE, the risk to human health is likely to be very low to negligible. However, given the paucity of data on L- and H-type BSE, a close watching brief should be maintained on the findings of research in this area.


SEAC July 2007

 

References

1SEAC 97 discussion papers available at http://www.seac.gov.uk/agenda/agen100507.htm

2Published and unpublished data from the Institute for Novel and Emerging Infectious Diseases, Germany presented by Dr M. Groschup, the Instituto Nazionale Neurologico, Italy presented by Dr F. Tagliavini, the Unite Agents Transmissibles Non Conventionnels, France presented by Dr T. Baron, the Istituto Zooprofilattico Sperimentale del Piemonte, Italy presented by Dr P. Acutis, the National Animal Disease Centre, USA presented by Dr J. Richt, the National Veterinary Services Laboratories, USA presented by Dr M. Hall, the Commissariat à L’Energie Atomique, France presented by Professor C. Lasmezas, the Veterinary Laboratories Agency, UK presented by Dr. L. Terry and the National Institute of Infectious Diseases, Japan provided by Dr Y. Yamakawa.

3Jacobs et al. Molecular discrimination of atypical bovine spongiform encephalopathy strains from a geographical region spanning a wide area in europe. J Clin Microbiol. 2007;45(6):1821-9.

4Casalone et al. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A. 2004;101(9):3065-70.

5 Buschmann et al. Atypical BSE in Germany--proof of transmissibility and biochemical characterization. Vet Microbiol. 2006;117(2-4):103-16.

6Yamakawa et al. Expert Committee for BSE Diagnosis, Ministry of Health, Labour and Welfare of Japan. Atypical proteinase K-resistant prion protein (PrPres) observed in an apparently healthy 23-month-old Holstein steer. Jpn J Infect Dis. 2003;56(5-6):221-2.

7Brown et al. On the question of sporadic or atypical bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Emerg Infect Dis. 200;12(12):1816-21.

8Biacabe et al. Distinct molecular phenotypes in bovine prion diseases. EMBO Rep. 2004;5(1):110-5.

9Richt et al. Identification and characterisation of two bovine spongiform encephalopathy cases diagnosed in the United States. J Vet Diagn Invest 2007;19:142-54

10Capobianco et al. Conversion of the BASE Prion Strain into the BSE Strain: The Origin of BSE? PLoS Pathog. 2007;3(3):e31

11Baron et al. Transmission of new bovine prion to mice. Emerg Infect Dis. 2006;12(7):1125-8.

12Beringue et al. Isolation from cattle of a prion strain distinct from that causing bovine spongiform encephalopathy. PLoS Pathog. 2006;2(10):e112.

13Beringue et al. A bovine prion acquires an epidemic bovine spongiform encephalopathy strain-like phenotype on interspecies transmission. J Neurosci. 2007;27(26):6965-71.

 

Page updated: 1 August, 2007