1. Bovine Spongiform Encephalopathy: An Update Linda A.Detwiler Senior Staff Veterinarian USDA, APHIS, VS

2. Transmissible Spongiform Encephalopathies l prolonged incubation period l progressive debilitating neurological illness l pathological changes confined to CNS l fatal

3. Transmissible Spongiform Encephalopathies l Scrapie Associated Fibrils (SAF) - negative stain EM l Transmissibility

4. Transmissible Spongiform Encephalopathies: Etiology l agent not fully characterized l smaller than smallest known virus l ellicits no detectable immune or inflammatory response in the host l resistant to most disinfectants and treatments which normally destroy nucleic acids

5. Transmissible Spongiform Encephalopathies: Agent Theories l VIRUS - unconventional, unusual biochemical and biopysical properties l VIRINO - host-derived protein coat coupled to a small noncoding regulatory nucleic acid l PRION - host-coded normal cellular protein becomes partially protease resistant through post tranlational conformation change

6. Transmissible Spongiform Encephalopathies: Human l Creutzfeldt-Jakob Disease (CJD) l Gerstmann-Straussler-Scheinker syndrome (GSS) l fatal familial insomnia (FFI) l Kuru l variant CJD (vCJD)

7. Transmissible Spongiform Encephalopathies: Scrapie l Reported most sheep producing regions l Known over 250 years l Sheep, goats, moufflon

8. Transmissible Spongiform Encephalopathies: Chronic Wasting Disease l First recognized as disease syndrome - 1967 l Colorado, Wyoming - endemic areas l Farm raised elk

9. Transmissible Spongiform Encephalopathies: Transmissible Mink Encephalopathy l Affects ranch raised mink l First recognized in 1947 l Detected and documented in Canada, Finland, (East) Germany, Russia l Associated with feed

10. Transmissible Spongiform Encephalopathies: Animal l Bovine Spongiform Encephalopathy l Feline Spongiform Encephalopathy l TSE of Exotic Ruminants

11. Distribution of Infectivity bone marrow distal ileum brain trigeminal ganglia spinal cord dorsal root ganglia

12. Transmission

13. BSE Diagnostics l No live animal test l No preclinical test l Need brain tissue l Histology, IHC, WB, ELISA l "Negatives" do not guarantee absence of infectivity

14. TSE Diagnostics: EU Approved l Histology l Standard IHC and Western Blot l Prionics AG - modified Western Blot (8 hrs) l Enfer Ltd. - High throughput chemiluminescent ELISA (3-4 hrs) l CEA - Sandwich Immunoassay (3-4 hrs) l all require brain/clinical cases

15. BSE STATISTICS for GREAT BRITAIN* (as of February 9, 2001) Total number of confirmed cases: 177,717 Total number of affected herds: 35,150 Proportion of dairy herds affected: 61.3% Proportion of beef suckler herds affected: 16.6% Confirmed total herd incidence: 37.5% * England, Scotland, Wales

16. Confirmed cases of BSE in Great Britain by year of restriction (1986 - 1 December 2000)* *Includes 46 cases not subject to official restriction and identified by proactive surveillance or at autopsy.

17. UK MAFF Actions l Mammalian to food animal feed ban l Over thirty month scheme l Selective Cull l Offspring Cull l SRM/SBO bans l Beef on the bone prohibition - No longer in place

18. 00 86 90 Ireland Portugal Switzerland France 94 97 Netherlands Belgium Luxembourg Denmark Germany Spain Italy Total number of cases (3-12-01) UK >180,000 Belgium - 23 Ireland -653 Spain - 32 Italy - 4 Portugal - 528 Netherlands - 13 Switzerland - 370 Liechtenstein - 2 France - 279 Denmark - 2 Germany - 44 Luxembourg - 1 First cases of BSE

19. BSE Incidence Rate (per million cattle > 2 yrs) 98 99 United Kingdom 596 422 Portugal 147 236 Switzerland 16 53 Ireland 22 27 France 2 3 Belgium 4 2 Netherlands 1 1

20. BSE: Control Measures in EU l SRM bans on sheep, goats, cattle (Oct 2000) l Prohibit feeding of most processed animal proteins (excluded fish meal) to farmed animals (Jan 2001) l test of all cattle >30months at slaughter (if cannot test destroy) (Jan 2001)

21. EU BSE Surveillance l CNS cases l Fallen stock and emergency slaughter l herdmates of positive cases in some countries l all bovines to slaughter > 30 months of age or older l Negative doesn't guarantee lack of infectivity

22. BSE: Comparison of surveillance l France l 450,000 > 30 mos tested - 10 pos (1-01 to 3-01) l 54,000 fallen stock tested - 68 pos (summer 2000 to 3- 01) l Switzerland l 14,900 normal slaughter - (3 pos 99; 0 pos 00) l 22,900 fallen and ES - (22 pos 99; 16 pos 00)

23. Fallout from BSE (Nov-Feb) l Meat sales drop dramatically l Loss of consumer confidence l Politicians resign or lose jobs l Disposal Problems (carcasses/MBM) l Logistical test problems

24. EU Geographical BSE Risk l 25+ countries evaluated l Member states l Non member states l Examined: l Challenges l Stability of system

25. EU Geographical BSE Risk l Challenges l External l cattle l MBM l Internal l cattle l MBM

26. EU Geographical BSE Risk (continued) l Stability l Feed bans l Rendering l Time l Temperature l Pressure l SRM bans

27. EU Categories of Risk l I - Highly Unlikely l II - Unlikely but Cannot be excluded l III - l Likely but not confirmed l BSE confirmed at a lower level l IV - BSE confirmed at a higher level

28. Category I l Argentina l Australia l Chile l New Zealand l Norway l Paraguay l Uruguay l Botswana l Namibia l Nicaragua, l Swaziland

29. Category II l Austria l Finland l Sweden l Canada l United States

30. Category III l Germany l Italy l Spain l Lithuania l Belgium l Denmark l France l Ireland l Luxembourg l Netherlands l Switzerland

31. Category IV l United Kingdom l Portugal

32. CJD vs. vCJD l sporadic, genetic, iatrogenic l 55-75 yrs of age l < 6 mos clinical course l memory loss, myoclonus, dementa l no plaques in brain l food contaminated with BSE infected CNS l 28 yrs. median l avg 14 mos clinical course l psychiatric followed by neuro l florid plaques

33. vCJD Cases (as of April 2001) * vCJD cases - 98 definite and probable * vCJD cases - 2 definite, 1 probable

34. vCJD cases by Year

35. vCJD = BSE ? transgenetic studies strain-typing glycoform patterns epidemiology macaques

36. vCJD: Distribution of Infectivity l Different than classical CJD l Spleen, tonsil, appendix l Retrospective study - 3000 samples - negative results l leucodepletion of blood supply l UK imports plasma and plasma products l US and Canadian deferrals

37. USDA ACTIONS: Prevention and Surveillance l Import Regulations l Surveillance l Formal Risk Assessments l TSE Working Group

38. BSE - Prevention l Import Restrictions - countries with BSE l July 1989 - live ruminants l November 1989 - ruminant products l 1991 - formal regulations l Import Restrictions - Europe l December 1997 l January 1998 - interim rule l all live ruminants and most ruminant products

39. BSE - Prevention l Import Restrictions - Europe l December 6, 2000 - all MBM, etc. regardless of species l Evaluations of other countries l South America underway l Central America l Asia

40. Import Policies and Regulations l North American Policy

41. USDA ACTIONS: Surveillance l Field CNS Cases l VDL data l CNS condemns at slaughter l "Downers"

42. BSE Surveillance: Total Bovine Brain Submission by State May 10, 1990 thru March 31, 2001 Source: USDA, APHIS,NVSL Note: None of the US Brain Submission Have Tested Positive for BSE Total = 12,341 1502 1540 2212 1255 474 353 467 310 143 196 213 157 117 186 187 156 137 127 NJ-320 63 VT-96 266 89 43 55 79 71 221 51 220 226 25 65 49 42 MD-22 217 35 NH-14 16 CT- 19 2 182 17 MA- 35 44 DE-2 13 5

43. BSE Surveillance NVSL Bovine Brain Submissions FY 93-99 Total Submissions Tested by IHC 412 495 112 465 168 584 388 855 842 731 729 988 982 651 219 266 223 199 Downers (fallen stock) 344

44. NVSL BSE Surveillance Bovine Brain Submissions FY 00-01 (as of 3-31-01) Total Submissions Tested by IHC "Downers" (fallen stock) 2309 2135 1895 548 643 713

45. US Surveillance: Current Direction l Regional Goals

46. US Regions for BSE Surveillance NW C SW SC SE NC NE E

47. US Regional Goals for BSE Surveillance - FY 2001 564 466 734 644 606 462 312 766

48. US Regional Goals for BSE Surveillance (2001) REGIONGOAL 2x OIE goals FY 99FY 2000FY 2001* NW56427134118 SW46625622668 C76615912060 SC7342811094250 NC60613524054 NE462331461122 E312263016 SE64419436751 * as of March 31, 2001

49. Increase of submissions l Down cattle: l aged; dairy vs. beef l condemns at slaughter l 3D/4D l Renderers l Remind VDLs to submit data

50. Surveillance Reminders l Submissions need: l obex l age of bovine l ID l clinical signs (or down) l 10-4 & supplemental l plant number l Questions call NVSL (515-663-7521)

51. Test Methodology l Histology l Immunohistochemistry l Western Blot l New tests: l Enfer (High throughput chemiluminescent ELISA - 3-4 hrs) l Prionics (modified WB - 8 hrs) l Biorad (Sandwich Immunoassay (3-4 hrs) l All need brain

52. Status of Cattle Imported into the US from the United Kingdom and Ireland (as of May 2, 2001) VT-3

53. Status of Cattle Imported into the US from other European countries in 1996-97 (as of May 2, 2001) 1 3 2

54. www.aphis.usda.gov/oa/bse

55. BSE Risk Assessment Harvard School of Public Health Tuskegee University

56. BSE Risk Assessment l Define scope l Describe potential pathways BSE infectivity into national herd or food supply l Characterize and quantify steps in pathways l Identify key steps for research or risk management

57. BSE Response Plan l First version early 1990's l Slightly revisions early 1996 l Major revisions 1996-98

58. BSE Prevention: Feed Ban l FDA Authority l Prohibited to feed most mammalian proteins to ruminants l Exceptions: l milk l blood l gelatin l plate waste l pure equine/pure porcine

59. BSE in Sheep: Research (Foster et. al.) BSE negative line positive line 6 negative 5 positive 1 clinical, BSE identified 2 clinical, atypical TSE oral

60. BSE in Sheep: Research Distribution of Infectivity brain spinal cord spleen blood-1 report intestine (PrPsc)

61. BSE in Sheep: European Situation l Exposure to contaminated MBM l Must differentiate from scrapie - mouse bioassay system (2-3 yrs) l Surveillance for natural cases l None to date - limited number assessed l Public Health Protection - SRM ban on sheep and goat tissues

62. Imported Sheep in Vermont l Two shipments imported from Belgium and Netherlands l August and November 1996 l 65 head total l Distribution: l 52 - Vermont farm 1 l 11 - Vermont farm 2 l 2 rams - New York farm

63. Imported Sheep in Vermont l Monitored since entry l Quarantined since 10-98 l 9 progeny sold prior to quar.

64. Imported Sheep in Vermont l USDA bought culls, sicks and picked up deads l Sampled and incinerated l Results: l Histology - vacuolated neurons, astrocytosis, neuronal degeneration l CE - blood positives l Western - 4 brain positives

65. Imported Sheep in Vermont l Test cannot differentiate "strains" or variants of scrapie from BSE l Mouse bioassay l 2-3 years l Named atypical (histology) TSE of foreign origin

66. Imported Sheep in Vermont l Owners asked to voluntarily depopulate - one agreed l Declaration of Extraordinary Emergency and Emergency declared on July 14, 2000 l Orders issued to seize sheep of 2 flocks

67. Imported Sheep in Vermont l Two owners went to court for a temporary restraining order (TRO) - July 2000 l Judge ruled in USDA's favor and did not grant TRO l Owners did not comply l Motion for order to comply and rule on merits

68. Imported Sheep in Vermont (continued) l Feb. 6, 2001 - Judge denied plaintiffs motion for summary judgment l Granted defendants motion for judgment and orders for compliance l Plaintiffs ordered to comply with Secretary's Declaration forthwith l Plaintiffs file motion for stay

69. Imported Sheep in Vermont (continued) l Federal District Court Judge denies motion for stay l Plaintiffs file motion for stay with Second Circuit Court l Motion denied l Sheep removed from farms week of March 19, 2001

70. Imported Sheep in Vermont (continued) l April 10, 2001 - Arguments in front of second circuit court l April 20, 2001 - Court rules appeal is moot

71. CONCLUSIONS l No BSE in US to date l Continue conservative approach l Continue and increase surveillance l Adjust as science and policy dictates