1. The transmissible spongiform encephalopathies and allergen vaccines

2. Allergenic products - summary n most allergen extracts are produced without any bovine components n mold extracts are stored and propagated in culture media, some of which contain bovine components of uncertain origin n the risks associated with these contaminations are minimal

3. TSE timeline (selective) n 5/91: CBER letter to manufacturers n 12/93: FDA letters to manufacturers n 12/97: USDA expands list of banned countries to include all of Europe n 4/00: CBER letter to manufacturers n 5/00: 1st memo to Allergen Manufacturers n 7/00: TSEAC/VRBPAC (http://www.fda.gov/ ohrms/dockets/ac/00/transcripts/3635t1.rtf) n 8/00: 2nd memo to Allergen Manufacturers

4. Risk assessment n Quantify/estimate risk based on animal source (time, place)animal source (time, place) tissuetissue processing/dilutionsprocessing/dilutions protein doses associated with ITprotein doses associated with IT route-specific risksroute-specific risks

5. Categories n I: high infectivity (brain, spinal cord, eye) n II: medium infectivity (ileum, lymph nodes, proximal colon, spleen, tonsils, dura mater, pineal gland, placenta, CSF, pituitary gland, adrenal gland) n III: low infectivity (distal colon, nasal mucosa, peripheral nerves, bone marrow, liver, lung, pancreas, thymus) n IV: no detected infectivity (blood clot, feces, heart, kidney, mammary gland, milk, ovary, saliva, salivary gland, seminal vesicle, serum, skeletal miscle, testis, thyroid gland, uterus, fetal tissue, bile bone, cartilage, connective tissue, hair, skin, urine)

6. Special categories n glycerol most glycerol in allergen extracts is of plant originmost glycerol in allergen extracts is of plant origin not considered to be infectiousnot considered to be infectious n milk not considered to be infectiousnot considered to be infectious n gelatin originally not considered to be infectiousoriginally not considered to be infectious TSEAC now recommends against parenteral useTSEAC now recommends against parenteral use

7. Estimating the infectivity of bovine-derived media n tissue LD50/g n g tissue/cow n cows/lot n regional risk (per cow) n process reductions n medium LD50/lot n medium LD50/mL

8. Media supplements n No bovine components Proteose peptone 2Proteose peptone 2 Proteose peptone 3Proteose peptone 3 PeptaminPeptamin Neurospora culture agarNeurospora culture agar Malt extract brothMalt extract broth n Bovine gelatin only PeptonePeptone Malt extract agarMalt extract agar YM Agar and BrothYM Agar and Broth

9. Media supplements (II) n Bovine milk only NeopeptoneNeopeptone NZ AmineNZ Amine TryptoneTryptone TryptoseTryptose SaboraudSaboraud –Dextrose agar –Dextrose Broth –Emmon’s modified (SDB) –Fluid medium Tryptic soy brothTryptic soy broth CasitoneCasitone

10. Media supplements (III) n Bovine muscle/organs/neural tissue PolypeptonePolypeptone Proteose peptoneProteose peptone Proteose peptone 4Proteose peptone 4 Brain heart infusionBrain heart infusion

11. Estimating the infectivity of the mold allergen extract n medium LD50/mL n process reductions (dilutions) n species barrier n route barrier n annual US dose (mL) n LD50/year n years/case

12. Results - three scenarios n Use of uncertified media (from Category IV tissue) in mold propagation n Use of uncertified media (containing gelatin) in mold seed stocks n Use of uncertified media (from Category I tissue) in mold seed stocks

13. Use of uncertified media (derived from Category IV tissue) in mold propagation

14. Use of uncertified media (containing gelatin) in mold seed stocks

15. Use of uncertified media (derived from Category I tissue) in mold seed stocks

16. Allergenic products - summary n most allergen extracts are produced without any bovine components n mold extracts are stored and propagated in culture media, some of which contain bovine components of uncertain origin n the risks associated with these contaminations are minimal n manufacturers have been directed to assure that all bovine components be certified to be from approved sources

17. In July 2000, TSEAC/VRBPAC suggested that the master seed stocks of vaccines need not be rederived to reduce the likelihood of TSE transmission. The joint committee came to this conclusion after agreeing that the risk of TSE transmission was remote, and the risks associated with rederivation of the master seed stocks of bacterial vaccines were substantial. In contrast, CBER does not believe that there are any risks to product efficacy or safety associated with the rederivation of the master stocks of mold strains used for allergenic extracts.

18. Question asked of APAC in 2001 Does the Committee agree with CBER that master stocks of mold strains used for allergenic extracts should be rederived to reduce the theoretical possibility of TSE transmission?

19. As of March 2002… n The theoretical concerns regarding TSE in allergen extracts have been resolved

20. 18 Countries with BSE in Native Cattle [yr first reported & approx. total cases through 2001 per OIE Dec 2001] l UK 1986 (>180 000) [1443 cases in 2000; >688 in 2001] l Ireland 1989 (721) l Switzerland 1990 (390) l France 1991 (410) l Portugal 1994 (581) l Belgium 1997 (44) l Netherlands 1997 (19) l Luxembourg 1997 (1) l Liechtenstein 1998 (2) l Denmark 2000 (5) l Germany 2000 (112) l Spain 2000 (66) l Italy 2000 (27) l Greece 2001 (1) l Czech Repub 2001 (2) l Slovakia 2001 (1) l Japan 2001 (3) l Slovenia 2001 (?1)

21. USDA/Animal and Plant Health Inspection Service website http://www.aphis.usda.gov/oa/bse/