The transmissible spongiform encephalopathies and allergen vaccines.

The transmissible spongiform The transmissible spongiform encephalopathies and allergen encephalopathies and allergen

vaccinesvaccines

Allergenic products - summaryAllergenic products - summary

most allergen extracts are produced most allergen extracts are produced without any bovine components without any bovine components

mold extracts are stored and mold extracts are stored and propagated in culture media, some of propagated in culture media, some of which contain bovine components of which contain bovine components of uncertain originuncertain origin

the risks associated with these the risks associated with these contaminations are minimalcontaminations are minimal

TSE timeline (selective)TSE timeline (selective)

5/91: CBER letter to manufacturers5/91: CBER letter to manufacturers 12/93: FDA letters to manufacturers12/93: FDA letters to manufacturers 12/97: USDA expands list of banned countries to 12/97: USDA expands list of banned countries to

include all of Europeinclude all of Europe 4/00: CBER letter to manufacturers4/00: CBER letter to manufacturers 5/00: 1st memo to Allergen Manufacturers5/00: 1st memo to Allergen Manufacturers 7/00: TSEAC/VRBPAC (http://www.fda.gov/ 7/00: TSEAC/VRBPAC (http://www.fda.gov/

ohrms/dockets/ac/00/transcripts/3635t1.rtf)ohrms/dockets/ac/00/transcripts/3635t1.rtf) 8/00: 2nd memo to Allergen Manufacturers8/00: 2nd memo to Allergen Manufacturers

Risk assessmentRisk assessment

Quantify/estimate risk based onQuantify/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

CategoriesCategories I: high infectivityI: high infectivity (brain, spinal cord, eye)(brain, spinal cord, eye)

II: medium infectivityII: medium infectivity (ileum, lymph nodes, proximal (ileum, lymph nodes, proximal colon, spleen, tonsils, dura mater, pineal gland, placenta, colon, spleen, tonsils, dura mater, pineal gland, placenta, CSF, pituitary gland, adrenal gland)CSF, pituitary gland, adrenal gland)

III:III: low infectivitylow infectivity (distal colon, nasal mucosa, peripheral (distal colon, nasal mucosa, peripheral nerves, bone marrow, liver, lung, pancreas, thymus)nerves, bone marrow, liver, lung, pancreas, thymus)

IV: no detected infectivityIV: no detected infectivity (blood clot, feces, heart, (blood clot, feces, heart, kidney, mammary gland, milk, ovary, saliva, salivary gland, kidney, mammary gland, milk, ovary, saliva, salivary gland, seminal vesicle, serum, skeletal miscle, testis, thyroid gland, seminal vesicle, serum, skeletal miscle, testis, thyroid gland, uterus, fetal tissue, bile bone, cartilage, connective tissue, uterus, fetal tissue, bile bone, cartilage, connective tissue, hair, skin, urine)hair, skin, urine)

Special categoriesSpecial categories glycerolglycerol

• most glycerol in allergen extracts is of plant most glycerol in allergen extracts is of plant originorigin

• not considered to be infectiousnot considered to be infectious milkmilk

• not considered to be infectiousnot considered to be infectious gelatingelatin

• originally not considered to be infectiousoriginally not considered to be infectious• TSEAC now recommends against TSEAC now recommends against

parenteral useparenteral use

Estimating the infectivity of Estimating the infectivity of bovine-derived mediabovine-derived media

tissue LD50/gtissue LD50/g g tissue/cowg tissue/cow cows/lotcows/lot regional risk (per cow)regional risk (per cow) process reductionsprocess reductions medium LD50/lotmedium LD50/lot medium LD50/mLmedium LD50/mL

Media supplementsMedia supplements

No bovine No bovine componentscomponents• Proteose peptone 2Proteose peptone 2• Proteose peptone 3Proteose peptone 3• PeptaminPeptamin• Neurospora culture Neurospora culture

agaragar• Malt extract brothMalt extract broth

Bovine gelatin onlyBovine gelatin only

• PeptonePeptone

• Malt extract agarMalt extract agar

• YM Agar and BrothYM Agar and Broth

Media supplements (II)Media supplements (II)

Bovine milk onlyBovine milk only• NeopeptoneNeopeptone

• NZ AmineNZ Amine

• TryptoneTryptone

• TryptoseTryptose

• SaboraudSaboraud– Dextrose agarDextrose agar– Dextrose BrothDextrose Broth– Emmon’s modified (SDB)Emmon’s modified (SDB)

– Fluid mediumFluid medium

• Tryptic soy brothTryptic soy broth

• CasitoneCasitone

Media supplements (III)Media supplements (III)

Bovine muscle/organs/neural tissueBovine muscle/organs/neural tissue• PolypeptonePolypeptone

• Proteose peptoneProteose peptone

• Proteose peptone 4Proteose peptone 4

• Brain heart infusion Brain heart infusion

Estimating the infectivity of the Estimating the infectivity of the mold allergen extractmold allergen extract

medium LD50/mLmedium LD50/mL process reductions (dilutions)process reductions (dilutions) species barrierspecies barrier route barrierroute barrier annual US dose (mL)annual US dose (mL) LD50/yearLD50/year years/caseyears/case

Results - three scenariosResults - three scenarios

Use of uncertified media (from Category Use of uncertified media (from Category IV tissue) in mold propagationIV tissue) in mold propagation

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

Use of uncertified media (from Category Use of uncertified media (from Category I tissue) in mold seed stocksI tissue) in mold seed stocks

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

Tissue LD50/g 0.1g tissue/cow 750Cows/lot 2000Regional per cow risk 1.E-04Process reductions 1Medium LD50/lot 2.E+01Medium LD50/mL 3.E-07Mfr process reductions (dilutions) 0.3Species barrier 1Route barrier (SC) 4.1E-05Annual US dose (mL) 30000LD50/year 1.1E-07Years/case 18,500,000

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

Tissue LD50/g 1000g tissue/cow 750Cows/lot 2000Regional per cow risk 1.E-04Process reductions 1Medium LD50/lot 2.E+05Medium LD50/mL 6.E-03Mfr process reductions (dilutions) 0.08Species barrier 1Route barrier (SC) 4.1E-05Annual US dose (mL) 20320LD50/year 4.0E-04Years/case 5000

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

Tissue LD50/g 1.E+07g tissue/cow 750Cows/lot 2000Regional per cow risk 1.E-04Process reductions 1Medium LD50/lot 2.E+09Medium LD50/mL 2.E+01Mfr process reductions (dilutions) 0.00018Species barrier 1Route barrier (SC) 4.1E-05Annual US dose (mL) 30000LD50/year 4.2E-03Years/case 470

Allergenic products - summaryAllergenic products - summary

most allergen extracts are produced without most allergen extracts are produced without any bovine componentsany bovine components

mold extracts are stored and propagated in mold extracts are stored and propagated in culture media, some of which contain bovine culture media, some of which contain bovine components of uncertain origincomponents of uncertain origin

the risks associated with these the risks associated with these contaminations are minimalcontaminations are minimal

manufacturers have been directed to assure manufacturers have been directed to assure that all bovine components be certified to be that all bovine components be certified to be from approved sourcesfrom approved sources

In July 2000, TSEAC/VRBPAC suggested that the master In July 2000, TSEAC/VRBPAC suggested that the master seed stocks of vaccines need not be rederived to reduce seed stocks of vaccines need not be rederived to reduce the likelihood of TSE transmission. The joint committee the likelihood of TSE transmission. The joint committee came to this conclusion after agreeing that the risk of TSE came to this conclusion after agreeing that the risk of TSE transmission was remote, and the risks associated with transmission was remote, and the risks associated with rederivation of the master seed stocks of bacterial rederivation of the master seed stocks of bacterial vaccines were substantial.vaccines were substantial.

In contrast, CBER does not believe that there are any risks In contrast, CBER does not believe that there are any risks to product efficacy or safety associated with the to product efficacy or safety associated with the rederivation of the master stocks of mold strains used for rederivation of the master stocks of mold strains used for

allergenic extracts.allergenic extracts.

Question asked of APAC in 2001Question asked of APAC in 2001

Does the Committee agree with CBER that Does the Committee agree with CBER that master stocks of mold strains used for master stocks of mold strains used for allergenic extracts should be rederived to allergenic extracts should be rederived to reduce the theoretical possibility of TSE reduce the theoretical possibility of TSE transmission?transmission?

As of March 2002…As of March 2002…

The theoretical concerns regarding TSE The theoretical concerns regarding TSE in allergen extracts have been resolvedin allergen extracts have been resolved

18 Countries with BSE in Native Cattle18 Countries with BSE in Native Cattle[yr first reported & approx. total cases through 2001 per OIE Dec 2001][yr first reported & approx. total cases through 2001 per OIE Dec 2001]

UKUK 1986 (>180 000) [1443 1986 (>180 000) [1443 cases in 2000; >688 in cases in 2000; >688 in 2001]2001]

IrelandIreland 1989 (721)1989 (721)

SwitzerlandSwitzerland 1990 (390)1990 (390)

FranceFrance 1991 (410)1991 (410)

PortugalPortugal 1994 (581)1994 (581)

BelgiumBelgium 1997 (44) 1997 (44)

NetherlandsNetherlands 1997 (19)1997 (19)

LuxembourgLuxembourg 1997 (1)1997 (1)

LiechtensteinLiechtenstein 1998 (2)1998 (2)

Denmark Denmark 2000 (5)2000 (5)

Germany Germany 2000 (112)2000 (112)

Spain Spain 2000 (66)2000 (66)

Italy Italy 2000 (27)2000 (27)

Greece Greece 2001 (1)2001 (1)

Czech Repub Czech Repub 2001 2001 (2)(2)

Slovakia Slovakia 2001 (1)2001 (1)

Japan Japan 2001 (3)2001 (3)

Slovenia Slovenia 2001 (?1)2001 (?1)

USDA/Animal and Plant Health USDA/Animal and Plant Health Inspection Service websiteInspection Service website

http://www.aphis.usda.gov/oa/bse/http://www.aphis.usda.gov/oa/bse/