# Presentation: 557497

## The transmissible spongiform encephalopathies and allergen vaccines

## Allergenic products - summary

*most allergen extracts are produced without any bovine components *
*mold extracts are stored and propagated in culture media, some of which contain bovine components of uncertain origin*
*the risks associated with these contaminations are minimal*

## TSE timeline (selective)

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

## Risk assessment

*Quantify/estimate risk based on*
*animal source (time, place)*
*tissue*
*processing/dilutions*
*protein doses associated with IT*
*route-specific risks*

## Categories

*I: high infectivity** **(brain, spinal cord, eye)*
*II: medium infectivity** **(ileum, lymph nodes, proximal colon, spleen, tonsils, dura mater, pineal gland, placenta, CSF, pituitary gland, adrenal gland)*
*III:** **low infectivity** **(distal colon, nasal mucosa, peripheral nerves, bone marrow, liver, lung, pancreas, thymus)*
*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)*

**Notes:**
 The four tissue-risk categories are based on two kinds of information:  those tissues actually demonstrated to be infectious in cattle with natural or experimental BSE in the UK MAFF study (brain, cord, [and adjacent trigeminal and dorsal root ganglia], eye, ileum [experimental only] and sternal bone marrow [probably artifactual contaminant], plus tissues known from scrapie to be consistently or occasionally infectious, so nobody wants to take a chance.  There are three limitations to all the studies of distribution of infectivity in tissues of animals and people with TSEs:  1)  Sensitivity of animal assays.  E.g., mice are 1000x less sensitive than cows to BSE agent so they don't detect small amounts of infectivity.  2)  Small inoculum size--max 0.05 ml into a rodent i.c. and 0.03 is the more usual volume tested.  So only a small amount of tissue is assayed.  3)  In some organs infectivity may be present only inconsistently, at least in amounts detectable in the animal assay used.

## Special categories

*glycerol*
*most glycerol in allergen extracts is of plant origin*
*not considered to be infectious*
*milk*
*not considered to be infectious*
*gelatin*
*originally not considered to be infectious*
*TSEAC now recommends against parenteral use*

**Notes:**
Since glycerol is a distilled product....

Gelatin, subject of Guidance issued in September 1997

## Estimating the infectivity of bovine-derived media

*tissue LD50/g*
*g tissue/cow*
*cows/lot*
*regional risk (per cow)*
*process reductions*
*medium LD50/lot*
*medium LD50/mL*

## Media supplements

*No bovine components*
*Proteose peptone 2*
*Proteose peptone 3*
*Peptamin**	*
*Neurospora culture agar**	*
*Malt extract broth*

*Bovine gelatin only*
*Peptone**	*
*Malt extract agar*
*YM Agar and Broth*

## Media supplements (II)

*Bovine milk only*
*Neopeptone**	*
*NZ Amine**	*
*Tryptone**	*
*Tryptose**	*

*Saboraud*
*Dextrose agar**	*
*Dextrose Broth*
*Emmon’s modified (SDB)*
*Fluid medium**	*
*Tryptic soy broth*
*Casitone**	*

## Media supplements (III)

*Bovine muscle/organs/neural tissue*
*Polypeptone**	*
*Proteose peptone**	*
*Proteose peptone 4**	*
*Brain heart infusion *

## Estimating the infectivity of the mold allergen extract

*medium LD50/mL**	*
*process reductions (dilutions)**	*
*species barrier**	*
*route barrier**	*
*annual US dose (mL)**	*
*LD50/year**	*
*years/case*

## Results - three scenarios

*Use of uncertified media (from Category IV tissue) in mold propagation*
*Use of uncertified media (containing gelatin) in mold seed stocks*
*Use of uncertified media (from Category I tissue) in mold seed stocks*

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

**Notes:**
Lot size is variable: on the order of 100,000 L (hence a about factor of 10^8 here). This factor also incorporates the dilution of the media supplement in the actual media used.

Humans: 1 million years

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

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

**Notes:**
Notice here that that, because this media is present in the master seed stock but not introduced farther in the processing, there is a significant dilution effect - over 5000-fold. However, because the media in question was derived from category I tissue, the starting dose is many logs higher than in our previous calculations. In spite of this, and in spite of our very conservative assumption that there is no species barrier (which there almost certainly is)  we still calculate that nearly five centuries will pass before we see a case of human transmission from these products.

## Allergenic products - summary

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

*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.** *	*	*

## 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?*

## As of March 2002...		

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

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

***UK******  ******1986 (>180 000) [1443 cases in 2000; >688 in 2001]***
***Ireland****** ******1989 (721)***
***Switzerland****** ******1990 (390)***
***France****** ******1991 (410)***
***Portugal****** ******1994 (581)***
***Belgium****** ******1997 (44) ***
***Netherlands****** ******1997 (19)***
***Luxembourg****** ******1997 (1)***
***Liechtenstein****** ******1998 (2)***

***Denmark ******2000 (5)***
***Germany ******2000 (112)***
***Spain ******2000 (66)***
***Italy ******2000 (27)***
***Greece ******2001 (1)***
***Czech Repub ******2001 (2)***
***Slovakia ******2001 (1)***
***Japan ******2001 (3)***
***Slovenia ******2001 (?1)***

**Notes:**
This position was taken despite the fact that far more cases of BSE have been reported in the UK than in other BSE countries (almost 700 last year)—and that may seem paradoxical.  But, since other European BSE countries (countries identified by the USDA as having BSE or substantial BSE risk in native cattle) instituted measures to protect human food much later than did the UK (if at all), we concluded that time spent in those countries must be considered to pose an unknown but significant risk that was not mitigated after 1996 and that time spent there from 1980 until the present should be considered in determining the suitability of blood donors.  We intend to reconsider frequently our recommendations to defer donors who spent time in various BSE countries as more information becomes available about the estimated numbers of people who might have been infected with the BSE agent and about the potential of human blood to transmit vCJD.  We also expect to consider the effectiveness of measures taken by various countries to keep the BSE agent out of their food supplies in deciding when risk of human exposure has been sufficiently mitigated to warrant a change in blood donor deferral policy. 
Our current policy acknowledges that, by the end of 1996, efforts of the UK were sufficient to reduce the risk of further human exposures to a level presumably less than the risk in other BSE countries that, while recognizing smaller numbers of cattle with BSE, had not fully implemented similar effective measures to protect the food supply.  That FDA policy has not been universally endorsed, and some blood programs recently elected to defer donors who spent three months or more in the UK from 1980 through the present time.  We continue to believe that current UK measures to protect human food from contamination with the BSE agent have markedly reduced opportunities for human exposure and that the small additional reduction in theoretical risk afforded by deferring donors who spent time in the UK after 1996 does not justify the probable substantial loss of otherwise suitable donors.  However, we appreciate ongoing concern about the effectiveness of UK measures to protect human food, and we believe it to be in the public interest to review those measures.

## USDA/Animal and Plant Health Inspection Service website

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