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Bovine Spongiform Encephalopathy (BSE)

BSE is a progressive neurological disorder of cattle; its symptoms are similar to a disease of sheep, called scrapie. BSE has been called "mad cow disease". BSE and scrapie both result from infection with a very unusual infectious agent. As of July 2000, more than 176,000 cases of BSE were confirmed in Great Britain in more than 34,000 herds of cattle. The epidemic peaked in January 1993 at almost 1,000 new cases per week. The outbreak may have resulted from the feeding of scrapie-containing sheep meat-and-bone meal to cattle. There is strong evidence and general agreement that the outbreak was amplified by feeding meat-and-bone meal prepared from cattle to young calves.

      For questions and inquiries call: 1-800-835-4709 or 1-301-827-2000.

Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products - 1/9/2002 - (PDF), (Text)

   Questions and Answers on "Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products"

MMWR Notice to Readers: PHS Recommendations for the Use of Vaccines
Manufactured with Bovine-Derived Materials

Table of Contents
   Introduction: Recommendations for Use of Vaccines Manufactured with Bovine-Derived Materials
   Transcripts of 27 July, 2000, Joint Meeting of the Transmissible Spongiform Encephalopathy and Vaccines and Related Biologicals Advisory Committees    CBER and FDA Guidance Documents on Sourcing of Bovine-Derived Materials   Vaccines and Vaccinations: CDC / NIP / NVP Website
   Overview of Vaccine Manufacturing   Estimating Risk for vCJD in Vaccines Using Bovine-Derived
Materials
   Questions and Answers
   Current list of Vaccines Using Bovine-Derived Materials from countries on the USDA's BSE list or from Unknown Countries    Countries/Areas Affected With Bovine Spongiform Encephalophathy [CFR 94.18] - Animal and Plant Health Inspection Service (APHIS), US Department of Agriculture
   Related Links

Recommendations for the Use of Vaccines Manufactured with Bovine-Derived Materials Bovine-derived materials have traditionally been used in the manufacture of many biological products, including vaccines. Bovine spongiform encephalopathy (BSE), so-called "mad-cow disease," was first recognized in the United Kingdom (UK) in the 1980s(1). The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) has been concerned about eliminating any potential for contamination of biological products with the BSE agent. This concern was heightened by the appearance of the human transmissible spongiform encephalopathy known as variant Creutzfeldt-Jakob Disease (vCJD, also referred to as new-variant CJD) in the UK in 1996; vCJD has been attributed, among other possibilities, to eating beef products from cattle infected with the agent of BSE (2). To date, there are no reports of BSE contamination of pharmaceutical or biological products. To minimize the possibility of contamination in such products, the FDA, in 1993 (published in the Federal Register on August 29, 1994, 59 FR 44591), and again in 1996, recommended that manufacturers not use materials derived from cattle that were born, raised, or slaughtered in countries where BSE is known to exist; the FDA referred manufacturers to the listing of such countries that is maintained by the U.S. Department of
Agriculture (USDA)(3).

In 1991 the USDA list included only countries and other regions in which BSE was known to exist, such as France, Great Britain, Northern Ireland, the Republic of Ireland, Oman, and Switzerland. In 1998, the USDA expanded the list to include countries and other regions in which BSE had not been documented but in which import requirements were less restrictive than requirements that would be acceptable for import into the United States or in which surveillance was inadequate. Thus, all European countries, even those that have had no reported BSE cases, are currently on the USDA list, which is published in the Code of Federal Regulations, title 9, part 94 (9 C.F.R. part 94).

In 2000, CBER learned that its recommendations regarding the sourcing of bovine materials for the manufacture of vaccines had not been followed in at least one instance. As a result of this finding, CBER requested all vaccine manufacturers to review the source for all bovine-derived materials used in the manufacture of their vaccines. This review identified additional vaccines manufactured with bovine-derived materials that had been obtained from European countries on the USDA list.

No evidence exists that any case of vCJD has resulted from the administration of a vaccine product(4), and no cases of vCJD have been reported in the United States. To evaluate the risk of disease that might result from a vaccine manufactured with a process that utilizes bovine materials potentially contaminated with the BSE agent, CBER conducted risk assessments and convened a special joint meeting of the Transmissible Spongiform Encephalopathy Advisory Committee and the Vaccines and Related Biological Products Advisory Committee on July 27, 2000. In assessing the potential risk of vaccines, CBER and the joint Committees considered: (1) the likelihood that any cattle that were used might be infected (i.e., the time period and country of origin) and animal husbandry procedures; (2) the amount of bovine material that might be present in the final vaccine; and (3) the inherent infectivity of the various types of bovine materials that were used. The joint Committees concluded that the risk of vCJD posed by vaccines in the scenarios that were presented was theoretical and remote. They also noted that the benefits of vaccination far outweigh any remote risks of vCJD. The joint  Committees made several recommendations.

Bovine-derived materials used in the routine production of vaccines that are sourced from countries on the USDA list should be replaced with bovine-derived materials from countries not on the USDA list.   Working bacterial and viral seed banks and working cell banks that were established using bovine-derived materials sourced from countries on the USDA list should be re-derived with bovine-derived materials from countries not on the USDA list. However, master bacterial and viral seed banks established in a similar manner do not need to be re-derived; the potential risk presented by the master seed banks is even more remote than that presented by the working seed banks and is outweighed by the risk of altering the bacterial or viral vaccine through re-derivation. These issues are of public interest and, therefore, the public should be informed about the safety of vaccines that used materials sourced from countries on the USDA list, and the assessment of the nature of any risk of vCJD from such vaccines.

As noted above, there is no evidence that any case of vCJD has been caused by or is related to vaccines manufactured with bovine-derived materials obtained from countries in which BSE or a significant risk of BSE exists (i.e., countries on the USDA list), and thus the risk of vCJD is theoretical. The joint Committees' recommendation to replace such bovine-derived materials with bovine-derived materials from countries not on the USDA list is a precautionary measure intended to minimize even the remote risk of vCJD from vaccines.

The vaccines that use bovine-derived materials from countries on the USDA list include: Aventis Pasteur Inc.'s Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccine, Tripedia (the pertussis components manufactured by The Research Foundation for Microbial Diseases of Osaka University ("BIKEN") for use in Tripedia are the only components of the vaccine manufactured with bovine-derived materials from a country on the USDA list); Aventis Pasteur, S.A.'s Haemophilus Influenzae Type b Conjugate Vaccine, ActHIB (ActHIB is also marketed as OmniHIB by SmithKline Beecham Pharmaceuticals); North American Vaccine Inc.'s DTaP Vaccine, Certiva (the tetanus toxoid manufactured by Statens Seruminstitut for use in Certiva is the only component of the vaccine manufactured with bovine- derived materials from a country on the USDA list); SmithKline Beecham Biological's DTaP Vaccine, Infanrix (the diphtheria toxoid manufactured by Chiron Behring GmbH & Co. for use in Infanrix is the only component of the vaccine manufactured with bovine-derived materials from a country on the USDA list), Hepatitis A Vaccine, Havrix, and the Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine, TWINRIX.

In some other cases, the source of the bovine-derived materials is unknown, in part because manufacturers have not always maintained or had access to records of the source of such materials, particularly in the 1980s and early 1990s, before the connection between BSE and vCJD was first suggested. Vaccines that use bovine-derived material of unknown origin obtained in 1980 or thereafter (the current best estimate is that BSE first emerged in 1980) include: Aventis Pasteur, S.A.'s Polio Vaccine, Inactivated, IPOL and Lederle Laboratories' Pneumococcal Vaccine, Polyvalent, PNU-IMUNE 23.

Vaccines using bovine-derived materials from a country on the USDA list or from an unknown source to manufacture only the master seed are not listed above; the joint Advisory Committees indicated that master seeds need not be re-derived. Additional information on such vaccines can be obtained upon request.

The FDA has requested that manufacturers of vaccines using bovine-derived materials obtained from countries on the USDA list or from an unknown source replace these materials with materials from countries not on the USDA list, consistent with the recommendations of the joint Advisory Committees. The manufacturers have agreed to fully implement these changes. Indeed, several manufacturers initiated a number of these changes before the July 27, 2000, joint Advisory Committee meeting. FDA anticipates that the majority of these changes will be completed within one year. The FDA will revise the list of vaccines using bovine-derived materials from countries on the USDA list or from an unknown source as the requested changes are implemented and the vaccines come to market (see section VIII for the current listing).

The Public Health Service (PHS) recommends that all children and adults continue to be immunized according to current immunization schedules(5). At the present time, the PHS has no preference for using one licensed vaccine product over another based on the source of bovine-derived materials used in vaccine production. The recommendations of the FDA Advisory Committees and the actions of the FDA are, as described, precautionary and have been taken to reduce even the remote potential of a risk of vCJD and to maintain public confidence in the safety of vaccines. Failure to obtain the recommended vaccinations with licensed vaccines poses a real risk of serious disease.

References

   Wells G.A.H. et al. 1987. A novel progressive spongiform encephalopathy in cattle. Veterinary Record 121:419-420    Spongiform Encephalopathy Advisory Committee of UK statement of 20 March 1996 (http://www.defra.gov.uk/)    USDA 9 CFR part 94.18
   P. D. Minor, R.G. Will and D. Salisbury. 2000. Vaccines and
variant CJD. Vaccine 19:409-410.
   http://www.cdc.gov/nip/recs/child-schedule.PDF;
http://www.cdc.gov/nip/recs/adult-schedule.pdf

Table of Contents

Transcripts of 27 July, 2000, Joint Meeting of the Transmissible Spongiform Encephalopathy and Vaccines and Related Biologicals Products Advisory Committees On July 27, 2000, the Center for Biologics Evaluation and Research (CBER) convened a special joint meeting of the Transmissible Spongiform Encephalopathy and the Vaccines and Related Biological Products Advisory Committees. The purpose of the joint meeting was to ask these committees to consider the potential risks and possible actions that should be taken with regard to licensed and investigational vaccines that contain bovine derived material sourced from countries on the current USDA list of BSE-risk countries. The transcripts of this meeting and copies of the briefing materials provided to the committee members can be found at: http://www.fda.gov/ohrms/dockets/ac/cber00.htm

CBER and FDA Guidance on Sourcing of Bovine Derived Raw Materials Letters to manufacturers and other guidance documents are part of the mechanism by which regulated industry and the public are informed about safety issues and expectations of the FDA regarding the development, testing and licensure of vaccines. Although these documents do not have the force of law, they do represent the current thinking of the agency on licensure and control of FDA regulated  products.

The following is a summary of the guidance documents and letters from FDA and CBER which relate to the potential for contamination of products with the agent that causes BSE.

   Dear Biologic Product Manufacturer
In a May 1991 letter to manufacturers of biological products, CBER requested information on sourcing and control of animal substances. Specifically CBER asked for a list of materials of bovine origin used in the product or in manufacture of the product, as well as supplier information and a description of controls to assure and document the health and origin of the animals used.   Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics In a letter to manufacturers in July 1993 CBER asked manufacturers to review the May 1993 revision of the 1987 document "Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics". In the revised version of this document CBER indicated that manufacturers should be able to provide detailed information on cell culture history, isolation, media, identity, and adventitious agent testing of cell lines used in the production of biological products.

   Manufacturers of FDA-regulated Products
Since 1993 the FDA has recommended that bovine-derived material from cattle which have resided in or originated from countries where BSE has been diagnosed not be used for the manufacture of FDA-regulated products intended for administration to humans. This letter referred to a list of countries where BSE is known to exist - France, Great Britain (including the Falklands), Northern Ireland, Oman and Switzerland. This list is maintained by the USDA. The USDA has the authority to restrict the importation of certain animals, birds, poultry, animals by-products, hay and straw into the US in order to prevent the introduction of various animal diseases including BSE.  Letter to Manufacturers of FDA-regulated Drug/Biological/Device Products

In 1996 following the appearance of vCJD CBER recommended that manufacturers take whatever steps necessary to ensure they are not using bovine material from cattle born, raised or slaughtered in BSE-countries. At that time the BSE-list included France, Great Britain and the Falklands, Northern Ireland, the Republic of Ireland, Oman, Switzerland and Portugal.

   Guidance for Industry - The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use In September 1997 following an April 1997 TSE advisory committee review FDA issued a guidance document for industry addressing the sourcing and processing of gelatin to reduce the potential risk of transmission of BSE through FDA-regulated products for human use.
 
   1998 USDA Interim Rule on Import Restrictions of Ruminant Material from Europe (FR 63(3):406-408, 1/6/98) In January, 1998, the USDA updated the list of BSE-countries to  include not only those countries where BSE was known to exist but to include countries where no case of BSE had been identified but which the USDA believed had less restrictive import requirements than the US and/or inadequate surveillance. This expansion applied all the USDA ruminant and import restrictions to the whole of Europe, including those countries where BSE had not been shown to exist.

   Letter to Manufacturers of Biological Products: Recommendations Regarding Bovine Spongiform Encephalopathy - (Text), (PDF) In April 2000 CBER sent a letter to manufacturers requesting that ruminant derived material from Europe not be used in the manufacture of FDA-regulated products for humans.

Vaccines and Vaccinations
For more information on the US vaccination program and on vaccine preventable disease, please visit the following web sites:

CDC - Public Health Achievements

Achievements in Public Health, 1900-1999 Impact of Vaccines
Universally Recommended for Children -- United States, 1990-1998

CDC - National Immunization Program

Current list of vaccines using bovine-derived materials from countries on the USDA's BSE list or from unknown countries Vaccines that use bovine-derived materials from countries on the USDA list include:

   Aventis Pasteur, Inc.'s Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccine, Tripedia
   Aventis Pasteur, S.A.'s Haemophilus Influenzae Type b Conjugate Vaccine, ActHIB (ActHIB is also marketed as OmniHIB by SmithKline Beecham Pharmaceuticals)
   North American Vaccine Inc.'s DTaP Vaccine, Certiva
   SmithKline Beecham Biological's DTaP Vaccine, Infanrix
   SmithKline Beecham Biological's Hepatitis A Vaccine, Havrix.
   SmithKline Beecham Biological's combined Hepatitis A Vaccine and Hepatitis B (Recombinant) Vaccine, TWINRIX.

Vaccines that use bovine-derived materials of unknown geographical origin include:

   Aventis Pasteur, S.A.'s Polio Vaccine, Inactivated, IPOL
   Lederle Laboratories' Pneumococcal Vaccine, Polyvalent, PNU-IMUNE 23.

1This information will be periodically updated to reflect the most current status.

Related links
Center for Veterinary Medicine BSE

FDA BSE

Center for Disease Control and Prevention (CDC) BSE

USDA Animal and Plant Health Inspections Services (APHIS) BSE

Last Updated: 1/9/2003
 

Fetal calf serum used to derive viral seed and cell banks

Fetal calf serum from the United Kingdom was used in the production of certain viral seeds and cell banks. The calf serum that was used was produced in the mid-1980s, when the BSE epidemic was just getting underway in the UK (5). The U.S. Department of Agriculture estimated the incidence of BSE in adult cattle at about 1 in 200 at that time(6). [Although many fewer cattle were observed to suffer from mad cow disease at that time, the long incubation time for the disease means that more cattle were infected than appeared diseased.] Since fetal calf serum was used in the production of the cell and viral seed banks, it is necessary to address the question of maternal-fetal transmission. Whether there is mother to fetus transmission of BSE is still unknown. One study may be interpreted as indicating that maternal-fetal transmission occurs at a rate of approximately 10%; i.e., that the calves of one of ten infected mothers may become infected with the BSE agent (7). However, other data indicate that maternal-fetal transmission does not occur or, if it does occur, it is below this 10% rate (8). As noted above, the U.S. Department of Agriculture estimates that, during the mid 1980s, approximately 1 in 200 cows in the United Kingdom was infected with BSE. Assuming that the rate of transmission from mother to fetus is 10% we would then estimate that 1 in 2000 fetal calves would have been infected.

When fetal calf serum is manufactured, the sera from approximately 1500 calves are pooled together. If 1 in 2000 calves is infected, it is likely that any given serum pool is infected. As mentioned above, although no infectivity has been observed with serum, there are limits to detectability. These experiments only rule out an infectivity that is greater than 1 infectious unit per milliliter (mL) of blood (3,9,10). Although serum is listed as category IV, we are using the highest estimate consistent with infectivity experiments. In the following risk estimate, we assume that the serum of an infected fetal calf can contain up to 1 infectious unit per mL.

In our risk calculation, we assume that the number of infectious BSE units that enters the vaccine production process is equal to the number of infectious units that remain in the vaccine at the end; that is, that the risk for vCJD is the input number of infectious units divided by the number of doses of vaccine that is in the batch. Thus, the risk estimate does not account for any purification step that might be present in the viral vaccine manufacturing process; although there are steps that probably remove infectivity, these are not considered in our risk estimate since none of the manufacturing steps have been demonstrated to remove BSE infectivity. We have also assumed that the BSE agent does not replicate during the manufacturing process; this is a reasonable assumption, bolstered by the many failed attempts to propagate the BSE agent in cell culture (11). The BSE infectivities that are estimated in Table I are derived from data using direct intra-cerebral inoculation (direct injection of the material into the brain). Vaccines are given intramuscularly, a less efficient route of transmitting the disease. In our risk estimate, we have allowed a factor of 200 for reduced transmission by the intramuscular route.

In general, there is a species barrier for the transmissible spongiform encephalopathies; that is, it is easier to infect the same species of animal than another species (for example, bovine material is more infectious for cows than it is for other animals, such as mice) (3,4). The species barrier from cows to humans is not known; in our calculations, we will therefore assume that there is none.

Given these assumptions, we can estimate the risk for vCJD from fetal calf serum (FCS) being used to prepare a viral working seed as the product of four separate risk factors. The level of BSE agent in the serum of an infected calf is estimated at 1 infectious unit per mL. Approximately 1 infected calf is present in each pool, deriving from approximately 1500 calves, of fetal calf serum. The infectivity of the pooled FCS is thus diluted to 1/1500 infectious units per mL (ca. 6.7 x 10-4 infectious units/mL). The amount of FCS that was used to produce a vial of a working viral seed is approximately 4 mL, and the number of doses of vaccine coming from that batch is approximately 500,000. The risk for acquiring vCJD is therefore:

The number of infected calves in each pool

1/1500

       Multiplied by

 

The number of infectious units per mL of serum

1

       Multiplied by

 

The number of mLs of serum used

4

       Divided by

 

The number of doses of vaccine

500,000

       Divided by

 

The reduction in infectivity related to the route of administration

200

This yields a final risk estimate for vCJD of approximately 2.5 per 100 billion or 1 in 40 billion doses of vaccine [(1/1500) x 1 x 4 x (1/500,000) x (1/200)]. This level of risk would correspond to one case of vCJD arising every 5,000 years (assuming two doses per child) when vaccinating the entire birth cohort of the Unites States (four million children). Because of the assumptions that were used, this is an overestimate of the risk, and the true risk is likely to be significantly less. The risk that would be calculated for the use of a master seed that was prepared with fetal calf serum is again considerably less, due to an additional dilution that attends the preparation of the working seed from the master seed.

Beef broth used to manufacture a bacterial vaccine: a bacterial toxoid as an example

The potential risk of vCJD from a bacterial vaccine that used bovine-derived material in the nutrient broth to grow the bacterial strain during vaccine production is as follows. In the example that we are using, tissue derived from a single cow is used to prepare the fermentation broth. For this estimate, the incidence of BSE in European cows is taken to be 1 in 10,000. This value was derived by multiplying the average BSE rate in this region over the last five years by a factor of ten (1) to account for any uncertainty in the actual rates. The nutrient medium that is used to grow the bacteria for the vaccine contains approximately 750 grams of skeletal muscle (a Category IV material) and 200 grams of a pancreatic extract (a Category III material); see Table I. Because the broth is autoclaved (heated at high temperature), some of its potential infectivity is lost; a reduction factor of 20 is assigned to the autoclaving process(2).

The risk, per dose of vaccine, for vCJD from a vaccine using a beef/pancreatic extract can be calculated as the product of the risk of using an infected cow (1 in 10,000) times the inherent risk of the bovine material after correction for the autoclaving process (approximately 1000 units; [200 grams of Category III material is estimated to contain no more than 20,000 infectious units and the 750 grams of Category IV material no more than 75 infectious units (20, 075 units total); the autoclaving process reduces this infectivity to approximately 1000 units]), divided by the number of doses that are in a batch of vaccine (approximately 1 million), corrected for the route of administration (a reduction factor of 200).

Risk of an infected cow

1/10,000

       Multiplied by

 

Amount of infectious material

1000 units

       Divided by

 

The number of vaccine doses

1,000,000

       Divided by

 

The reduction in infectivity related to the route of administration

200

(1/1,000,000) x (1/200)]. A second scenario can also be considered, namely one in which a small amount of neural tissue inadvertently might contaminate the beef broth. We consider a 0.01% contamination with neural tissue. This would increase the amount of infectious material from 1000 units to 50,000 units, raising the total risk to 1 in 40 million. Because of the overestimates that were used in the risk calculation, the true risk is likely to be significantly less.

Potential sources of error

In estimating the risk of BSE contamination, it is important to note that each risk factor carries its own uncertainty. The overall risk, which is the product of these factors, compounds these uncertainties. For example, we have assumed no species barrier and no purification effect. The actual risk could be 10 to 1,000 fold lower, but probably no greater. On the other hand, we have assumed a 200-fold reduction due to an intramuscular route of administration. In fact, this risk could be 10-fold greater or 10-fold lower. Finally, in the case of viral vaccines, and based on experiments with analogous cell lines, we have assumed that BSE cannot replicate in cell cultures that were used. These uncertainties must be considered in order to correctly interpret the risk of BSE in viral vaccines. These calculations are not a formal risk assessment, but an attempt to estimate risk based on information currently available.

It should be noted that for both the viral and bacterial vaccine examples used, the exposure to this risk is temporary. Manufacturing changes have already been implemented which eliminate exposure during vaccine manufacture to bovine materials from countries at risk of BSE contamination. Vaccines made by these procedures are expected to be available in 2001.

Table 1

Estimated infectivity of bovine tissue by categoryCategory
Tissue
ID50/gram*

I  Nervous tissue 107
II Spleen, lymph nodes, colon <2.5 x 104
III Pancreas, liver, lung <100
IV Muscle, bone, heart <0.1

Adapted from: Bader et. al, 1998 BioPharm *ID50/gram = number of infectious units per gram of tissue

References:

  1. Bader F, Davis G, Dinowitz M, Garfinkle B, Harvey J, Kozak R, Lubiniecki A, Rubino M, Schubert D, Wiebe M, and Woollett G, Assessment of risk of bovine spongiform encephalopathy in pharmaceutical products, Biopharm. Jan., 1998. pp. 20-31.

  2. Taylor DM, Fraser H, McConnell I, Brown DA, Brown KL, Lamza KA, and Smith GRA, Decontamination studies with the agents of bovine spongiform encephalopathy and scrapie, Arch Virol 139:313-326, 1994.

  3. Bradley R, BSE Transmission studies with particular reference to blood, Dev. Biol Stand, 99:35-40, 1999.

  4. Kimberlin RH, An overview of bovine spongiform encephalopathy Dev Biol Stand 75:75-82, 1991.

  5. Donnelly CA, Ghani AC, Ferguson, NM, and Anderson RM, Recent trends in the BSE epidemic, Nature 389:903, 1997.

  6. Linda Detwiler, USDA

  7. Wilesmith JW, Wells GAH, Ryan JBM, Gavier-Widen D, and Simmons MM, A cohort study to examine maternally-associated risk factors for bovine spongiform encephalopathy, The Vet Record 141:239-243, 1997.

  8. Transcript of June, 2000 meeting of the FDA TSE Advisory Committee.

  9. Brown P, Cervenakova L, McShane LM, Barber P, Rubenstein R, and Drohan WN, Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans, Transfusion 39:1169-1178, 1999.

  10. Brown, P, Rohwer RG, Dunstan BC, MacAuley C, Gajdusek DC, and Drohan WN, The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy, Transfusion 38: 810-816, 1998..

Harris, DA, Cellular biology of prion diseases, Clin. Mocro. Rev, 12: 429-444,

Scientists warn of CJD risk in vaccines given to children (SUNDAY TIMES 22/2/1998)

by Lois Rogers and Bryan Christie

THE government is preparing to warn doctors that British blood products, including vaccines given to children, could be at risk of contamination from CJD, the human form of "mad cow" disease. A letter being drafted by Ken Calman, the chief medical officer, will reveal that scientific advisers to a European medical committee meeting this week have concluded that all products derived from British blood - including vaccines - could transmit the disease.

British experts on CJD are anxious to emphasise that the life-saving benefits of blood transfusions and vaccinations against killer diseases far outweigh the risk of CJD, which is believed to be minimal. However, the newly identified form of beef-related CJD can theoretically pass from person to person and could be more infectious than "classic" CJD. The expert report will be presented to a meeting of the Committee on Proprietary Medicinal Products (CPMP), a pan-European advisory body, on the safety of medical products when it meets this week.

Europe may impose a ban on the export of British blood and blood-derived protein called albumin prepared from donor plasma, which is used in pharmaceutical products including vaccines. This could provoke a political outcry. Noel Wadhion, the committee's spokesman, said no formal response would be made by the CPMP until the end of the week. The principal vaccine containing human serum albumin is for measles, mumps and rubella (MMR), and is received by millions of children. British supplies are produced in America which has no cases of the new variant of CJD. However, British albumin is used in other vaccines and exported to vaccine manufacturers elsewhere.

Calman said blood collected here has a safety record second to none in terms of risk of transmitting hepatitis, HIV or other viruses. "We don't know that the theoretical risk of CJD transmission is from blood, if it's there at all," he said. "The letter to doctors isn't finalised. "We have discussed the consequences of this report, but it depends on the final statements from the European committee and advice from the Committee on Safety of Medicines here. To get a blood product from another country which has a high risk of some other infection doesn't seem a particularly good idea to me."

Calman's letter will guide doctors on how to explain to patients what is known so far about the risk from new-variant Creutzfeldt-Jakob disease (nvCJD) which, it is emphasised, is far outweighed by the dangers of not having the treatment. Ministers believe the public should be informed of any risk of BSE infection, however slight - as they were over beef on the bone, banned from sale in December. So far there have only been 23 confirmed cases of the so-called nvCJD. However, scientists think there are many more undiagnosed victims. A World Health Organisation (WHO) meeting two weeks ago concluded the possibility of a "significant nvCJD epidemic" in 10 years can no longer be ignored.

Martin Ziedler, an adviser on the disease at the WHO, said calculations a year ago, when there were just 14 confirmed cases of nvCJD, indicated there could be up to 80,000 more British victims. Now it is impossible to predict the possible scale of any epidemic

 EDITORIAL OBSERVER
The Whole Cow and Nothing but the Whole Cow
By VERLYN KLINKENBORG

In the mid-1990's, British officials had been trying for almost a decade to respond to the appearance of bovine spongiform encephalopathy, or mad cow disease, in a herd near Ashford, England. At first, they simply dismissed public concern or proclaimed their faith in British beef. Even when humans began dying of variant Creutzfeldt-Jakob disease the human equivalent of B.S.E. government officials found it hard to act coherently. They had the one excuse that we lack: they didn't know what they were confronting. In time, the British government put in place a set of prohibitions against the use of meat and bone meal as food for cattle and against the sale of certain kinds of offal for human consumption. Those steps have seriously reduced the incidence of mad cow disease.

The British government also introduced a strict system for tracking every cow in the country, something we are only now edging toward. By the mid-1990's in England, you could follow a cow's paper trail right up to the slaughterhouse door. But what then? Live cattle almost certainly can't spread mad cow disease. Dead cattle can, if the wrong things are done with them. After a decade of wrangling, the British decided to create an system to track cow parts.

It sounded like a good idea, but it was never completed. The reason is that the parts of a slaughtered cow go everywhere. The official British B.S.E. Inquiry Report put it this way: "It has been said, and not altogether facetiously, that the only industry in which some part of the cow is not used is concrete production." The problem isn't just global meat. It's global cow.

Here's the scale of the question. In 2002, commercial slaughterhouses in the United States killed 36,780,000 cattle and calves. How much of a cow carcass becomes meat depends on whom you talk to. The United States Department of Agriculture says 70 percent, some knowledgeable cattle buyers say 63 percent, and the British government's studies say 53 percent. Even the U.S.D.A.'s figure means that if you add up the non-meat remains of the cattle slaughtered annually in this country, you would have a herd of 11 million whole animals. You can begin to see why it seemed like a smart idea to feed bovine meat and bone meal to other cows the practice, now banned, that transmitted mad cow disease in the first place. There's just so much of the stuff.

What isn't meat leaves the slaughterhouse for the rendering plant. There it is converted into basic raw materials that are processed all around the world into a thousand different forms, most broken down all the way to their molecular components, into proteins and fats and fatty acids. Just how widely these are dispersed industrially can be gauged from a letter sent out from an office of the Food and Drug Administration in 1992, asking manufacturers of dietary supplements to check the sources of bovine "neural and glandular tissue(s) or tissues extracts" to make sure they were not contaminated. Letters also went out to the manufacturers of "drugs, biological drugs, medical devices and biological device products," to the manufacturers of veterinary drugs and animal feed, and to the makers and importers of cosmetics.

In fact, the list is nearly endless. Vaccines are often prepared in media that may contain byproducts from slaughtered cattle. Until recently, heparin, a widely prescribed anticoagulant, was made from bovine mucosa and lung, and steroids come from adrenal glands. Chemicals derived from bovine tissue appear in plastics, paper coatings, rubber and asphalt. Glycerin appears in countless products. Collagen is a bovine byproduct.

Some of these products vaccines, for instance are strictly regulated, and many of the industrial uses of cattle parts derive from cow parts that are not associated with mad cow disease. In fact, it is possible to stand back and marvel at the industrial ingenuity that has found so many uses for what looks utterly useless as it comes out of the slaughterhouse. The logic behind this ingenuity is blunt. The F.D.A., explaining why vaccines are prepared with cattle byproducts, said: "Cow components are often used simply because cows are very large animals, and thus much material is available."

It isn't clear whether we would be better off, environmentally and economically, if other raw materials, not from animals, were used for products made from cow parts. But the inventiveness that converts cattle tissue into thousands and thousands of apparently nonagricultural products like gelatin capsules and jet engine lubricants also provides part of the economic rationale for expanding the global cattle herd, regardless of the consequences. It's easy to grasp the problem of feeding bovine blood and bone meal to cows. But economic pressure forces the use of cow parts further downstream, until blood and bone meal are fed to farmed fish.

Without the industrial market for bovine byproducts, the size of the cattle herd in the world could never have grown as large as it has. When people talk about industrial farming, they usually refer to the often deplorable conditions in which livestock is raised these days, usually confined in close quarters, often indoors. But you might also call the capacity to turn a cow into fabric softener a kind of industrial farming as well, a kind we all participate in, whether we know it or not, whether we choose it or not.

 

http://www.nytimes.com/2004/02/06/national/nationalspecial2/06FEED.html

 

Mad Cow Quandary: Making Animal Feed

 

 

The following column appeared in Portland's newspaper,
the Oregonian:
__________________________________________________

One Cow, Hundreds of Uses
by Steve Woodward

The mad cow scare may have prompted some consumers to give up T-bone steak.

But there's no escaping the humble cow.

Gel capsules often are made from bovine gelatin. Bars of soap probably come from processed cow tallow, which is solid fat. Asphalt roads may contain bovine fatty acids. Cars and trucks may ply those roads on rubber tires made with cow oils. Even wars can depend on cows. The explosive nitroglycerine
is manufactured from glycerine, which is extracted from cow fat.

Cattle byproducts, simply put, are one of the glues that hold together the industrialized world. The discovery of a Washington Holstein with mad cow disease turned the spotlight on the world of beef cattle, brains, spinal cords and meat. The discovery also pointed to a largely unseen world in which cattle parts turn into chicken feed, mayonnaise and sex hormones -- and the potential that byproducts from an infected cow might transmit bovine spongiform encephalopathy to humans. Federal authorities insist that is not a significant risk.

The diseased Washington cow had enormous reach, it turns out. The 1,200-pound Holstein was cut, ground and added to 20,000 pounds of potentially infected meat in eight states, while its nonmeat parts might have made their way into as much as 1.5 million pounds of animal byproducts processed by Baker
Commodities, one of the nation's largest renderers. That multiplier effect illustrates the cow's pervasiveness in modern life -- and the high stakes of tracking mad cow disease. Cattle byproducts go into everything from photographic film to matchstick heads, says Bob Dickson, manager of the Clark Meat Center at Oregon State University.

Consider:

Glue made from cow's blood is widely used to make plywood. The cow's nasal septum is processed into chondroitin sulfate, an alternative medical treatment for arthritis. Extracted protein from horns and hooves goes into foam for fire extinguishers. The root gland of the tongue yields pregastric lipase, which is used in cheese production as a curdling agent. Tissue from the small intestines becomes catgut for racket
strings or surgical sutures.

And, of course, cowhide becomes leather shoes or sporting goods. According to "Scientific Farm Animal Production," a 1998 textbook, one cowhide can yield about 144 baseballs, or 20 footballs, or 18 soccer balls, or 12 basketballs. British inventory of uses The most extensive inventory of the uses of cow parts was completed in 2000 by the British government, which held an inquiry into mad cow disease and its human counterpart, variant Creutzfeldt-Jakob disease,
in the United Kingdom.

That inventory documented that cow heads, meat, organs, blood, hide, feet and fluids made their way into a variety of human food, pet food, animal feed, pharmaceuticals, cosmetics and industrial uses. "Indeed, it has been said, and not altogether facetiously, that the only industry in which some part of the cow is
not used is concrete production," the inquiry reported.

Even that is no longer true. France and Switzerland now allow incinerated meat and bonemeal to be added to cement, according to the London Sunday Telegraph. "Until the latter half of the 20th century, the only major uses for beef byproducts were leather and soap and candles," wrote author Verlyn Klinkenborg in the August 2001 issue of Discover magazine. "But given an extraordinary spike in beef
consumption after World War II, as well as a parallel explosion in industrial diversity, cows were suddenly fractionated right down to the molecular level."

Though most byproducts go into animal feed, there is perhaps no more miraculous use of a cow than in pharmaceuticals. Many health products Heparin, an anticoagulant used to thin blood, comes from a cow's lungs and intestines. Epinephrine from the adrenal gland can treat hay fever, asthma or other allergies, or stimulate the heart in the event of cardiac arrest. Catalase, a liver enzyme, goes into contact lens care products. Are these products safe from mad cow disease, scientifically known as bovine spongiform encephalopathy (BSE)?

For example, cholesterol, which is used to make male sex hormone, comes from the cow's spinal cord, a tissue at high risk for containing prions, the rogue protein that causes mad cow disease. The U.S. Food and Drug Administration says the rigorous pre approval process for new drugs assures the public that
prions don't make their way into medicines. "There are ways to assure that bovine-derived products are
indeed products that come from BSE-free areas," said Murray Lumpkin, principal associate commissioner of the FDA. "That's what we've been doing for years." Vaccines, he noted, are grown in fetal calf serum, not central nervous system tissue.

But the pre-approval process doesn't cover dietary supplements, which are regulated as food, not drugs.
So supplements such as Brain 360, which are 360-milligram tablets of raw cow brain concentrate made by Illinois-based Atrium, face less stringent regulations.  Limits on supplements Banning potentially dangerous dietary supplements isn't easy under FDA food regulations. The FDA's recently announced ban on ephedra, for example, took place only after the herbal supplement was linked to more than
100 deaths.

"On something like bovine brain, the law says they have to prove beyond a reasonable doubt that people have died as a result," said Jean Halloran, a food safety expert with the Consumers Union. Lumpkin said foreign-made supplements are governed by import laws, which restrict the importation of supplements made from ruminants such as cows. But U.S.-made supplements face no such restrictions.  "We're going to have to look at companies sourcing domestically," he said, adding the agency will act against sellers of food "to the extent it's not fit for human consumption."

Cattle byproducts also find other ways into the human food supply, largely through the use of gelatin, which is created by treating bones with acid. According to the 2000 British government report, 60 percent of gelatin is used in food preparation. The rest is used to coat tablets, bind chemicals to photographic film and other nonfood uses.

Take a simple example of pie a la mode. The pie crust probably is made with gelatin. The dollop of ice cream probably contains gelatin for a binder. In addition, the sugar for the pie filling may have been bleached with cow bone. Other gelatin-based foods include jelly beans, marshmallows and, naturally, instant gelatin.

Halloran said gelatin is safer than muscle meats, which government and industry officials say are safe to eat because they don't contain central nervous system tissue. Still, she doesn't recommend eating any product, including gelatin, that comes from an animal with mad cow disease. "It falls under saying that no part of an infected animal should be eaten," she said.

Plenty to render, recycle Only about half of a beef cow ends up in the meat case, according to the National Renderers Association. The castoffs from beef production -- 35 million cattle slaughtered annually -- would quickly overflow the nation's landfills if they weren't rendered and recycled.

So the humble cow continues to yield fertilizer from dried blood, buttons from hooves, neat's-foot oil from shin bones and toothpaste from fats. Even the lowly gallstone is exported to China, where it is thought to have mystical values, according to "The Meat We Eat" (Interstate Publishers, 1994, 1,193 pages).

"We're sometimes referred to as the original recyclers," said Tom Cook, president of the National Renderers Association. "We take a lot of material that would otherwise have no value and convert it into products that do have value."

Steve Woodward: 503-294-5134; stevewoodward@news.oregonian.com
__________________________________________________

(Thanks to JonF <finnbe@earthlink.net> for sending us this column)

Robert Cohen
http://www.notmilk.com
 

http://www.nytimes.com/aponline/health/AP-FDA-Safer-Vaccines.html
The New York Times
September 22, 2004

Proposal Aimed at Reducing Mad Cow Risk
By THE ASSOCIATED PRESS

WASHINGTON (AP) -- The government is taking steps to reduce the already minimal risk of mad-cow tainted components ending up in childhood vaccines and other medications. Pharmaceuticals regulated by the Food and Drug Administration, including human vaccines and animal drugs used on farms, routinely use cow products in their manufacture. The agency this summer strengthened safety measures to reduce the chance of mad cow-tainted cow parts winding up in such consumer goods as lipstick and
hairspray. William Egan, FDA acting director in the office of vaccine research and review, told pharmaceutical representatives on Tuesday that the new rule is aimed at reducing even further mad cow risk in human and animal drugs. He did not offer specifics.

``It's under development. That's all I can say,'' Egan said during a conference co-sponsored by PDA, an association of scientists involved in drug development and manufacture. There have been no reported cases of mad cow transmitted by medications. Dozens of people, however, were infected with Creutzfeldt-Jakob disease, related to the human form of mad cow, by taking tainted human growth hormone between 1963 and 1985, according to the National Institutes of Health. The method of manufacturing the growth hormone was changed in response to that risk.

Eating beef from a diseased cow is thought to cause variant Creutzfeldt-Jakob disease. More than 150 cases of variant CJD have been reported in the world, primarily in Britain, and most of those people have
died. The one case of variant CJD in the United States was in a young woman who likely contracted the disease while living in Britain. In July 2000, the FDA told manufacturers to replace products in their vaccines derived from cows born, raised and slaughtered in countries with confirmed mad cow cases. Manufacturers hustled to find replacement materials from countries whose cows were free of the always fatal brain malady. At the time, no North American cases of mad cow, formally known as bovine spongiform encephalopathy, had been confirmed, until May 2003, when a 6- to  8-year-old cow in Alberta, Canada tested positive for mad cow. And, in December 2003, a second Canadian cow -- this one a 6 1/2-year-old imported into Washington state -- also was confirmed with mad cow.

More aggressive surveillance by the Agriculture Department since June 1, 2004, has tested 63,341 American cow samples, said Lisa Ferguson, a USDA senior staff veterinarian. Two samples initially were suspicious but, upon further testing, were found not to contain mad cow. The FDA's Egan said the agency has not yet decided whether manufacturers will have to replace American and Canadian cow products routinely used in vaccine manufacturing. Argentina, Australia, Iceland and Uruguay are among
the dwindling list of countries provisionally free of mad cow. Also not clear is how the FDA would handle licensed vaccines currently on the market or products progressing along lengthy development pipelines.

Even if American and Canadian sources of bovine-derived products were prohibited, it's not clear how sweeping the impact might be. One drug company, GlaxoSmithKline, already found alternate sources of
materials it uses to produce such products as hepatitis A vaccine and recombinant hepatitis A and B vaccine. While Danielle Halstrom, a GlaxoSmithKline spokeswoman, won't identify the source countries, she said they do not include the United States or Canada. ``The entire process was completed more than a year ago ... to ensure we only use materials from countries'' with no mad cow infections, Halstrom said.

Cow remnants left over from slaughter have long been used to manufacture drugs like vaccines. Serum is drawn from cow's blood and sugars from cow's milk. Amino acids from cow bones are added to growth media to coax along viral vaccines grown in living cells. Egan suggested the companies consider plant-based and synthetic compounds as substitutes, culturing methods that don't require serum, and ``closed'' cattle herds known to be free of mad cow. A Merck representative lobbied from the stage at Tuesday's conference, urging the agency to first issue a letter with its intentions so companies would have more time to prepare for changes that could affect 80 percent of pharmaceuticals. ``We have lifesaving medicines that we produce,'' said Taryn Rogalski-Salter, a director in the company's department of global regulatory policy, warning about potential supply disruptions.
 

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