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.
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Draft Guidance for Industry: Amendment (Donor Deferral for Transfusion in France Since 1980) to "Guidance for Industry: Revised Preventive Measures to Reduce the Possible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" - 8/8/2006
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
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"
Table of Contents
Countries/Areas Affected With Bovine Spongiform Encephalophathy [CFR 94.18] - Animal and Plant Health Inspection Service (APHIS), US Department of Agriculture
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 was a precautionary measure intended to minimize even the remote risk of vCJD from vaccines.
The source of the bovine-derived materials may be 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 (the current best estimate is that BSE first emerged in 1980). 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 on this website; 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 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 fully implemented these changes. No US-licensed vaccine uses bovine derived materials from countries on the USDA list.
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.
- 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
- USDA 9 CFR part 94.18
- P. D. Minor, R.G. Will and D. Salisbury. 2000. Vaccines and variant CJD. Vaccine 19:409-410.
- 2008 Child & Adolescent Immunization Schedules (for persons aged 0-6 years, 7-18 years, and "catch-up schedule)
- Recommended Adult Immunization Schedule for October 2007 - September 2007
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 - (PDF - 133 KB)
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:
Achievements in Public Health, 1900-1999 Impact of Vaccines Universally Recommended for Children -- United States, 1990-1998
Current list of vaccines using bovine-derived materials from countries on the USDA's BSE list
Vaccines that use bovine-derived materials from countries on the USDA list include:
No vaccine uses bovine derived materials from countries on the USDA list.