Bovine Spongiform Encephalopathy (BSE)

BSE (bovine spongiform encephalopathy) 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.

What causes BSE?

The nature of the infectious agent that causes BSE and scrapie is unknown. Currently, the most accepted theory is that the agent is a modified form of a normal cell protein known as a prion. A prion is not a bacterium, parasite, or virus, and thus treatments usually used for treating or preventing bacterial infections (e.g. antibiotics) or viral infections are not effective against prions.

Where is the BSE agent found in cattle?

In cattle naturally infected with BSE, the BSE agent has been found in brain tissue, in the spinal cord, and in the retina of the eye. Additional experimental studies suggest that the BSE agent may also be present in the small intestine, bone marrow, and dorsal root ganglia.

Which countries have reported BSE?

The vast majority of cases of BSE (more than 99% as of 1999) have been reported from the United Kingdom during an epidemic. However, endemic cases have also been reported in other European countries including: the Republic of Ireland, Switzerland, France, Liechtenstein, Luxembourg, Netherlands, Portugal and Denmark. The numbers of reported cases by country are available on the web site of the Office International des Epizooties (www.oie.int/). These numbers should be interpreted with caution, however, because the intensity and methods of surveillance probably vary over time and by country.

How was BSE spread?

It is thought that BSE was spread via meat-and-bone meal fed to cattle. The practice of using this material as a source of protein in cattle feed has been common for several decades. In the late 1970s there was a change in the production (rendering) process used to make this meat and bone meal. One hypothesis is that this change permitted the infectious agent of scrapie (a transmissible spongiform encephalopathy, or TSE, of sheep) to survive the rendering process, and get transmitted to other animals, such as cows, that are fed meat-and-bone meal nutritional supplements.

What has the British government done in response to the BSE epidemic?

What is the new variant form of CJD that the experts in the United Kingdom believe might be related to the BSE outbreak in cattle?

In contrast to the classic form of CJD, the new variant or variant form (vCJD) in the United Kingdom and France affects younger persons (average age at onset: 28 years), and has different clinical features from CJD. People with vCJD begin with serious psychiatric problems or problems with their senses (ears, eyes or smell). This first set of symptoms is followed weeks or months later by poor muscle coordination, problems with muscle spasms, and mental confusion; these patients also have abnormal electroencephalograms (EEG). The illness lasts for at least 6 months, but most people die approximately 13 months after their symptoms begin. When patients’ brains are examined by autopsy, there are clear changes in brain tissue structure, including many "spongiform," or open spongy-looking areas, abnormal spots of prion protein called plaques, and other areas with much prion protein accumulation.

Exactly how does this newly recognized variant of CJD differ from classical CJD?

In 1996 the Spongiform Encephalopathy Advisory Committee (SEAC) of the UK announced the identification of 10 cases of variant CJD (vCJD, Lancet, 1996, 347: 921-25). The following features describe how vCJD cases differ from the sporadic or classical form of CJD:

• The affected individuals were much younger than the classical CJD patient. Typically, CJD patients are over 63 years old. The average patient with vCJD is 28 years old; patients ranged from 12-52 years old.
• The course of vCJD averaged 13 months. Classical CJD cases average a 6 month duration.
• In the vCJD cases, electroencephalographic (EEG) electrical activity in the brain was not typical of classical CJD.
• Although changes in brain tissue structure of patients with vCJD were recognizable as CJD, the pattern was different from classical CJD, with large aggregates of prion protein plaques often surrounded by vacuoles.

How did people get this new variant of CJD?

On March 20, 1996 a statement from the Spongiform Encephalopathy Advisory Committee (SEAC) of the United Kingdom indicated concern that before November 1989, when inclusion of certain cow and sheep by-products in human food was banned, the BSE agent may have been transmitted to people through contaminated food products. The SEAC said that food might account for the 10 vCJD cases described in April, 1996 in the medical literature (Lancet 1996; 347:921-5). The specific foods, if any, that may be associated with the transmission of this agent from cattle to humans are unknown. However, the SEAC has indicated that milk and milk products are unlikely to pose any risk for human exposure to the BSE agent.

What is the evidence directly linking this newly recognized variant of CJD to BSE exposure?

There is strong epidemiologic and laboratory evidence suggesting that new variant CJD (vCJD) and BSE are caused by the same infectious agent. For instance, there have been no confirmed cases of vCJD in other geographic areas where there have been no BSE cases. In addition, the time interval or "incubation period" between the most likely period for the initial exposure of the population to potentially BSE-contaminated food (1984-1986) and onset of initial vCJD cases (1994-1996), about 10 years, is similar to the known time intervals between exposure to the classical CJD agent and the development of CJD. An experimental study reported in June 1996 showed that three cynomologus macaque monkeys that were injected with brain tissue from cattle with BSE later developed symptoms and changes in brain tissue that were strikingly similar to vCJD (Nature 1996;381:743-4). Another study published in 1996 showed that prions obtained from 10 vCJD patients and BSE-infected animals had molecular characteristics that were similar to each other but that were distinct from prions obtained from patients with classical CJD (Nature 1996;383:685-90). Furthermore, intermediate results of an ongoing experimental study involving injection of a panel of mice with the agent that causes BSE and vCJD suggest that these agents cause a similar disease in mice (Nature 1997;389:498-501). A recent study using transgenic mice (PNAS 1999; 96:15137-15242) supports the hypothesis that the BSE agent from cattle causes vCJD.

How many cases of variant CJD have occurred?

Cases of variant CJD are very rare, and most have occurred in the United Kingdom. The latest information (October 2, 2000) issued by the Department of Health, United Kingdom (www.doh.gov.uk/cjd/) indicates that there have been 73 confirmed cases of vCJD in the United Kingdom. These cases have all been diagnosed since 1995. France has reported two cases. The Republic of Ireland reported one case in 1999. No cases have been recognized in other European countries, or in the United States

Could anyone in Europe diagnosed with the newly recognized variant of CJD (vCJD) have acquired this from vaccines?

In the UK the majority of cases of vCJD were born before 1980, and it is very unlikely that they received vaccines contaminated with the BSE agent (Vaccine 2000 19:409-410). Surveillance of vCJD in the UK has identified three "risk factors," or characteristics common to most if not all of the people who had vCJD: i) residence in the UK; ii) a particular genetic susceptibility (met/met homozygosity at codon 129 of the PrP gene); and iii) age. Epidemiological evidence to date suggests that these cases of vCJD acquired the disease from eating beef products containing the BSE agent after 1980. To date (October, 2000) there have been 76 confirmed cases of vCJD. Of these, 73 have occurred in the UK. A case of vCJD was reported in the Republic of Ireland in June 1999 in a person who had been a UK resident from 1989-1995. Two cases of vCJD have been diagnosed in France, one in 1996 and the other in 1999. Neither of these people had lived or traveled in the UK. However, according to data published by the UK (HM Customs and Excise), France was a leading European importer of bovine products during the period 1980-1996. No other cases of vCJD have been found in Europe.

Vaccines contain either killed or weakened forms of disease-causing bacteria or viruses, or components of these that stimulate a response by the body’s immune system, which then protects against the development of disease. In the late 19^th century, microbiologists began to grow bacteria in the laboratory. The early bacteriologists tried to mimic as closely as possible the infected person’s tissues by using sugars, salts, and various meat extracts to make "growth media." These kinds of conditions were quite successful in growing bacteria and then viruses in the lab, because these media supplied the many necessary nutrients. Although synthetic media have been developed for growth of many medically important microorganisms, some still require additional nutrients which are easily provided by animal-derived products such as serum and blood.

Which bovine derived materials are used in vaccine manufacture?

Microorganisms for vaccine manufacture are grown under controlled conditions in media which provide the nutrients necessary for growth. Cow components are often used simply because cows are very large animals, and thus much material is available. Animal-derived products used in vaccine manufacture can include amino acids, glycerol, detergents, gelatin, enzymes and blood. Cow milk is a source of amino acids, and sugars such as galactose. Cow tallow derivatives used in vaccine manufacture include glycerol. Gelatin and some amino acids come from cow bones. Cow skeletal muscle is used to prepare certain complex media. Many difficult to grow microorganisms require the addition of serum from blood to the growth media.

Do all bovine materials have the same risk of transmitting the BSE agent?

Scientists have found that different bovine tissues contain different amounts of the BSE agent. It is generally believed that the highest amounts of infectivity are found in the brain and spinal cords from animals in the final stages of clinical disease. Some tissues such as skeletal muscle and milk have never been shown to have any infectivity. However, the slaughtering and butchering methods used to obtain tissues and prepare materials can affect the amount of infectivity that may be present. Also the production processes used to prepare bovine-derived materials (such as heat sterilization and chemical treatment) may reduce or remove infectivity.

What measures have the FDA taken to ensure that people are not exposed to the BSE agent in vaccines?

It is believed that variant CJD was acquired from eating food products containing the BSE agent. However, FDA wants to minimize any chance that the BSE could be introduced into biologic products during manufacture. The Center for Biologics Evaluation and Research (CBER) is responsible for regulation of biologic products, including vaccines. In a 1991 letter to manufacturers CBER expressed concern about bovine sourced material. In December 1993 and May 1996 FDA issued letters advising that bovine derived materials from animals born in or residing in countries where BSE had occurred should not be used to manufacture FDA-regulated products intended for administration to humans. A 1993 Points to Consider document ("Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics") stressed the importance of control of sourcing of bovine materials. On April 19, 2000, CBER issued a letter reminding manufacturers that the USDA list of BSE-countries had been expanded to include not only those countries where BSE was known to exist but also those where BSE may exist (FR, January 6, 1998). CBER strongly recommended "that manufacturers take whatever steps are necessary to assure that materials derived from all species of ruminant animals born, raised or slaughtered in countries where BSE is known to exist, or countries where the USDA has been unable to assure FDA that BSE does not exist, are not used in the manufacture of FDA-regulated products intended for administration to humans."

How did the FDA discover that some manufacturers are not universally following letters, PTC and guidance documents?

During review of new license applications manufacturers are asked to provide detailed descriptions of the manufacturing process and documentation of source country for all materials of animal origin. During review of a recent license application it was determined that some of the material used during manufacture had been obtained from countries which are on the USDA list of countries which either have or may have BSE. This finding prompted an inquiry of all licensed vaccines.

What is FDA doing now to assure that companies follow guidance, letters, and PTC documents?

The Center for Biologics Evaluation and Research (CBER) has asked licensed vaccine manufacturers to evaluate all bovine sourced material used at any stage of manufacture. Manufacturers have been requested to identify all material of animal origin. For materials of bovine origin CBER has asked manufacturers to identify the source country from which the animals originated, the date the material was obtained and the date the material was used in manufacture of vaccine lots.

When it is determined that any bovine-derived component used to make the working seeds or during routine production was obtained from a country on the current USDA list of countries which either have or may have BSE, the manufacturer has been asked to change the source of such material. CBER inspects vaccine manufacturers on a routine basis to determine whether sourcing and documentation are consistent with current recommendations contained in letters and guidance documents.

Why did the FDA ask the Transmissible Spongiform Encephalopathy Advisory Committee and the Vaccines and Related Biological Products Advisory Committee meet on July 27^th, 2000?

The Center for Biologics Evaluation and Research (CBER), FDA regulates biological products including vaccines. For several years CBER has recommended that bovine derived components from countries which have or may have BSE (bovine spongiform encephalopathy, the so called "mad cow disease") not be used for the manufacture of US-licensed biological products including vaccines. The consumption of food contaminated with the BSE agent has been linked to a fatal disease in people called new variant or variant CJD (vCJD). There is no evidence that any case of vCJD has resulted from use of a vaccine, and there is no evidence that any vaccines harbor the BSE agent. CBER had recently determined that some vaccines were manufactured using bovine components from countries which the USDA has determined have or may have BSE. CBER believed that the chance of getting vCJD through vaccines is remote and theoretical. However, CBER has responsiblility to ensure that vaccines used in the US are safe and asked for this special joint meeting to ask vaccine and TSE experts to formally discuss the risk of transmitting vCJD from vaccines.

What is the chance/risk that a vaccine on the market in the US contains the BSE agent?