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From: Terry S. Singeltary Sr. (216-119-144-2.ipset24.wt.net)
In Reply to: vaccines posted by melissa on August 29, 2004 at 6:32 am:
8. The Secretary of State has a number of licences. We understand that http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf http://www.bseinquiry.gov.uk/report/volume7/chapted2.htm http://www.bseinquiry.gov.uk/files/yb/1989/02/14011001.pdf although 176 products do _not_ conform to the CSM/VPC http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf 5.23 This alerted Sir Donald Acheson to the fact that concerns about the http://www.bseinquiry.gov.uk/report/volume7/chapted2.htm WHO/CDS/CSR/APH/2000.2 3.5 Animal vaccine-related Transmissible Spongiform Encephalopathy risks: Scrapie outbreak in Italy Maurizio Pocchiari: Historically, Italy has had a low incidence of scrapie; however, in 1997 snip... 7.6 Could vaccines prepared from animal brain tissue pose a risk of Over 40,000 deaths due to rabies are reported annually worldwide and WHO/CDS/CSR/APH/2000.2 34 WHO Consultation on Public Health and Animal TSEs publication strongly suggests that scrapie was transmitted to sheep and snip... Recommendation 25 Human vaccines prepared from whole ruminant brains may carry the risk of "The (Expert) Committee reiterated, as stated in its 1983 report, its Recommendation 26 The use of veterinary vaccines prepared from whole ruminant brains, for snip... http://www.who.int/emc-documents/tse/docs/whocdscsraph20002.pdf http://216.239.37.100/search?q=cache:ha1lZiMaWG4C:www.who.int/emc-documents/tse/docs/whocdscsraph20002.pdf+Acquisition+of+spongiform+encephalopathies+in+India+through+sheep-brain+rabies+vaccination.&hl=en&ie=UTF-8 55 III.3.1 VACCINES for goats of 26% and for sheep of 10%. The total number of cases in III.3.2.OTHER MEDICINAL PRODUCTS DERIVED FROM TSE-SUSCEPTIBLE SPECIES http://europa.eu.int/comm/food/fs/sc/ssc/out236_en.pdf Indian J Pediatr 1991 Sep-Oct;58(5):563-5 Arya SC. Centre for Logistical Research and Innovation, Greater Kailash, New Delhi. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1813404&dopt=Abstract BMJ 1996 Nov 30;313(7069):1405 Comment on: * BMJ. 1996 Aug 24;313(7055):441. Arya SC. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8956737&dopt=Abstract BMJ 1996;313:1405 (30 November) In many countries in Asia and Africa limited supplies of imported rabies Before accepting blood donations from immigrants it would be desirable Clinical microbiologist Centre for Logistical Research and Innovation, Subhash C Arya http://bmj.com/cgi/content/full/313/7069/1405/a : Neuroepidemiology 1991;10(1):27-32 Creutzfeldt-Jakob disease in India (1971-1990). Satishchandra P, Shankar SK. Department of Neurology, National Institute of Mental Health and Thirty cases including 20 definite and 10 probable cases of http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2062414&dopt=Abstract i recieved the 1947 report of the Louping-ill vaccine Louping-ill vaccine (scrapie transmission by vaccine) THE VETERINARY RECORD NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND ANNUAL CONGRESS, 1946 snip... The enquiry made the position clear. Scrapie was developing in (1) the infective agent of scrapie was present in the brain, spinal Two Frenchmen, Cuille & Chelle (1939) as the result of experiments As a result of this experience a large-scale transmision experiment The prolonged incubative period of the disease and the remarkable http://www.vegsource.com/talk/lyman/messages/7634.html USA IMPORTS VACCINE PRODUCTS FROM BSE COUNTRIES http://www.mad-cow.org/00/may00_news.html Furthermore, we showed that http://www.pnas.org/cgi/content/full/041490898v1 Human vaccine prepared in animal brains http://www.mad-cow.org/00/nov00_late_news.html#fff http://www.whale.to/v/singeltary7.html http://www.mad-cow.org/00/may00_news.html http://www.mad-cow.org/00/jul00_dont_eat_sheep.html#hhh STUDY DESIGN AND METHODS: BSE was passaged through macaque monkeys and RESULTS: All three inoculated microcebes became ill after incubation CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months http://www.blackwell-synergy.com/servlet/useragent?func=synergy&synergyAction=showAbstract&doi=10.1046/j.1537-2995.2002.00098.x Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001 snip... [host Richard Barns] [TSS] [no answer, you could hear in the back ground, [host Richard] [TSS] [not sure whom ask this] [TSS] [not sure who is speaking] [TSS] [not sure whom speaking] snip... http://vegancowboy.org/TSS-part1of8.htm Meanwhile, health officials with the Food and Drug Administration say "The MRC-5 line was developed & from lung tissue taken from a 14-week http://www.worldnetdaily.com/news/article.asp?ARTICLE_ID=25362 SMALLPOX VACCINE, Dried, Calf Lymph Type Dryvax, Wyeth Laboratories, Marietta, PA (1960) Ingredients calf lymph chloriatracycline hydrochloride; http://www.vaccineawareness.org/IllinoisIssues/SmallpoxInsert.htm TSS ########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############ http://www.vegsource.com/talk/madcow/messages/9912194.html From: TSS In Reply to: MAD COW DISEASE, SMALLPOX VACCINE (Dried Calf Lymph Type) and TSEs Humans may catch mad cow from sheep December 13 2002 at 07:41PM London - The number of people with a human form of mad-cow disease could be much higher than originally thought, according to a new study. Since 1990, there have been 117 confirmed deaths in Britain from the variant CJD, which until now was assumed to be the only disease linked to eating BSE-infected beef. But scientists at the Medical Research Council's Prion Unit in London believe they have identified links between BSE and a second type of the human brain disease - sporadic CJD. The government's latest figures show that from 1990 to November this year, 588 people died from sporadic CJD, including 28 in 1990, 63 in 1998, and 53 last year. 'Some patients with sporadic CJD may have a disease arising from BSE exposure' The researchers wrote: "It remains of considerable concern whether BSE has transmitted to, and is being maintained in, European sheep flocks". They said that given the widespread infection of sheep breeds with scrapie, it was possible some had contracted BSE but that this infection had been hidden by the other disease. A full study is needed of all the tonsils surgically removed over a 12-month period - around 80 000 - to map the extent of CJD infection in the population, the Medical Research Council argued. The British Department of Health is thought to be considering such a plan. The research team used a series of experiments on mice that had been genetically altered so they would display the human effects of a prion - an infectious protein. The "transgenic" mice were then exposed to BSE-infected material and the changes in the prion protein were monitored. As expected, some developed vCJD, but the researchers wrote that, surprisingly, other mice showed effects of sporadic CJD. "These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with sporadic CJD may have a disease arising from BSE exposure," they wrote. The researchers said their findings were important when considering the present sporadic CJD outbreak in Switzerland, which had the highest incidence of cattle BSE in Europe over the past 12 years. There was a two-fold increase in sporadic CJD in the last 18 months in Switzerland, while cases of vCJD remain low, a spokesman for the MRC said. - Sapa-DPA http://iol.co.za/index.php?click_id=143&art_id=iol103980126094S532&set_id=1 TSS http://www.vegsource.com/talk/madcow/messages/9912195.html ================================================= 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 1. Introduction: Recommendations for Use of Vaccines Manufactured with Bovine-Derived Materials 2. Transcripts of 27 July, 2000, Joint Meeting of the Transmissible Spongiform Encephalopathy and Vaccines and Related Biologicals Advisory Committees 3. CBER and FDA Guidance Documents on Sourcing of Bovine-Derived Materials 4. Vaccines and Vaccinations: CDC / NIP / NVP Website 5. Overview of Vaccine Manufacturing 6. Estimating Risk for vCJD in Vaccines Using Bovine-Derived Materials 7. Questions and Answers 8. Current list of Vaccines Using Bovine-Derived Materials from countries on the USDA's BSE list or from Unknown Countries 9. Countries/Areas Affected With Bovine Spongiform Encephalophathy [CFR 94.18] - Animal and Plant Health Inspection Service (APHIS), US Department of Agriculture 10. 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 1. Wells G.A.H. et al. 1987. A novel progressive spongiform encephalopathy in cattle. Veterinary Record 121:419-420 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 Table of Contents 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 * Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics * Manufacturers of FDA-regulated Products * Letter to Manufacturers of FDA-regulated Drug/Biological/Device Products * 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 * 1998 USDA Interim Rule on Import Restrictions of Ruminant Material from Europe (FR 63(3):406-408, 1/6/98) * Letter to Manufacturers of Biological Products: Recommendations Regarding Bovine Spongiform Encephalopathy - (Text), (PDF) Table of Contents 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 Table of Contents 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 Vaccines that use bovine-derived materials of unknown geographical origin include: * Aventis Pasteur, S.A.’s Polio Vaccine, Inactivated, IPOL 1This information will be periodically updated to reflect the most current status. Table of Contents http://www.fda.gov/cber/bse/bse.htm Bovine Spongiform Encephalopathy (BSE) Estimating Risks for vCJD in Vaccines Using Bovine-Derived Materials The risk of vCJD from bovine-derived materials The risk of developing an illness such as vCJD from the use of bovine-derived material in the manufacture of vaccines is a function of a number of factors, including the nature and the amount of the bovine tissue that is used in manufacture, as well as the date and country of origin of the cows (1). Other factors, such as how the cows were fed, are also important. In this regard, the CDC estimates that the risk, if any, for vCJD from eating a beef meal in Europe is less than approximately 1 in 10 billion [http://www.cdc.gov/travel/madcow.htm]. CBER’s survey of vaccine manufacturers revealed a number of vaccines that utilized bovine materials that were obtained from countries where BSE or a significant risk for BSE exists. An estimate of the risk that the use of these materials might pose is presented in the following sections. Two examples have been chosen for presentation here, namely, the risk from the use of fetal calf serum sourced from the United Kingdom (UK) in the derivation of a viral working seed that is subsequently used in vaccine manufacture and the use of European-sourced (excluding the UK) beef broth in the production of a bacterial toxoid. Based on CBER’s survey of the use of bovine-derived materials sourced from countries on the USDA BSE-list, the potential risk that would be associated with other uses of bovine-derived materials in vaccine production would be less than might be associated with these two situations. The infectivity of most bovine-derived materials has not been determined experimentally. More is known about the infectivity of various ovine-derived (from sheep) materials. The knowledge of the infectivities of different ovine tissues relative to each other can be used to estimate the relative infectivities of bovine tissues. For example, if we know that, on a gram for gram basis, sheep brain is 100 million times more infective than sheep muscle, we can assume that bovine brain is also 100 million times more infective than bovine muscle. Thus, if the infectivity of bovine brain has been measured, and contains 10 million infective doses per gram, then we can estimate that bovine muscle is 100 million times less infective and contains 0.1 infective dose per gram. Not surprisingly, since BSE and scrapie (the corresponding disease in sheep) are neural diseases, the greatest infectivity is found in neural tissue. Based on experimental studies, infected bovine brain contains approximately ten million infectious units per gram when administered to other cattle (2,3). In other tissues, such as serum or skeletal muscle, no infectivity has been detected. This does not mean that there is no infectivity associated with these materials; only that, if they are infectious, then the infectivity is at a level that is too low to be measured by current tests. Table I presents the estimated infectivity of different bovine-derived tissues as determined by The European Agency for the Evaluation of Medicinal Products (EMEA) The actual infectivity of skeletal muscle or serum, for example, may be well below the values shown; we will, nevertheless, use these values in our risk estimates. It should be noted that these values are based on experiments in which animals were infected by intra-cerebral injection with affected tissue; this is the most effective means of infecting experimental animals. When another route of administration, namely intramuscular injection, is used, infection rates are estimated to be approximately 200 fold lower (4). The risk assessments follow. 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 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 This yields a risk estimate for vCJD of 1 case in 2 billion doses of vaccine [(1/10,000) x 1,000 x (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 # 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. Table of Contents http://www.fda.gov/cber/bse/risk.htm oint Meeting of the July 27, 2000 The TSEAC and VRBPAC were requested to consider appropriate precautions to be taken with regard to the use of bovine-derived materials in the manufacture of vaccines when those materials were obtained from countries in which BSE is known to exist or from countries where the USDA has been unable to assure the FDA that BSE does not exist ("BSE-risk countries"). The committees were also asked to consider the potential risks and possible actions to be taken with regard to licensed or investigational vaccine products that may be affected. The following questions were presented to the committee for discussion and comments. There were no formal votes on any of the questions. 1. Please discuss the potential risk presented by the use of bovine-derived materials, sourced from Europe (including the UK), in currently licensed vaccines. In this discussion, please comment on the various risk estimates that have been presented to the Committee. In this discussion, please include: 1. Preparation of bacterial and viral master and working seeds; preparation of master and working cell banks (e.g., use of calf serum, fetal calf serum). Committee members stated that the risk of TSE agents in fetal calf serum is very low, but there could be a potential risk. The committee expressed concern about manufacturers using serum from BSE-risk countries for routine vaccine production and agreed that such manufacturers should switch to appropriate sources immediately. The committee members stated that use of a small amount of fetal calf serum sourced from the UK and used to derive master cell banks presented a negligible (as opposed to a significant) risk. The risk of exposure to the BSE agent is small compared to the possible risks related to changes in a vaccine product due to changes of the master seed material. The risk of calf serum was not specifically discussed. 2. Fermentation process (e.g., use of bovine-derived media) 3. Formulation of the final products (e.g., use of gelatin, etc.) For both parts "b" and "c", while the potential risk was acknowledged to be very small, steps in a manufacturing process (e.g., chromatography, filtration) may help reduce any possible contamination with the BSE agent. The committee also discussed the possibility of manufacturers investigating test methods to rule out the presence of the BSE agent. Additionally, in this discussion, please include risk assessments for bovine materials sourced, at different times, from different European countries (e.g., UK, Germany, France). The committee stated that 1980 was the cut off date previously decided upon regarding the risk of exposure to the BSE agent for blood donations. In light of that decision, the committee agreed that 1980 would be an appropriate cut-off date for concern about BSE risk in bovine-derived material used in vaccines. The committee stated that in light of current scientific knowledge, the risk of bovine-derived materials sourced from BSE-risk countries in currently licensed vaccines is a "theoretical" risk. The risk assessment is dependent on the geographic source, the type of tissue, and the processing. None of the current estimates of risk can be precisely quantified. This theoretical risk must be balanced against the benefits of the vaccination program (or the real risk of not being vaccinated). 2. The following item pertains to currently licensed US vaccines that contain bovine-derived material obtained from Europe (including the UK). Please discuss those circumstances, if any, under which FDA should take specific regulatory action regarding these vaccines. Some examples of regulatory actions which are available to the FDA include product recall, modification of the package insert, and/or issuance of a "Dear Doctor/Health Care Provider" letter. Committee members agreed that some form of notification to vaccine recipients or "public disclosure" should be made regarding vaccines which may be manufactured with bovine materials sourced from BSE-risk countries. The committee discussed but was not in full agreement on what would be the most appropriate means of disclosure. The options discussed included issuance of a Dear Health Care Provider letter, inclusion of such information in the package insert, a joint statement of the agencies within the Department of Health and Human Services, or publication by journal article. The committee agreed that any disclosure should be carefully worded in order to express the theoretical risk of exposure to the BSE agent versus the benefit of receiving the vaccine. 3. The following item pertains to investigational (non-US licensed) vaccines that contain bovine-derived material obtained from Europe (including the UK). This includes certain investigational vaccines (used under IND) that contain currently-US licensed vaccines as components (such as components of a new investigational combination vaccine). In addition, this includes the "usual" investigational vaccines without previously US licensed components. Please discuss those circumstances, if any, under which FDA should take specific regulatory action regarding these investigational vaccines, such as stopping a clinical trial (pending an acceptable remedy of the product) or modification of the informed consent form. While the theoretical risk of vaccine products under investigation is the same as the theoretical risk of licensed vaccines, committee members agreed that products under investigation do not have a proven benefit as compared to licensed vaccine products. Therefore, investigational vaccines should be considered separately from licensed products. The committee members agreed that participants in clinical trials should be notified through informed consent about the theoretical risk of vaccines produced with bovine-derived materials from a BSE-risk country. Last Updated: 5/7/2002 http://www.fda.gov/cber/advisory/tse/tsesum072700.htm ALSO; W.H.O. http://www.who.int/vaccines-diseases/safety/hottop/bse.shtml http://www.vegsource.com/talk/lyman/messages/7622.html http://www.vegsource.com/talk/lyman/messages/7631.html TSS
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