Medical Product Certified Herd Use For Bovine-Derived Source
Materials Proposed By FDA

Use of certified cattle herds for medical product bovine source material
to reduce the risk of contamination by bovine spongiform encephalopathy,
or mad cow disease, is one proposal FDA wants its Transmissible
Spongiform Encephalopathies Advisory Committee to consider at a Feb.
12-13 meeting.

To reduce the risk of BSE, "additional measures, such as use of
certified herds, the use of animals under 24 or 30 months of age, and/or
the use of rapid PrP testing for BSE might be considered either as a
general measure or one for specific materials, products, or uses
determined to present higher potential transmission risks," FDA said.

"FDA seeks the committees discussion of its current risk reduction
approaches for medical products as well as such additional and/or
alternative approaches."

The committee will hear an update on the recent discovery of mad cow
disease in a dairy cow in Washington State. "The finding of a case of
BSE in the USA in a cow imported from Canada suggests that the BSE risk
is low but not zero," FDA noted.

Bovine-derived materials are used in drugs, devices, vaccines, blood
products, and human and tissue-based products.

At a July meeting
,
the TSE committee recommended that FDA clarify its recommendations to
industry about safe sources of bovine bone gelatin for use in cosmetics,
dietary supplements and drugs. In particular, the committee said that
FDA should further define in its guidance what it means by a "BSE-free"
herd when referring to acceptable sources of materials for gelatin, used
in drug capsules and other medical products, from countries where BSE
has occurred.

The guidance states: "At this time, there does not appear to be a basis
for objection to the use of gelatin in FDA-regulated products for oral
consumption and cosmetic use by humans when the gelatin is produced from
bones obtained from cattle residing in...BSE countries, if the cattle
come from BSE-free herds and if the slaughterhouse removes the heads,
spines and spinal cords directly after slaughter."

An animal feed rule issued in 1997 by the agency prohibits the feeding
of most mammalian protein to ruminants, such as cows. In December,
following the mad cow case, the U.S. Department of Agriculture issued
new regulations to further reduce the risk. The Department of Health and
Human Services said in January that it would publish an interim final
rule that would prohibit the use of mammalian blood, poultry litter, and
plate waste in ruminant feed.

To watch a live or archived webcast of this meeting, click the button
below. To arrange for live videoconferencing or to order videotapes &
CDs, email webcasthelp@elsevier.com  or
call 800-627-8171.
















This meeting will be held February 12, 2004 at the Holiday Inn in Silver
Spring, Md. beginning at 8 a.m. The committee discussion on mad cow
disease and medical products continues on Feb. 13.
Committee Information




Transmissible Spongiform Encephalopathies Advisory Committee

Executive Secretary: William Freas (HFM-71), (301) 827-0314

February 12-13, 2004

* Notice of Meeting (PDF)
* February 12-13, 2004 Agenda (PDF) (Word)

DRAFT AGENDA 02/4/04

FOOD AND DRUG ADMINISTRATION
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE

February 12 & 13, 2004
Holiday Inn Silver Spring
8777 Georgia Avenue
Silver Spring, MD 20910

First Day, Thursday, February 12, 2004

8:00 a.m. Administrative Remarks (10)
8:10 Retirement awards for departing committee members
Dr. Jesse Goodman (not confirmed)(10)
Director, Center for Biologics Evaluation and Research (CBER)
8:20 Opening Remarks
FDA - Dr. Jesse Goodman (requested) (10)
Dr. Suzette Priola, TSEAC Chairperson (10)

8:40 Topic # 1  Informational presentations on risk of transfusion
transmission of variant Creutzfeldt-Jakob Disease (vCJD)

A. A presumptive transfusion-transmitted case of vCJD in the U.K. 
Dr. Robert Will, Consultant Neurologist
National CJD Surveillance Unit, (30)

B. Epidemiology of vCJD and CJD
1. Epidemiological approach: CJD Blood risk  Dr. James Sejvar, Division
of Viral and Rickettsial Diseases, CDC (15)
2. Comparison of the transfusion risk for CJD vs. vCJD  Dr. Steve
Anderson, FDA (15)
3. Canadian risk assessment: transfusion risk for vCJD  Dr. Susie
ElSaadany, Center for Disease Prevention and Control, Health Canada (15)

C. Recent experimental studies in animals regarding TSE infectivity in
blood and transfusion transmission of TSEs
1. Review of recent experiments in rodents and in sheep -
Dr. Robert Rohwer, Director Molecular Neurovirology Unit, VA
Medical Center, Baltimore (45)
2. Review of recent experiments in non-human primates -
Dr. Paul Brown, Medical Director, Laboratory of
Central Nervous System Studies NIH (15)

TSEAC AGENDA

First Day, Thursday, February 12, 2004 (continued)

10:55 a.m. Break (20)
11:15 Open Public Hearing (30)
11:45 Committee Discussion (45)
12:30 Lunch

1:30 Topic # 2  Update on Bovine Spongiform Encephalopathy (BSE) in the
United States

A. Review of the reported case of BSE in Washington State
1. Case Presentation and USDA Surveillance Program- Dr. Lisa Ferguson,
USDA (15)
2. Confirmation of BSE in the affected cow - Dr. Al Jenny, National
Veterinary Services Laboratory, USDA (10)
3. Food Safety Regulations for BSE  Dr. Mary Porretta, Regulations
Development and Analysis Division
Food Safety and Inspection Service, USDA (20)
4. Status of the U.S. Feed Ban
Dr. Stephen Sundlof, Director, Center for Veterinary Medicine (10)

2:25 p.m. FDA Introduction to Topics #3 and #4  Dr. David Asher, CBER (15)

Topic #3 - Models for Risk-Based Sourcing of Bovine Materials in
FDA-regulated medical products

A. New and proposed BSE-related USDA requirements -
Dr. Lisa Ferguson, D.V.M. Senior Staff Veterinarian,
U.S. Department of Agriculture (15)
B. Harvard Risk Analysis - Dr. Joshua Cohen, Senior Research Associate,
Harvard Center for Risk Analysis (30)
C. Canadian and U.S. BSE Risk - Dr. Steven Anderson, FDA (20)
D. USDA Consultant Risk Assessment  (TBD)??

3:45 Open Public Hearing (30)
4:15 Committee discussion on factors to consider in risk-based sourcing
models for bovine materials (75)
5:30 p.m. Adjourn for the day

TSEAC AGENDA

Second Day, Friday, February 13, 2004

8:00 a.m. Administrative Remarks

8:10 a.m. Topic #4 - Minimizing risks of TSE agents in FDA-regulated
medicinal products

A. Current Safeguards for Blood Products
a. Approach to products containing or exposed to bovine materials - Dr.
Dorothy Scott, OBRR/CBER (15)
b. Current blood donor deferrals and their impact - Dr. Alan Williams,
OBRR/CBER (15)
B. Minimizing the Risks of TSE Agents in Human Tissues - Dr. Melissa
Greenwald, OCTGT, CBER (15)
C. The Use of Bovine-derived Products in the Manufacture of Vaccines and
Allergenic Products - Dr. William Egan, OVRR, CBER (15)
D. Minimizing the Risk of TSE Agents in Drugs - Dr. Gerald Feldman, CDER
(15)
E. Minimizing Risk of TSE Agents in Medical Devices - CDR Martha OLone,
CDRH (15)
F. Food and Cosmetic Safety - Dr. Morris Potter, CFSAN (15)

10:10 Break
11:00 Open Public Hearing
12:00 Lunch

1:00 Committee Discussion of safeguards for FDA-regulated medicinal
products in light of the recent case of presumptive
transfusion-transmission of vCJD and the report of a BSE positive cow in
the U.S.
3:00 p.m. Adjourn

* February 12, 2004 Roster (PDF) (Word)

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


EXECUTIVE SECRETARY


Freas, William, Ph.D.
Scientific Advisors & Consultants Staff
Center for Biologics Evaluation
and Research, FDA, HFM-71
1401 Rockville Pike
Rockville, MD 20852-1448
TEL: (301) 827-1295
FAX: (301) 827-0294

COMMITTEE MANAGEMENT SPECIALIST

Langford, Sheila D.
Scientific Advisors & Consultants Staff
Center for Biologics Evaluation
and Research, FDA, HFM-71
1401 Rockville Pike
Rockville, MD 20852-1448
TEL: (301) 827-1294
FAX: (301) 827-0294
MEMBERS

Chairperson

Priola, Suzette A., Ph.D. 01/31/05
Investigator
Laboratory of Persistent and Viral Diseases
NIH/NIAID
Rocky Mountain Laboratories
903 South 4th Street
Hamilton, MT 59840

Members
Bailar, John C., III, M.D., Ph.D. 01/31/05
Professor Emeritus
Department of Health Studies
University of Chicago
5841 South Maryland Avenue, MC2007
Chicago, Illinois 60637-1470

Bias, Val D. 01/31/07
Co-Chairman
Blood Safety Working Group
National Hemophilia Foundation
7700 Edgewater Drive
Suite 710
Oakland, CA 94621

Bracey, Arthur W., M.D. 01/31/07
Associate Chief, Pathology
Department of Pathology
St. Lukes Episcopal Hospital
6720 Bertner Avenue, MC 4-265
Houston, TX 77030

Creekmore, Lynn H., D.V.M. 01/31/07
Staff Veterinarian
U.S. Department of Agriculture
APHIS, Veterinary Services
2150 Center Avenue, Bldg. B, MS 3E13
Fort Collins, CO 80526-8117


DeArmond, Stephen J., M.D., Ph.D. 01/31/05
Professor
Department of Pathology, HSW-430
University of California
School of Medicine
San Francisco, California 94143-0506

Gambetti, Pierluigi, M.D. 01/31/05
Professor and Director
Division of Neuropathology
Case Western Reserve University
2085 Adelbert Road
Cleveland, OH 44106

Hogan, R. Nick, M.D., Ph.D. 01/31/07
Associate Professor of Opthalmology, Pathology,
Neurology, and Neurosurgery
Neuro-Ophthalmology and Ocular
Pathology/Oncology Sections
University of Texas Southwestern Medical
Center
Dallas, TX 75390

Johnson, Richard T., M.D. 01/31/06
Professor of Neurology
Department of Neurology
Johns Hopkins University School of Medicine
600 North Wolfe Street
Meyer 6-181A
Baltimore, MD 21287

Page 2 - TSE Roster

Non-Voting Industry Representative

Petteway, Stephen R., Jr., Ph.D. 01/31/05
Bayer Corporation
Pharmaceutical Division
Biological Products
85 T.W. Alexander Drive
Research Triangle Park, NC 27709

Updated 01/13/04

* February 13, 2004 Roster (PDF) (Word)

Invited Speakers for
TSEAC
February 12 & 13, 2004


Paul W. Brown, M.D.
Medical Director
Laboratory of Central Nervous System
Studies
National Institute of Neurological
Disorders and Strokes
NIH, Building 36, Room 5CB21
36 Convent Drive
Bethesda, MD 20892-4122

Joshua Cohen, Ph.D.
Senior Research Associate
Harvard Center for Risk Analysis
718 Huntington Avenue
Boston, MA 02115-5924

Susie ElSaadany, Chief
Statistics and Risk Assessment Section
Blood Safety Surveillance and Health
Care Acquired Infections Division
Centre for Infectious Disease Prevention
and Control
Population and Public Health Branch
Health Canada
A.L. 0601E2, Building No. 6
Tunney 's Pasture
Ottawa, ON K1A 0L2

Lisa A. Ferguson, , D.V.M.
Senior Staff Veterinarian
U.S. Department of Agriculture
APHIS, Veterinary Services
Emergency Programs
4700 River Road, Unit 41
Riverdale, MD 20737-1231

Allen L. Jenny, D.V.M.
Pathobiology Laboratory
National Veterinary Services Laboratory
Ames, IA 50010

Mary Porretta
Regulations Development and Analysis
Division
Food Safety and Inspection Service, USDA
300 12th Street, SW
Washington, DC 20250


Robert Rohwer, Ph.D.
Director, Molecular Neuro-Virology Unit
VA Medical Center 151
10N. Green Street
Baltimore, MD 21201

James J. Sejvar, MD
Neuroepidemiologist
Division of Viral and Rickettsial
Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
1600 Clifton Road, MS A-39
Atlanta GA 30333

Professor Robert G. Will, M.D.
Consultant Neurologist
National CJD Surveillance Unit
Western General Hospital,
Crewe Road,
EDINBURGH, EH4 2XU UK

Consultants for
TSEAC
February 12 & 13, 2004



Jeanne V. Linden, M.D., M.P.H.
Director, Blood and Tissue Resources
New York State Department of Health
Wadsworth Center
Empire State Plaza
Albany, NY 12201-0509

George Nemo
Nemo, George
Division of Blood Diseases and
Resources
National Institutes of Health, NHLBI
6701 Rockledge Drive
Rockledge II Room 10142
Bethesda, MD 20893-7950

Ferguson, Lisa A., D.V.M.
Senior Staff Veterinarian
U.S. Department of Agriculture
APHIS, Veterinary Services
Emergency Programs
4700 River Road, Unit 41
Riverdale, MD 20737-1231

Allen L. Jenny, D.V.M.
Pathobiology Laboratory
National Veterinary Services Laboratory
Ames, IA 50010

Khabbaz, Rima F., M.D.
Associate Director for Epidemiologic
Science
CDC/NCID, MS C12
1600 Clifton Road
Atlanta, GA 30333
Kenrad E. Nelson, M.D.
Professor, Department of Epidemiology
Johns Hopkins University School of
Hygiene & Public Health
615 N. Wolfe St., Room E-7132
Baltimore MD 21205

James J. Sejvar, MD
Neuroepidemiologist
Division of Viral and Rickettsial
Diseases
National Center for Infectious Diseases
Centers for Disease Control and
Prevention
1600 Clifton Road, MS A-39
Atlanta GA 30333

Walker, Shirley J.
(Consumer Representative)
Vice President of Health &
Human Services
Urban League of Greater Dallas &
North Central Texas
4315 South Lancaster Road
Dallas, TX 75216

Wolfe, Sidney M., M.D.
Director
Public Citizen Health Research Group
Public Citizen
1600 20th Street, NW
Washington, DC 20009

* February 12, 2004 Briefing Information

Food and Drug Administration
Transmissibe Spongiform Encephalopathies Advisory Committee

February 12, 2004

Briefing Information

Presumptive Transfusion Transmission of Variant Creutzfeldt-JakobDisease
(vCJD): Possible Implications for FDA Policies (HTM) (PDF) (Word)

Update on Bovine Spongiform Encephalopathy (BSE) in the United States
(HTM) (PDF) (Word)

Models for Risk-Based Sourcing of Bovine Materials in FDA-Regulated
Medical Products (HTM) (PDF) (Word)

http://www.fda.gov/ohrms/dockets/ac/04/briefing/4019b1.htm

February 13, 2004 Briefing Information

Food and Drug Administration
Transmissibe Spongiform Encephalopathies Advisory Committee

February 13, 2004

Briefing Information

Current Safeguards for Blood Products: Approach to Products Containing
or Exposed to Bovine Materials (HTM) (PDF) (Word)

Minimizing Risks of TSE Agents in Human Tissues (HTM) (PDF) (Word)

The Use of Bovine-Derived Products in the Manufacture of Vaccines and
Allergenic Products (HTM) (PDF) (Word)

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE MEETING

February 12 and 13, 2004
Silver Spring, MD

Issue Summary, Topic 4.C


The Use of Bovine-derived Products in the Manufacture of
Vaccines and Allergenic Products

Current Regulatory Approach to Vaccines and Allergenic Products
Manufactured with Bovine-derived Materials


Background

Vaccines and allergenic products may utilize bovine-derived materials
during manufacturing or in the final formulation. FDA and CBER have
requested, in a series of letters and in a Points to Consider document
on cell substrates (1993), that materials from cattle born, raised, or
slaughtered in countries where BSE is known to exist not be used in the
manufacture of FDA-regulated products intended for administration to
humans; FDA has referenced the USDA (APHIS) list of BSE-countries. Since
BSE has spread beyond Europe, it has become increasingly difficult to
ensure consistent sourcing of all bovine materials from BSE-free areas.
Switching sources for bovine-derived materials to countries not on the
USDA list requires considerable time and raises a number of issues
related to products that are in distribution, products that are in the
process of being manufactured, as well as cell and seed banks that have
been established prior to the recognition of BSE in a country.

Types of Bovine Materials Used in Vaccines and Allergenic Products

Bovine-derived products are used during the manufacture or formulation
of a large number of vaccines and allergenic products (molds). The
bovine-derived products that are commonly used include: fetal calf
serum, beef muscle/organ extracts, gelatin, and a variety of small
molecules (such as, protein digests, lactose, Tween, and glycerol).
These materials are used in the derivation of master and working cell
banks, master and working bacterial and viral seed banks, cell culture
and fermentation, immunogen purification, and product formulation.


FDA Actions to Minimize the Risk of TSE Agents in Vaccines and
Allergenic Products

In an effort to minimize risks from TSE agents, FDA has:

· Requested manufacturers to source bovine materials from non-BSE countries
· Reviewed the use of all bovine-derived materials and their sources for
licensed and IND products
· Encouraged the use of non-animal sources when feasible

In addition to these measures, product labeling provides risk
communication and the Office of Vaccines Research and Review website
contains a discussion of BSE-related issues that have arisen (vide
infra). For products that contain human serum albumin (e.g., the mumps,
measles, and rubella vaccine), the warnings section of the package
insert contains the statement: This product contains albumin, a
derivative of human blood. Based on effective donor screening and
product manufacturing, it carries an extremely remote risk for
transmission of viral diseases. Although there is a theoretical risk for
transmission of Creutzfeldt-Jakob disease (CJD), no cases of
transmission of CJD or viral disease have ever been associated with the
use of albumin.

In 2000, CBER learned that its recommendations regarding sourcing of
bovine-derived materials were not universally followed for all vaccines
and allergenic products. OVRR reviewed the use of bovine-derived
products and their sources for all vaccines and allergenic products.
Recommendations were made to the affected manufacturers and subsequently
discussed in a joint session with the TSE Advisory Committee and the
Vaccines and Related Biological Products Advisory Committee [see,
http://www.fda.gov/cber/bse/bse.htm]. Issues that were discussed
included: the use of fetal calf serum from the U.K. in the establishment
of several master and working seeds and cell banks, the use of
European-sourced beef muscle/organ extract for bacterial fermentation,
the use of European-sourced gelatin derivatives, and the use of a number
of European-sourced low molecular weight materials in vaccine
manufacture. 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 presented was theoretical and remote. They
also noted that the benefits of vaccination far outweigh any remote
risks of vCJD. However, the joint Committees recommended that: (1)
bovine-derived materials used in the routine production of vaccines and
sourced from countries on the USDA list should be replaced with
bovine-derived materials from countries not on the USDA list; (2)
working bacterial and viral seed banks and working cell banks that were
established using bovine-derived material from countries on the USDA
list be re-derived using bovine-derived materials from countries not on
the USDA list; (3) master cell and seed banks established using
bovine-derived materials from countries on the USDA list need not be
re-derived with bovine-derived materials from countries not on the USDA
list, the risk to altering the vaccine through re-derivation being
significantly greater than the theoretical risk from the BSE agent; (4)
these issues are of public concern and the public should be informed
about the safety of vaccines that used bovine-derived materials from
countries on the USDA list and the assessment of the nature of any risk
for vCJD from such vaccines. These recommendations from CBER and the
Advisory Committees have been implemented for vaccines. Several similar
issues were identified with allergenic mold extracts; the mold master
stocks were re-derived.

A number of bovine-derived materials that are used in U.S.-licensed
vaccines, and in vaccines under development, are sourced from, inter
alia, North America (the U.S. or Canada) or Canada. These bovine-derived
materials are used either in manufacture or in the derivation or cell
and seed banks. Based on an continuing assessment of risks and benefits,
the Office of Vaccines Research and Review has not requested
manufacturers to seek alternate sources of bovine-derived materials for
products where Canadian sourced materials are, or have been, used.

Current CDER Approaches to Minimizing the Risk of TSE Agents in Drugs
(HTM) (PDF) (Word)

CDER Current Recommendations on Measures to Minimize Risk of TSE Agents
in Medical Devices (HTM) (PDF) (Word)

Memorandum Regarding TSE/BSE Letter to Manufacturers of FDA-Regulated
Medical Devices Containing Animal Tissue Products or Components (PDF)

Impact on FDA-Regulated Foods, Including Dietary Supplements, and
Cosmetics (HTM) (PDF) (Word)

Food and Drug Administration
Transmissible Spongiform Encephalopathies Advisory Committee

February 12, 2004

Issue Summary for Topic #4 F, Update on the Washington State BSE Case

Issue: Impact on FDA-regulated Foods, including Dietary Supplements, and
Cosmetics

Background:
FDA has jurisdiction over most food products, including those that
contain a relatively small proportion of meat (exempted under the
Federal Meat Inspection Act). Many of the foods, including dietary
supplements, food additives, and food ingredients, and cosmetics
regulated by FDA contain beef or components of beef. Examples of the
bovine-origin products regulated by FDA are soups and stocks, beef
flavors and extracts, gelatin, collagen, amino acids, and foods that
contain small amounts of beef, such as pizza, multi-component frozen
meals, and entrees. Many cosmetics contain tallow or tallow derivatives,
gelatin, collagen, and other bovine components. Dietary supplements are
often enclosed in gelatin capsules and may be composed of a variety of
bovine tissues.
Foods, including dietary supplements, food additives, and food
ingredients may be formulated from any ingredient that is safe and
wholesome, unless specifically prohibited by regulation. Since 1992, the
agency has strongly recommended that firms manufacturing or importing
foods that might contain bovine tissues, including extracts or
substances derived from these tissues, take whatever steps are necessary
to reduce the potential risk of human exposure to or transmission of the
infectious agent that causes BSE. Since 1992, FDA has advised dietary
supplement manufacturers and distributors that they should take steps to
ensure that no dietary supplement ingredients come from cattle born,
raised or slaughtered in any country known to have BSE or that has
inadequate controls to detect and control it.
Except for color additives and those ingredients prohibited or
restricted by regulation, a manufacturer may essentially use any
ingredient in the formulation of a cosmetic product provided the product
is safe, properly labeled, and not adulterated by use of the ingredient.
As is true for foods, including dietary supplements, since 1994, we have
strongly recommended that firms manufacturing or importing cosmetic
products that contain bovine tissues, including extracts or substances
derived from these tissues, take
whatever steps are necessary to reduce the potential risk of human
exposure to or transmission of the infectious agent that causes BSE.
Gelatin produced from bovine hides and bones is used in foods, including
dietary supplements, cosmetics, and many other FDA-regulated products.
In 1997, to reduce the risk of BSE transmission, the agency published
guidance on production of gelatin for oral consumption that recommended
removal of the skull, spine and spinal cord and made recommendations on
sourcing of bones and hides. During the July 2003 TSEAC meeting,
evidence on the effectiveness of gelatin processing was presented to the
committee. We are considering the need to revise the guidance in view of
the pending issuance of the BSE regulation recently announced by FDA. If
the gelatin guidance is still necessary, we will revise it taking into
consideration the committees comments and the provisions of the
regulation. The agency also recently received a petition to modify the
guidance. If the gelatin guidance is revised, it will be presented at a
TSEAC meeting later in 2004.
The identification of the first case of BSE in the United States., even
though the animal was imported from Canada, triggered emergency response
reactions by USDA and FDA to retrieve products of the slaughter that
went to edible and inedible rendering. USDA published regulations that
prohibit the inclusion in human food of downer cattle, SRMs from cattle
30 months of age or older, and the product Mechanically Separated Beef,
and established new standards for Advanced Meat Recovery meat to limit
central nervous system tissue in the product. The general flow of
bovine-origin materials into FDA-regulated foods, dietary supplements,
and cosmetics influences the degree of BSE risk to consumers in the
United States, and is under agency review.

CURRENT
On January 26, 2004, FDA announced that it intends to publish a
regulation that bans in human foods, including dietary supplements, and
cosmetics:
· Use of non-ambulatory disabled animals and animals that die before
being presented for slaughter
· Specified Risk Materials,
· Mechanically Separated (Beef), and
· Tissue from animals that are inspected and not passed for human
consumption
This will be an interim final regulation, open to public comment, that
essentially parallels actions taken by USDA in their interim final rules
published January 12, 2004.

http://www.fda.gov/ohrms/dockets/ac/04/briefing/4019b2.htm

http://www.fda.gov/ohrms/dockets/ac/cber04.html#TransmissibleSpongiform

Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001
Date: Tue, 9 Jan 2001 16:49:00 -0800
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy BSE-L
To: BSE-L

snip...

[host Richard Barns]
and now a question from Terry S. Singeltary of
CJD Watch.

[TSS]
yes, thank you,
U.S. cattle, what kind of guarantee can you
give for serum or tissue donor herds?

[no answer, you could hear in the back ground,
mumbling and 'we can't. have him ask the question
again.]

[host Richard]
could you repeat the question?

[TSS]
U.S. cattle, what kind of guarantee can you
give for serum or tissue donor herds?

[not sure whom ask this]
what group are you with?

[TSS]
CJD Watch, my Mom died from hvCJD and we are
tracking CJD world-wide.

[not sure who is speaking]
could you please disconnect Mr. Singeltary

[TSS]
you are not going to answer my question?

[not sure whom speaking]
NO

snip...

http://vegancowboy.org/TSS-part1of8.htm

(don't let the vegancowboy.org url fool you, the meeting really
took place and I really ask the question, and they really did not
answer it...TSS)

RE-The Use of Bovine-derived Products in the Manufacture of
Vaccines and Allergenic Products

THEY KNEW ALL ALONG !!!........TSS

MEDICINES ACT 1968 'NO RESTRICTIONS EXCEPT FOR SCRAPIE'

PLEASE NOTE, the data below posted to vegsource site can _now_
be well verified through url if anyone needs one. back when I
posted this data, i was getting the info. via the FOIA in both
the UK and the USA. the UK documents were being flown to me
''BY AIR MAIL PAR AVION ROYAL MAIL''. I then transferred
to computer via scanner and put on the www to document all the lies
that we have been told. THIS was done well before the data was
released to the public via the BSE Inquiry. NOW the data is available
via the online BSE Inquiry, and I can now look up the old YB#s and
go back and find the documents I have had, on a site that is not
a site such as the dreaded veg sites. These dreadful sites gave
me a platform to post this critical data when know one else would.
I thank them for that. OH, if it will make anyone feel better,
don't tell nobody, but I never stopped eating beef, pork, or
chicken, never did like deer meat. just got sick after I figured
out what had really been going on with the industry, the more I
educated myself, the less I ate. NOW, back to TSEs...TSS

http://www.vegsource.com/talk/lyman/messages/7573.html

8. The Secretary of State has a number of licences. We understand that
the inactivated polio vaccine is no longer being used. There is a stock
of smallpox vaccine. We have not been able to determine the source
material. (Made in sheep very unlikely to contain bovine ingredients).

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
guidelines.

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
safety of vaccines had not yet been resolved. He contacted Dr Pickles,
and their conversation led him to ask Dr Harris to look into the matter:
My attention has been drawn to a sentence in Dr Pickles' draft of a
submission to the Secretary of State on this matter. It reads: 'At the
present time we can't give any complete guarantee of safety for human
medicines that use bovine materials in manufacture such as most
vaccines.' Having looked at the report I am not able to find any
statement which supports this statement of concern. I have, however,
therefore spoken to Dr Pickles on the telephone and she reports to me
that for some considerable time she has had serious concern about the
safety of bovine-based vaccines in the light of the fact it has been
discovered that contamination with placental material (which is known to
be heavily infected with the BSE particle) is a distinct possibility in
the preparation of material for human vaccines derived from foetal
serum. This matter as described to me by Dr Pickles gives me sufficient
cause for concern to ask you to look into it urgently together with
Medicines Division. I shall amend the submission to indicate that the
question of the safety of vaccines derived from bovine material is a
matter which has not been dealt with directly by Southwood's group, but
is one in which I am making urgent enquiries. 22

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
there was a dramatic increase in the number of reported flocks. This
increase in reports included a relatively high proportion of goat
flocks, generally considered more resistant to natural scrapie than
sheep. Details of the timing of the flock outbreaks, composition of the
flocks and vaccination status were provided. It was noted that
vaccination for Mycoplasma agalactiae was provided to a large proportion
of the flocks developing scrapie, and that this vaccine is made from
sheep brain and mammary gland. Small batches of brain and mammary glands
are mixed, and given subcutaneously to adult and young animals,
providing considerable possible exposure to contaminated material. Some
flocks receiving this vaccine did not develop scrapie, and western blot
and transmission experiments are underway. However, the consultation
agreed that the epidemiologic evidence points toward a vaccine origin
for the scrapie disease seen in some of the flocks.

snip...

7.6 Could vaccines prepared from animal brain tissue pose a risk of
transmission of Transmissible Spongiform Encephalopathies to humans?
FranÒ§ois Meslin:

Over 40,000 deaths due to rabies are reported annually worldwide and
each year seven to eight million people receive antirabies vaccine
treatment following dog bites. Dog rabies poses a significant public
health problem in Asia, as 85% of the human deaths due to rabies
reported worldwide and 80% of the vaccine doses applied in
developing countries come from this part of the world.
In many Asian countries such as Bangladesh, India, Nepal and Pakistan,
sheep-brain based Semple vaccine 15 is the only vaccine available free
of cost. It represents 50 to 95% of all vaccine doses used for rabies
post-exposure treatment, depending upon the country. A complete
treatment consists of 10 subcutaneous daily injections
of 2 to 5 ml (depending mainly on patient size and nature of the
exposure) plus booster doses; that is a total of 25 to 50 ml of the 5 %
sheep brain suspension injected over a 10-day period.
According to the literature, the reported rate of neuroparalytic
complications following the use of this vaccine varies from 1:600 to
1:1575 administrations, and 20-25% of these lead to death. The exact
incidence of neuroparalytic complications throughout India or other
countries in the area is not known. However, in the State of
Karnataka, India, 112 cases of neuroparalytic accidents were admitted in
the past 20 years following Semple vaccine administration. In contrast,
the newly developed cell culture or embryonating egg vaccines are
effective and safe, with lower and less severe complication rates.
In many Asian countries, Semple type vaccine has been used for the past
90 years. In India forty million ml of this vaccine are produced in this
country to treat at least 500 000 persons each year. In Pakistan 450 000
and in Bangladesh 60 000 people receive Semple type vaccine after
possible exposure to rabies. There is a theoretical risk of TSE
transmission to humans through parenteral administration of
these products. Although there is to date no evidence of such
occurrences in human medicine, recent events in the TSE field have
demonstrated that an animal TSE agent could affect human beings.
The situation is very similar regarding rabies vaccines for animal use.
For example various Indian veterinary vaccine institutes prepare 100
million ml of Semple vaccine for use in both rabies pre-and
post-exposure prophylaxis in dogs and food production animals each year.
Scrapie could be theoretically transmitted to animal vaccine recipients,
especially ruminants, through sheep-brain based vaccines such as
Semple type vaccine. This could happen because scrapie infectivity, if
present, would not be inactivated by the manufacturing process. In this
connection, a recent 15 Ã’x-propiolactone inactivated or phenolized
antirabies vaccine containing 5% suspension of sheep brain infected with
a fixed strain of rabies virus.

WHO/CDS/CSR/APH/2000.2

34 WHO Consultation on Public Health and Animal TSEs
Epidemiology, Risk and Research Requirements

publication strongly suggests that scrapie was transmitted to sheep and
goats through the administration of a veterinary vaccine whose method of
preparation is similar to the Semple type vaccine. In addition, various
Asian countries have begun to use animal tissues as feed supplement for
intensive sheep and dairy cattle production. This introduces an
additional, though still theoretical, possibility that scrapie, or even
BSE, could spread among the sheep population and enter the sheep flocks
that are used as a source of rabies vaccine production for human or
animal use. In areas where the status of animal TSE is not well
documented, this risk cannot be totally ruled out, though it may be
remote, as there is no test available at present to detect
pre-clinical cases of prion disease in sheep.

snip...

Recommendation 25

Human vaccines prepared from whole ruminant brains may carry the risk of
transmission of animal TSE agents, because the inactivation processes
usually applied to these products do not inactivate TSE agents. In
particular, considering the recent emergence of vCJD in humans related
to BSE in cattle, the consultation recommends that the use of these
vaccines should be avoided if suitable alternatives can be made
available. The Consultation strongly supported the recommendation made
by WHO Expert Committee on Rabies, which states:

"The (Expert) Committee reiterated, as stated in its 1983 report, its
support for the trend to limit or abandon completely - where
economically and technically possible - the production of
encephalitogenic brain-tissue vaccines, and strongly advocated the
production and use of inactivated cell-culture rabies vaccines in both
developed and developing countries."

Recommendation 26

The use of veterinary vaccines prepared from whole ruminant brains, for
use in ruminants, should be avoided unless the process ensures TSE
inactivation and/or removal, or the source animals have been
demonstrated to be free of any TSE.

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. IATROGENIC TRANSMISSION
Iatrogenic transmission of BSE has not been reported, or even suspected,
in cattle but there are some definite occurrences of scrapie in sheep
that have been reliably attributed to the use of non-commercial vaccines
containing ovine starting materials. For this reason, the issue is
discussed below. Other forms of iatrogenic transmission of TSE have been
restricted to humans and human tissues. For the sake of completeness and
convenience, these subjects are briefly discussed below.

III.3.1 VACCINES
Reference has already been made to the occurrence of at least several
hundred cases of scrapie in British sheep as a direct result of the use
of a vaccine against the tick transmitted, viral disease, louping-ill
(Gordon, Brownlee and Wilson, 1939, Gordon, 1946 and Greig, 1950). This
occurrence resulted from the accidental use of scrapie-infected source
material and processing methods that did not inactivate the scrapie
agent that was unknowingly present. A more recent possible occurrence of
possible iatrogenic scrapie has recently been reported in Etna Silver
crossbred goats in Italy by Cappucchio et al., (1998). The goats were
kept at grass and concentrate rations were not fed, thus eliminating a
source of infection from feed via mammalian proteins. Animals over two
months old were annually vaccinated against contagious agalactia caused
by Mycoplasma agalactiae. The vaccine included central nervous system
from pathogen-free sheep. The mortality rate in the goats reached
28% in 1 herd, 60% in the second and 5.5% in a third herd. About half
the 56 goats were between 2.5 - 3 years old. Only 1.15% of sheep that
were kept with the goats developed scrapie. Scrapie was confirmed by
microscopic examination of the brain and by detection of PrPSc including
by immunocytochemistry. PrPSc was widespread in the brain and beyond
sites of vacuolar change. The high mortality, severe loss of weight and
simultaneous appearance in the three herds were distinctly unusual
features in this outbreak. The source of infection remains uncertain and
unproven but iatrogenic transmission must be considered.
A larger epidemic involving 20 outbreaks of scrapie in sheep and goats,
also in Italy, has been even more recently reported by Agrimi et al.,
(1999). The annual incidence ranged from 1% to 90% with a mean incidence
for goats of 26% and for sheep of 10%. The total number of cases in
sheep and goats together was 1040. The clinical disease was confirmed by
microscopic examination of the brain and PrP immunocytochemistry or
Western blotting. The high incidence in goats, the high
within-flock/herd incidence, the temporal clustering, absence of
commercial concentrate feeding in eight flocks and association with the
use of a sub-cutaneously administered M. agalactiae vaccine, prepared
locally using brain and mammary tissue from clinically healthy sheep,
strongly suggests an iatrogenic origin. Scrapie appeared between 23 and
35 months after the vaccine was administered. A third outbreak in
southern Italy attributed also to the same vaccine has been described by
Caramelli et al, (2001) in a mixed flock of Comisana sheep and half-bred
goats in an upland area of southern Italy. High crude mortality and
scrapie incidence occurred in both species and a large proportion of
aged animals were affected. The neuropathology was similar to that in
other sheep in Italy with iatrogenic disease but different from
conventional natural scrapie. Affected sheep were all of the most
susceptible genotype (Codon 171 QQ). It is stressed that the vaccines
incriminated in the transmission of scrapie in all these incidents are
not commercially produced. They have been prepared and distributed
locally within the country. Dr Subash Arya has repeatedly drawn
attention to the possible risk of transmitting CJD to humans vaccinated
with sheep-brain derived vaccines in India, e.g. Arya, (1994). However,
neither Dr Arya nor any of his colleagues has yet found any such case.
The episodes of scrapie resulting from the use of vaccines prepared from
infected sheep tissues emphasises the need for caution and mandatory
selection of safe sources for starting materials used in the manufacture
of vaccines. Such vaccines could theoretically at least, be used in
cattle thus creating a potential risk, though it is most unlikely that
they would be licensed for this purpose in Europe. Vaccines have not
been incriminated in the transmission of BSE (Wilesmith et al., 1988,
J.W.Wilesmith, personal communication). Furthermore, large numbers of
doses of commercially produced vaccines that have used bovine starting
materials, have been inoculated by parenteral and oral routes into
cattle throughout the world and a substantial proportion have been
produced in Europe, but no incident of BSE has been attributed to their
use. This is important because, since there is no species barrier, any
chink in the armour protecting vaccines from contamination would have
been revealed, but none has.

III.3.2.OTHER MEDICINAL PRODUCTS DERIVED FROM TSE-SUSCEPTIBLE SPECIES
Animal sources of material used in medicinal products vary, but mostly
are derived from cattle. There is thus at least a possibility that
unless strict precautions are taken, disease could be transmitted in
this way. It cannot be ruled out that no case ever arose by this means,
but it is clear that the majority did not, even at the very beginning of
the BSE epidemic before publication of information on BSE, and before
any legislation was in place (Wilesmith et al., 1988). The highest risk
tissue is bovine brain from a clinically affected animal or one in the
immediate pre-clinical phase. Posterior pituitary extract (now prepared
biosynthetically), was available and used in veterinary practice mainly
in adult female cattle at the time of parturition, to assist treatment
of retained placenta or to assist in milk let down. However, no
association was found between its use and the occurrence of BSE
(Wilesmith et al., 1988).

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.


Blood donated after vaccination with rabies vaccine derived from
sheep brain cells might transmit CJD.

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)
Letters
Blood donated after vaccination with rabies vaccine derived from sheep
brain cells might transmit CJD
EDITOR,--Janet Morgan reports that the National Blood Authority in
Britain has decided to tighten the donor screening programme to exclude
transmission of Creutzfeldt-Jakob disease or its variant through blood
donations.1 Prospective donors will be prevented from donating blood if
they have a history of treatment with human growth hormone or if one of
their siblings, parents, or grandparents developed the disease. I would
point out that similar care should also be taken when immigrants from
Asia and Africa offer to donate blood, in case they received rabies
vaccine derived from culture of sheep brain cells when they were living
in their country of origin.

In many countries in Asia and Africa limited supplies of imported rabies
vaccines derived from culture of human cells have been available. Many
people continue to be offered indigenously produced sheep brain vaccine
after exposure to a rabid animal. Scrapie is known to exist in sheep
around many centres where the vaccine is produced. In the mountain sheep
of the Kumaon foothills in the Himalayas, for example, scrapie was
established more than four decades ago and 1-10% of the flock was
reported to have the disease in 1961.2 In the Himalayan foothills the
Central Research Institute continues to produce four to five million
doses of sheep brain vaccine annually. Transmission of abnormal prion
protein, PrPsc, in sheep brain vaccine might have occurred in some of
the 30 documented cases of Creutzfeldt-Jakob disease in different
regions in India.3 Because Creutzfeldt-Jakob disease has a latency of
about 20 years, many recipients of sheep brain rabies vaccine could
emigrate to Britain before becoming ill.

Before accepting blood donations from immigrants it would be desirable
to ask the potential donors whether they were exposed to a rabid animal
and immunised with sheep brain rabies vaccine in their country of
origin. Furthermore, indirect assessment should be possible through, for
example, assay looking for antibodies specific to rabies.

Clinical microbiologist Centre for Logistical Research and Innovation,
M-122 (of part 2), Greater Kailash-II, New Delhi-110048, India

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
Neurosciences (NIMHANS), Bangalore, India.

Thirty cases including 20 definite and 10 probable cases of
Creutzfeldt-Jakob disease (CJD) seen in India between 1971 and 1990 are
reported. Demographic analysis has shown similarities to the previously
published reports from other parts of the world. Though 21 (70%) of
cases were from two centers--Bombay and Bangalore-, suggesting
clustering, this seems to be more apparent than real. One subject worked
in the medical field, where possibility of iatrogenic transmission could
not be ruled out. None of the cases had positive family history of CJD.
There is no epidemiological data of CJD from India so far and hence this
report is one such pilot study.

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
incident and posted on www here;

Louping-ill vaccine (scrapie transmission by vaccine)

THE VETERINARY RECORD
516 No 47. Vol. 58
November 23rd, 1946

NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND

ANNUAL CONGRESS, 1946

snip...

The enquiry made the position clear. Scrapie was developing in
the sheep vaccinated in 1935 and it was only in a few instances
that the owner was associating the occurrence with louping-ill
vaccination. The disease was affecting all breeds and it was
confined to the animals vaccinated with batch 2. This was clearly
demonstrated on a number of farms on which batch 1 had been
used to inoculate the hoggs in 1935 and batch 2 to inoculate
the ewes. None of the hoggs, which at this time were three-
year-old ewes. At this time it was difficult to forecast whether all
of the 18,000 sheep which had received batch 2 vaccine would
develop scrapie. It was fortunate, however, that the majority of
the sheep vaccinated with batch 2 were ewes and therfore all
that were four years old and upwards at the time of vaccination
had already been disposed of and there only remained the ewes
which had been two to three years old at the time of vaccination,
consequently no accurate assessment of the incidence of scrapie
could be made. On a few farms, however, where vaccination was
confined to hoggs, the incidence ranged from 1 percent, to 35 percent,
with an average of about 5 percent. Since batch 2 vaccine
had been incriminated as a probable source of scrapie infection,
an attempt was made to trace the origin of the 112 sheep whose
tissues had been included in the vaccine. It was found that they
had been supplied by three owners and that all were of the
Blackface or Greyface breed with the exception of eight which
were Cheviot lambs born in 1935 from ewes which had been in
contact with scrapie infection. Some of these contact ewes
developed scrapie in 1936-37 and three surviving fellow lambs to
the eight included in the batch 2 vaccine of 1935 developed
scrapie, one in September, 1936, one in February, 1937, and one
in November, 1937. There was, therefore, strong presumptive
evidence that the eight Cheviot lambs included in the vaccine
althought apparently healthy were, in fact, in the incubative stage
of a scrapie infection and that in their tissues there was an
infective agent which had contaminated the batch 2 vaccine,
rendering it liable to set up scrapie. If that assumption was
correct then the evidence indicated that:-

(1) the infective agent of scrapie was present in the brain, spinal
cord and or spleen of infected sheep:
(2) it could withstand a concentration of formalin of 0-35 percent,
which inactivated the virus of louping-ill:
(3) it could be transmitted by subcutaneous inoculation;
(4) it had an incubative period of two years and longer.

Two Frenchmen, Cuille & Chelle (1939) as the result of experiments
commenced in 1932, reported the successful infection of
sheep by inoculation of emulsions of spinal cord or brain material
by the intracerebral, epidural, intraocular and subcutaneous routes
The incubation period varied according to the route employed,
being one year intracerebrally, 15 months intraocularly and 20
months subcutaneously. They failed to infect rabbits but succeeded
in infecting goats. Another important part of their work
showed that the infective agent could pass throught a chamberland
1.3 filter, thus demonstrating that the infective agent was a
filtrable virus. It was a curious coincidence that while they
were doing their transmission experiments their work was being
confirmed by the unforeseeable infectivity of a formalinized tissue
vaccine.

As a result of this experience a large-scale transmision experiment
involving the ue of 788 sheep was commenced in 1938 on a
farm specially taken for the purpose by the Animal Diseases
Research Association with funds provided by the Agricultural
Research Council. The experiment was designed to determine the
nature of the infective agent and the pathogenesis of the disease.
It is only possible here to give a summary of the result which
showed that (1) saline suspensions of brain and spinal cord tissue
of sheep affected with scrapie were infective to normal sheep
when inoculatted intracerebrally or subcutaneously; (2) the incubation
period after intracerebral inoculation was seven months and
upwards and only 60 percent of the inoculated sheep developed
scrapie during a period of four and a half years; (3) the incubation
period after subcutaneous inoculation was 15 months and upwards
and only about 30 percent of the inoculated sheep developed
the disease during the four and a half years: (4) the infective
agent was of small size and probably a filtrable virus.

The prolonged incubative period of the disease and the remarkable
resistance of the causal agent to formalin are features of
distinct interest. It still remains to determine if a biological test
can be devised to detect infected animals so that they can be
killed for food before they develop clinical symptoms and to
explore the possibilities of producing an immunity to the disease...

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
the strain responsible for iCJD is closely related to that of one
patient with sCJD, and, more unexpectedly, that these agents were
similar to the French scrapie strain studied (but different from the
U.S. scrapie strain).

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
then adapted to the prosimian microcebe (Microcebus murinus ). Brain
homogenate and buffy coat from an affected microcebe were separately
inoculated intracerebrally into three healthy microcebes (two animals
received brain and one received buffy coat).

RESULTS: All three inoculated microcebes became ill after incubation
periods of 16 to 18 months. Clinical, histopathologic, and
immunocytologic features were similar in each of the recipients.

CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months
earlier with BSE contained the infectious agent. This observation
represents the first documented transmission of BSE from the blood of an
experimentally infected primate, which in view of rodent buffy coat
infectivity precedents and the known host range of BSE is neither
unexpected nor cause for alarm.

http://www.blackwell-synergy.com/servlet/useragent?func=synergy&synergyAction=showAbstract&doi=10.1046/j.1537-2995.2002.00098.x

Meanwhile, health officials with the Food and Drug Administration say
the method of manufacturing the old vaccine, called Dryvax, which was
made by Wyeth using calf skin, is "no longer considered optimal."
Instead, the agency says the new smallpox vaccine "will be prepared in
MRC-5 cells"  a line of aborted fetal cells dating back to 1966 
because that method is more efficient.

"The MRC-5 line was developed & from lung tissue taken from a 14-week
fetus aborted for psychiatric reasons from a 27-year-old physically
healthy woman," said a description of the cell tissue by the Coriell
Institute for Medical Research at the University of Medicine and
Dentistry of New Jersey, where the line is maintained. The institute
further describes it as "normal human fetal lung fibroblast."

http://www.worldnetdaily.com/news/article.asp?ARTICLE_ID=25362

SMALLPOX VACCINE, Dried, Calf Lymph Type
Summary of Package Insert

Dryvax, Wyeth Laboratories, Marietta, PA (1960)

Ingredients
brilliant green:

calf lymph

chloriatracycline hydrochloride;
dihydrostreptomycin sulfate;
glycerin;
neomycin sulfate;
phenol;
polymixin B sulfate.

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 (216-119-163-199.ipset45.wt.net)
Subject: HUMANS MAY CATCH MAD COW FROM SHEEP !!!
Date: December 16, 2002 at 6:37 am PST

In Reply to: MAD COW DISEASE, SMALLPOX VACCINE (Dried Calf Lymph Type)
and TSEs posted by TSS on December 15, 2002 at 9:52 am:

Humans may catch mad cow from sheep

December 13 2002 at 07:41PM
Quickwire

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 scientists, led by Professor John Collinge, cast further doubt on
the safety of sheep meat by suggesting that more animals - including
humans -could carry and transmit the diseases than previously thought.

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

=================================================
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

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 Biologicals 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
2. Spongiform Encephalopathy Advisory Committee of UK statement of 20
March 1996 (http://www.defra.gov.uk/)
3. USDA 9 CFR part 94.18
4. P. D. Minor, R.G. Will and D. Salisbury. 2000. Vaccines and variant
CJD. Vaccine 19:409-410.
5. 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

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
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.

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
* 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 Biologicals DTaP Vaccine, Infanrix
* SmithKline Beecham Biologicals Hepatitis A Vaccine, Havrix.
* SmithKline Beecham Biologicals 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.

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].

CBERs 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 CBERs 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
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

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
Estimated infectivity of bovine tissue by category
Category 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:

# 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.
# 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.
# Bradley R, BSE Transmission studies with particular reference to
blood, Dev. Biol Stand, 99:35-40, 1999.
# Kimberlin RH, An overview of bovine spongiform encephalopathy Dev Biol
Stand 75:75-82, 1991.
# Donnelly CA, Ghani AC, Ferguson, NM, and Anderson RM, Recent trends in
the BSE epidemic, Nature 389:903, 1997.
# Linda Detwiler, USDA
# 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.
# Transcript of June, 2000 meeting of the FDA TSE Advisory Committee.
# 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.
# 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, 1999.

Table of Contents

http://www.fda.gov/cber/bse/risk.htm

oint Meeting of the
Transmissible Spongiform Encephalopathies Advisory Committee and
Vaccines and Related Biological Products Advisory Committee -
Preliminary Summary

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

Two million children innoculated with BSE vaccines

http://www.mad-cow.org/00/may00_news.html

http://www.vegsource.com/talk/lyman/messages/7622.html

http://www.vegsource.com/talk/lyman/messages/7631.html

BSE/TSE USA FEDERAL DOCKETS SUBMISSION...TSS

Docket Management Docket: 02N-0273 - Substances Prohibited From Use in
Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed
Comment Number: EC -10
Accepted - Volume 2

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html

PART 2

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html

PDF]Freas, William TSS SUBMISSION
File Format: PDF/Adobe Acrobat -
Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary
Sr. [flounder@wt.net] Monday, January 08,200l 3:03 PM freas ...

http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf

Asante/Collinge et al, that BSE transmission to the 129-methionine
genotype can lead to an alternate phenotype that is indistinguishable
from type 2 PrPSc, the commonest _sporadic_ CJD;

http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm

Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a

Comment Number: EC -2

Accepted - Volume 7

http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm


[PDF] Appendices to PL107-9 Inter-agency Working Group Final Report 1-1
File Format: PDF/Adobe Acrobat - View as HTML
Agent, Weapons of Mass Destruction Operations Unit Federal Bureau of
those who provided

comments in response to Docket No. ... Meager 8/18/01 Terry S.
Singeltary Sr ...

www.aphis.usda.gov/lpa/pubs/pubs/PL107-9_Appen.pdf - Similar pages

# Docket No: 02-088-1 RE-Agricultural Bioterrorism Protection Act of
2002; [TSS SUBMISSION ON POTENTIAL FOR BSE/TSE & FMD 'SUITCASE BOMBS'] -
TSS 1/27/03 (0)

http://www.vegsource.com/talk/madcow/messages/9912395.html


Dockets Entered On October 02, 2003

... Dockets Entered On October 2, 2003 Table of Contents, Docket #,
Title, 1978N-0301,

OTC External Analgesic Drug Products, ... EMC 7, Terry S. Singeltary Sr.
Vol #: 1, ...

www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm


Daily Dockets Entered on 02/05/03


DOCKETS ENTERED on 2/5/03. ... EMC 4 Terry S. Singeltary Sr. Vol#: 2.
... Vol#: 1.

03N-0009 Federal Preemption of State & Local Medical Device Requireme. ...

www.fda.gov/ohrms/dockets/dailys/03/Feb03/020503/020503.htm


Docket Management
Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater
Comment Number: EC -1
Accepted - Volume 1


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be11.html

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfe.html

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfc.html


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, TEXAS USA 77518