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From: Terry S. Singeltary Sr. (
Subject: Re: vaccines
Date: August 29, 2004 at 8:01 am PST

In Reply to: vaccines posted by melissa on August 29, 2004 at 6:32 am:

8. The Secretary of State has a number of licences. We understand that
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).

although 176 products do _not_ conform to the CSM/VPC

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


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.


7.6 Could vaccines prepared from animal brain tissue pose a risk of
transmission of Transmissible Spongiform Encephalopathies to humans?
François 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 Ãx-propiolactone inactivated or phenolized
antirabies vaccine containing 5% suspension of sheep brain infected with
a fixed strain of rabies virus.


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.


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.


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.

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.

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).

Indian J Pediatr 1991 Sep-Oct;58(5):563-5

Arya SC.

Centre for Logistical Research and Innovation, Greater Kailash, New Delhi.

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.

BMJ 1996;313:1405 (30 November)
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

: 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.

i recieved the 1947 report of the Louping-ill vaccine
incident and posted on www here;

Louping-ill vaccine (scrapie transmission by vaccine)

516 No 47. Vol. 58
November 23rd, 1946




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

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...


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).

Human vaccine prepared in animal brains

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.

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


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

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

[host Richard]
could you repeat the question?

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?

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

you are not going to answer my question?

[not sure whom speaking]


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."

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

Dryvax, Wyeth Laboratories, Marietta, PA (1960)

brilliant green:

calf lymph

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


########### ############

From: TSS (
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

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


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.


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 (
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.

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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:

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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.

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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

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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.

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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 [].

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

# 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.

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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


Two million children innoculated with BSE vaccines


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