From:
TSS (216-119-138-163.ipset18.wt.net)Subject: Louping-ill vaccine documents from November 23rd, 1946
Date: Sat, 9 Sep 2000 17:44:57 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
THE VETERINARY RECORD
516 No 47. Vol. 58
November 23rd, 1946
NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND
ANNUAL CONGRESS, 1946
The annual Congress, 1946, was held at the Royal Veterinary College,
Royal College Street, London, N.W.I. from September 22nd to September
27th.
Opening Meeting
[skip to scrapie vaccine issue...tss]
Papers Presented to Congress
The papers presented to this year's Congress had as their general theme
the progressive work of the profession during the war years. Their
appeal was clearly demonstrated by the large and remarkably uniform
attendance in the Grand Hall of the Royal Veterinary College throughout
the series; between 200 and 250 members were present and they showed a
keen interest in every paper, which was reflected in the expression of
some disappointment that the time available for discussion did not
permit of the participation of more than a small proportion of
would-be contributors.
In this issue we publish (below) the first to be read and discussed,
that by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary
Research." Next week's issue will contain the paper on "Some Recent
Advances in Veterinary Medicine and Surgery in Large-Animal Practice"
by Mr. T. Norman Gold, M.R.C.V.S. In succeeding numbers of the Record
will be reproduced, also with reports of discussions, that by Mr. W. L.
Weipers, M.R.C.V.S., D.V.S.M., on the same subject as relating to
small-animal practice, and the papers by Mr. J. N. Ritchie, B.SC.,
M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on
"War-time Achievements of the British Home Veterinary Services."
The first scientific paper of Congress was read by Dr. W. S.
Gordon, M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946,
when Professor J. Basil Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal
of the Royal Veterinary College, presided.
Advances in Veterinary Research
by
W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.
Agriculteral Research Council, Field Station, Compton, Berks.
Louping-ill, Tick-borne Fever and Scrapie
In 1930 Pool, Browniee & Wilson recorded that louping-ill was
a transmissible disease. Greig et al, (1931) showed that the infective
agent was a filter-passing virus with neurotropic characters and
Browniee & Wilson (1932) that the essential pathology was that of an
encephalomyelitis. Gordon, Browniee, Wilson & MacLeod (1932) and
MacLeod & Gordon (1932) confirmed and extended this work. It was
shown that on louping-ill farms the virus was present in the blood
of many sheep which did not show clinical symptoms indicating
involvement of the central nervous system and that for the perpetuation
and spread of the disease these subclinical cases were probably of
greater importance that the frank clinical cases because, in Nature,
the disease was spread by the tick, lxodes ricinus L. More recently
Wilson (1945, 1946) has described the cultivation of the virus in a
chick embryo medium, the pathogenic properties of this culture
virus and the preparation of louping-ill antiserum.
Between 1931 and 1934 I carried out experiments which resulted
in the development of an effective vaccine for the prevention
of louping-ill.* This vaccine has been in general use since 1935
and in his annual report to the Animal Diseases Research Association
this year, Dr. Greig stated that about 227,000 doses of vaccine
had been issued from Moredun alone.
Dr. Gordon illustrated this portion of his paper by means of graphs
and diagrams projected by the epidiascope.
This investigation, however, did not begin and end with the
study of louping-ill; it had, by good fortune, a more romantic
turn and less fortunately a final dramtic twist which led almost
to catastrope. After it had been established that a solid immunity
to louping-ill could be induced in sheep, a group of
immunized and a group of susceptible animals were placed together
on the tick-infected pasture of a louping-ill farm. Each day all
the animals were gathered and their temperatures were recorded.
It was anticipated that febrile reactions with some fatalities would
develop in the controls while the louping-ill immunes would remain
normal. Contrary to expectation, however, every sheep, both immune
and control, developed a febrile reaction. This unexpected
result made neccessary further investigation which showed that the
febrile reaction in the louping-ill immunes was due to a hitherto
undescribed infective agent, a Rickettsia-like organism which could
be observed in the cytoplasm of the grannular leucocytes, especially
the neutrophil polymorphs (MacLeod (1932), Gordon, Browniee,
Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod (1936).
MacLeod collected ticks over many widely separated parts of
Scotland and all were found to harbour the infective agent of
tick-borne fever, and it is probable that all sheep on tick-infested
farms develop this disease, at least on the first occasion that they
become infested with ticks. When the infection is passed in series
through susceptible adult sheep it causes a sever, febrile reaction,
dullness and loss of bodily condition but it rarely, if ever, proves
fatal. It is clear, however, that it aggravates the harmful effects
of a louping-ill infection and it is a serious additional complication
to such infections as pyaemia and the anacrobic infections which
beset lambs on the hill farms of Northern Britain.
Studying the epidemiology of louping-ill on hill farms it became
obvious that the pyaemic condition of lambs described by
M'Fadyean (1894) was very prevalent on tick infested farms
Pyaemia is a crippling condition of lambs associated with tick-bite
and is often confused with louping-ill. It is caused by infection
with Staphylococcus aureus and affected animals may show abscess
formation on the skin, in the joints, viscera, meninges and elsewhere
in the body. It was thought that tick-borne fever might
have ben a predisposing factor in this disease and unsuccessful
attempts were made by Taylor, Holman & Gordon (1941) to reproduce
the condition by infecting lambs subcutaneously with the
staphylococcus and concurrently produceing infections with tickborne
fever and louping-ill in the same lambs. Work on pyaemia
was then continued by McDiarmid (1946a, 1946b, 1946c), who
succeeded in reproducing a pyaemic disease in mice, guinea-pigs
and lambs similar to the naturally occuring condition by intravenous
inoculation of Staphylococcus aureus. He also found a
bacteraemic form of the disease in which no gross pyaemic lesions
were observed. The prevention or treatment of this condition
presents a formidable problem. It is unlikely that staphylococcal
???oid will provide an effective immunity and even if penicillin
proved to be a successful treatment, the difficulty of applying it
in adequate and sustained dosage to young lambs on hill farms
would be almost insurmountable.
>From 1931 to 1934 field trials to test the immunizing value
and harmlessness of the loup-ill vaccine were carried out on a
gradually increasing scale. Many thousands of sheep were vaccinated
and similar numbers, living under identical conditions
were left as controls. The end result showed that an average
mortability of about 9 percent in the controls was reduced to less
than 1 percent in the vaccinated animals. While the efficiency
of the vaccine was obvious after the second year of work, previous
bitter experience had shown the wisdom of withholding a biological
product from widespread use until it had been successfully produced
in bulk, as opposed to small-scale experimental production
and until it had been thoroughly tested for immunizing efficiency
and freedom from harmful effects. It was thought that after
four years testing this stage had been reached in 1935, and in
the spring of that year the vaccine was issued for general use. It
comprised a 10 percent saline suspension of brain, spinal cord
and spleen tissues taken from sheep five days after infection with
louping-ill virus by intracerebral inoculation. To this suspension
0-35 percent of formalin was added to inactivate the virus and
its safety for use as a vaccine was checked by intracerbral inoculation
of mice and sheep and by the inoculation of culture medium.
Its protective power was proved by vaccination sheep and later
subjecting them, along with controls, to a test dose of living virus.
Vaccine for issue had to be free from detectable, living virus
and capable of protecting sheep against a test dose of virus applied
subcutaneously. The 1935 vaccine conformed to these standards
and was issued for inoculation in March as three separate batches
labelled 1, 2, and 3. The tissues of 140 sheep were employed
to make batch 1 of which 22,270 doses were used; 114 to make
batch 2 of which 18,000 doses were used and 44 to make batch 3
of which 4,360 doses were used. All the sheep tissues incorporated
in the vaccine were obtained from yearling sheep. During 1935
and 1936 the vaccine proved highly efficient in the prevention
of loup-ill and no user observed an ill-effect in the inoculated
animals. In September, 1937, two and a half years after vaccinating
the sheep, two owners complained that scrapie, a disease which
had not before been observed in the Blackface breed, was appearing
in their stock of Blackface sheep and further that it was confined
to animals vaccinated with louping-ill vaccine in 1935. At that
stage it was difficult to conceive that the occurrence could be
associated with the injection of the vaccine but in view of the
implications, I visited most of the farms on which sheep had been
vaccinated in 1935. It was at this point that the investigation
reached its dramatic phase; I shall not forget the profound effect
on my emotions when I visited these farms and was warmly welcomed
because of the great benefits resulting from the application
of louping-ill vaccine, wheras the chief purpose of my visit was
to determine if scrapie was appearing in the inoculated sheep.
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.
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Greetings List Members,
pretty disturbing document. now, what would stop this from happening
with the vaccineCJD in children???
kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA