EPIDEMIOLOGY OF SCRAPIE IN THE UNITED STATES

[Terry S. Singeltary Sr.]

Slow Transmissible Diseases of the Nervous System: Volume 1

EPIDEMIOLOGY OF SCRAPIE IN THE UNITED STATES

Academic Preg

James Hourriganl, Albert Klingsporn2, W. W. Clark3, and M, de Camp4

United States Department of Agriculture, Animal and Plant Health Inspection Service, Veterinary Services

ABSTRACT Observations and experiences with scrapie in the United States during the past 25 years have con- sistently shown it was a disease that spreads from flock to flock, state to state, or from country to country by movement of infected, but apparently normal sheep which were incubating the disease but had not yet reached the age of clinical manifestation. The disease progressed relentlessly until the animal reached the age of mani-festation, irrespective of whether the animal remained in the parent flock or had been moved to another flock, state, or country.

The means of spread from animal to animal was more difficult to explain. A close study of parent-progeny relationships suggested that maternal transmission played a dominant role and that there is an inherited component in the level of incidence. When previously unexposed Angora or dairy goats or sheep of the Suffolk, Hampshire, Rambouillet, or Targhee breeds were placed in contact with natural cases of scrapie, and subsequently bred within their own groups, scrapie developed in a few of the sheep first exposed at 3 to 9 months of age and in 14 to 39% of the sheep progeny, born and reared in the infected environment. Scrapie occurred in the progeny of all breeds of goats so exposed. The incidence in Angora goat progeny was 26% and in dairy goat progeny 61%. Dairy goats removed from scrapie exposure at 6 months of age or older developed scrapie, however, those removed at birth did not. Sheep removed from exposure at birth or at 4, 9, or 20 months of age developed scrapie. There was a pro- gressive increase in scrapie incidence among those removed at older ages.

lFederal Center Building, Hyattsville, Maryland

2Federal Center Building, Hyattsville, Maryland

3Scrapie Field Trial, Mission, Texas

4scrapie Field Trial, Mission, Texas

INTRODUCTION’

Scrapie is a naturally occurring, fatal disease of sheep and goats caused by a filterable, transmissible, self- replicating agent considered by some workers to be a small virus. The virus is unusually resistant to heat and other physical and chemical abuse, including formaldehyde, and to ultraviolet and ionizing radiation. The early signs of natural scrapie are usually subtle changes in behavior or temperament followed by more obvious clinical signs which are progressive and include pruritus, debilitation, rubbing against fixed objects often accompanied by rapid movements of the tongue and lips, grinding of teeth, biting of feet and limbs, locomotor incoordination and, usually, loss of wool, condi- tion, and weight. The course of the clinical disease varies from 1 to 8 months, but may be much longer. Suspicious signs, which on rare occasions persisted or recurred over a period of more than 2 years, were seen. Recovery in an obvious clinical case was not observed. In Icelandic sheep, the signs were primarily those of incoordination of gait with- out prominent pruritus, Palsson and Sigurdsson, 1958 (1). Recently, pruritus was more evident, Palsson, Personal Communi- cations, 1978. In northern India, sheep showed a severe pruritus but not a protracted period of locomotor incoordina- tion, Zlotnik and Katiyar, 1961 (2). In Suffolk sheep in Britain, there was usually both pruritus and incoordination; however, either could be absent, and extensive neurological lesions could be present in the absence of unequivocal signs of both, Dickinson et al., 1965 (3)-

Fig. 1 showed the countries in which scrapie has been reported. The disease was recognized in England, Scotland, Wales, and continental Europe, including Germany, France, and Spain, about 250 years ago and has been reported there in many breeds of sheep. In Iceland, scrapie is called rida, Sigurdsson, 1954 (4). Reports of scrapie outbreaks in other countries, largely due to the importation of sheep from Britain, included those in New Zealand, Brash, 1952 (5), and Brash, 1952 (6)3 Australia, Bull and Murnane, 1958 (7); India, Zlotnik and Katiyar, 1961 (2); Hungary, Aldasy and Suveges, 1964 (8); the Netherlands, Van der Akker et al., 1968 (9); Bulgaria, Ivanov and Haralambiev, 1970 (10); Belgium, Hoorens and Oyaert, 1966 (11); Republic of South Africa, Van der Merwe, 1966 (12); and Kenya, Cooper, 1973 (13). Outbreaks have also occurred in The Federal’ Republic of Germany (West), Von Hiepe et al., 1973 (14); Isle of Man, Italy, Lebanon, Somalia, United Arab Emirates, Yemen, Norway, Ireland, Northern Ireland, and Colombia, South America (FAO-WHO-OIE, 1975, 1976, and 1977, Annual Health Yearbook) and in Austria and former East Prussia.

In the Western Hemisphere, scrapie was first reported in Canada in 1938, Schofield, 1938 (15), and in the United States in Michigan, in 1947, Thorp et al., 1952 (16). The basic source of scrapie in these countries was also British sheep. More extensive outbreaks were disclosed in the United States, in 1952, in California, Stuart et al., 1952 (17), and Ohio, Wagner et al., 1954 (18).

Scrapie has now been reported in the United States in 203 Suffolk flocks, 10 Cheviot flocks, 3 Hampshire flocks, 2 Montadale flocks, and 1 mixed breed flock, Klingsporn and Hourrigan, 1978 (19).

The States and counties involved in scrapie outbreaks were shown in Fig. 2. Although the 219 outbreaks were widespread geographically with 31 States involved, it was encouraging to note that the eradication program restricted further spread. For example, California had 13 outbreaks, but none since 1969. Indiana had 28 outbreaks but none since 1973, and Ohio with a total of 13 outbreaks had reported none since 1966.

Fig. 3 illustrated the spread of scrapie through the move- ment of sheep incubating the disease. In this particular Situation the disease became entrenched in particular flocks and spread to many other flocks in other States. In a typical situation, the disease became established, most often in purebred flocks, and spread by sheep sold at 2 or 3 or fewer years of age. When the index case was disclosed, all possibly-exposed sheep were traced often disclosing additional scrapied animals in other receiving flocks. Although there was substantial circumstantial evidence against certain suspected source flocks, it was often difficult to prove the disease was present in such flocks. This could have been because sheep were usually sold prior to the age of manifestation or perhaps the owners innocently or deliberately failed to report suspect cases for fear of jeopardizing customary markets.

Evidence of natural scrapie in goats is accumulating. The disease was reported in 1942 in a goat reared with a flock of scrapied sheep in France, Chellé, 1942 (20). In Scotland, 4 of 6 dairy goats maintained in a stall, in contact from the time they were less than 1 week old with a succes- sion of natural cases (mainly Suffolks), developed scrapie at 39, 39, 39, and 47 months of age. In a second similar experiment, 55% of 11 exposed goats developed serapie at 29, 32, 32, 32, 36, and 37 months of age, Brotherston et al., 1968 (21).

Three goats developed scrapie when held in contact from 1 day of age with scrapied sheep for 40 months, Stamp, 1962 (22).

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James Hourrigan et al.

Scrapie was diagnosed in a 5-year-old goat reared in a scrapied flock of Suffolk sheep in Missouri, Hourrigan et al., 1969 (23). In Canada, scrapie was diagnosed in a 7- or 8-year-old goat born in a flock where scrapie had occurred in sheep, Stemshorn, 1975 (24). In Britain, scrapie was reported in a 4-year-old and an 8-year-old Saanan goat which had very little contact with any sheep, Harcourt and Anderson, 1974 (25). Scrapie was diagnosed in an uninoculated control adult goat purchased at 3 years of age from a dealer, MacKay and Smith, 1961 (26).

Indirect transmission of natural scrapie to 10 of 25 test sheep following exposure on a rotational basis to pastures used by scrapied sheep was reported, Greig, 1940 (27).

Following exposure indoors to a succession of naturally scrapied sheep, 43% of 7 Scottish Blackface lambs, developed scrapie at 42 to 44 months of age, Brotherston et.al.,1968 (21). °

Scrapie occurred in 28% of purebred Scottish Blackface sheep due to lateral transmission under lifetime contact, Dickinson et al., 1974 (28).

METHODS

A Scrapie Field Trial was developed at Mission, Texas, to provide additional information for the eradication program on the epidemiology of natural scrapie. The Mission Field Trial Station is located on 450 acres of pastureland, part of the former Moore Air Force Base, near Mission, Texas. It was designed to bring previously exposed, and later also unexposed, sheep or goats to the Station and maintain and breed them under close observation for extended periods to determine which animals would develop scrapie and define more closely the natural spread and other epidemiological aspects of the disease.

The 547 previously exposed sheep brought to the Mission Station beginning in 1964 were of the Cheviot, Hampshire, Montadale, or Suffolk breeds. They were purchased as field outbreaks occurred, and represented 21 bloodlines in which scrapie had been diagnosed. Upon arrival at the Station, the sheep were maintained on pasture, with supplemental feeding as necessary. The station was divided into 2 areas: (1) a series of pastures and-pens occupied by male animals only, and (2) a series of pastures and pens occupied by females and young progeny of both sexes. Lambing and kidding occurred in the female area, with lambs remaining with the dams until weaning. At weaning, young males were removed to the male area, and females were temporarily separated from the (unreadable...tss) , but remained in the female area. . weaning,

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males and females were kept separated and not allowed to mix or use the same pastures or facilities, except for those males which were chosen for breeding and taken temporarily to the breeding pens. To study familial relationships of the disease, a particular ram was bred to a selected ewe and re- bred to the same ewe in succeeding years to produce as many full sibs as possible.

Numbered duplicate ear tags were placed in both ears of each animal. Sheep were also wool-branded with a number, corresponding to the ear tag number, and rebranded after each semiannual shearing.

Prior to the arrival of exposed sheep, in November 1964, the premises were considered free of contamination by scrapie virus. No livestock had occupied the pastures since 1942, when the Air Base had been established.

Previously unexposed animals were also taken to the Station beginning in 1965 and were placed in direct contact with the infected flock, The previously unexposed animals included 11 Angora goats, 6 Nubian or Toggenburg dairy goats, and 31 Rambouillet, 31 Targhee, 33 Hampshire, and 28 Suffolk sheep. These animals were carefully selected to assure freedom from previous exposure to scrapie. No field cases of scrapie have been found in Rambouillet or Targhee sheep or Angora goats in the United States. Only 1 field case has been reported in a dairy goat, Hourrigan et al., 1969 (23), and 3 field cases in Hampshire sheep. These 4 cases had been raised in flocks containing Suffolk sheep. Twenty of the Suffolks were imported from New Zealand, which had been scrapie-free for more than 20 years.

Later, certain sheep or goats born at the Station were removed from exposure at birth and at 4, 6, 9, or 20 months of age and placed in isolation pens at the Station for long~ term observation.

Scrapie incidence (percentage of scrapie) was calculated by dividing the number of scrapied animals by the number of animals at risk. Animals were not diagnosed as scrapied un- less confirmed by histological examination, McDaniel et al., 1966 (29) and/or by inoculation into mice.

To be considered at risk and scrapie-free, animals had to have reached at Least 24 months of age, and if they had died, high quality brain tissue was submitted to the laboratory and found to be histologically negative for scrapie. Animals brought to the Station and still alive had to reach at least 100 months of age and those born at the Station 60 months of age to be considered at risk and scrapie free.

The age (months) of scrapied animals at death or sacrifice was used “age scrapied" in all calculations.

Animals of doubtful category (clinically suspicious), histologically inconclusive, or showing post-mortem autolytic

Epidemiology of Scrapie in the United States

brain damage) were not considered at risk insofar as these calculations were concerned.

RESULTS

Table 1 indicated that previously exposed sheep brought to the Station at various times and ages (1 to 89 months old) included 333 Suffolks at risk. Of these, 98 (29%) developed scrapie. This demonstrated the necessity to slaughter such sheep to prevent further Spread of the disease, These pre- viously exposed Suffolks were bred at the Station and produced 446 progeny at risk. Of these 153 (34%) developed scrapie,

Although the minimum and average ages when scrapied were similar for both groups, some of the previously exposed Suffolks brought to the Station developed scrapie when much older--ewes 60 to 142 months old and rams 67 to 102 months old. O£ the 153 Suffolks born at the Station, only 3 were more than 60 months of age (65, 66, and 69 months old).

This difference in age scrapied was attributed to the fact that the Suffolks born at the Station may have been sub- ject to a greater exposure from birth.

It was also observed that when both dam and progeny were scrapied, the progeny nearly always developed clinical disease at a younger age than their respective dam. Thirty- two dams were scrapied at an average of 60 months of age. Forty-six of their progeny developed the disease at an average of 38 months (range 25 to 53 months). Thirty-seven of the 46 progeny were younger than the dam (average 20 months younger, range 2 to 99 months younger). Two were scrapied at the same age as their dams, and 8 were older (average 5 months, range 1 to 13 months older).

Although the incidence of scrapie was considerably Greater in the progeny of scrapied compared to free dams, the progeny of either scrapied or free dams manifested scrapie at the typical age and irrespective of the age their respective dams were scrapied. The differences in ages that dams and progeny were scrapied was believed due to difference of exposure, particularly whether they were exposed at an early age.

Table 2 summarized the data on exposed Suffolks and was Prepared so as to show scrapie incidence in the progeny of dams and sires of known Scrapie status. The scrapie incidence in the progeny of Free X Free parents was 25%, progeny of scrapied Sires 39%, and scrapied dams 42%. When both sire and dam were scrapied, the scrapie incidence in 18 Progeny at risk was 78%.

When the scrapie status of the sire was ignored, scrapie incidence in the progeny of free dams was 34% and in progeny of scrapied dams as 62%. When the scrapie status of the dam

TABLE 1 SCRAPIE--FATE OF PREVIOUSLY EXPOSED SUFFOLK SHEEP, BROUGHT TO MISSION AT VARIOUS AGES, AND THEIR PROGENY BORN AT MISSION

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was ignored, scrapie incidence in the progeny of free sires was 26% and in the progeny of scrapied sires was 45%.

Although the scrapie incidence was nearly double in the progeny of scrapied compared to free dams, the latter con- tributed a greater number of scrapied progeny, 116, compared to only 51 cases which had scrapied dams. This was because free dams made a considerably heavier contribution to the progeny at risk-342 compared to 82. It was felt that in farm flocks a similar situation could exist.

It was possible that free dams could have been mis- classified; however, this was unlikely to have been significant, unless "nonclinical or carrier" dams exist. In this Suffolk group, the ages of 100 free dams of scrapied progeny ranged from 25 to 160 (average 97) months. These free dams did not show clinical signs of scrapie, and there were no histopathological lesions suggesting scrapie in those which died. If one cannot classify as free, ewes which have reached 97 months (average) and did not develop the disease, from a practical standpoint, it is not possible to classify sheep as free, at least on the basis of clinical signs and histology. The free dams of 50% of the scrapied progeny were more than 100 months of age, averaging 126 months.

Upon arrival at the Mission Station at 3 to 9 months of age, the 140 previously unexposed sheep and goats were placed in infected pastures and corrals and were subjected to con- tact with a succession of natural cases of scrapie in sheep, and eventually also in goats. These animals were bred only within their respective groups and were not crossbred to other breeds of sheep or those brought to the Station from infected flocks or their progeny. The male or female animals mixed freely with animals of their respective sex of the infected Flock and were similarly identified and subjected to similar flock management and diagnostic procedures.

Table 3 indicated that natural scrapie had occurred in 5 of the 140 previously unexposed sheep. One case each occurred in Rambouillet, Targhee, and Hampshire ewes at 88, 89, and 89 months of age and in 2 Suffolk ewes at 73 and 102 months of age, and 85, 82, 80, 64, and 93 months following initial natural exposure. This represented a natural situation involving lateral spread, under the circumstances involved, when sheep were not exposed when very young. Scrapie was not detected clinically or histologically in any of the dairy or Angora goats brought to the Station. The disease occurred in an average of 27% of the progeny of previously unexposed sheep or goats born at the Station and included cases in progeny of all breeds of sheep or goats taken there. The incidence in the progeny ranged from 14% in Rambouillet sheep to 61% in dairy goats.

TABLE 2 SCRAPIE - IN PROGENY, BORN AT OR BROUGHT TO MISSION, OF PREVIOUSLY EXPOSED SUFFOLK SHEEP

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These data showed that scrapie spread laterally, by contact exposure, from scrapied te previously free animals, but at an apparently lower rate when exposure was first received at the age of 3 to 9 months. These animals were presumed to be susceptible to the disease, as their progeny developed scrapie at rates and ages similar (on the average) to the progeny, pf previously exposed Suffolk sheep born and reared in the same environment.

It was suggested that the progeny of previously unexposed animals developed scrapie at a much higher rate than their parents, and at a younger age, because they were subjected to exposure from birth. The data did not rule out the possibility that the animals born at the Station could have also received the virus from their dams "vertically" prior to, at, or following birth.

Table 4 summarized the scrapie incidence in the progeny, born at the Station, of previously unexposed dairy goats. The data were prepared so as to show scrapie incidence in the progeny of dams and sires of known scrapie status.

The 58% incidence in the progeny (24 at risk) of Free X Free parents was more than twice the 25% seen in the Suffolk group (Table 2). Scrapied sires did not increase the incidence in goat progeny (it was 44%); scrapied dams increased the incidence to 71%. When both sire and dam were scrapied the incidence was 89%, with only 9 goat progeny at risk.

When the scrapie status of the sire was ignored, the scrapie incidence in the progeny of free dams was 56% and in the progeny of scrapied dams it was 74%.

Free dams contributed 34 progeny at risk and scrapied dams 31 progeny.

When the scrapie status of the dam was ignored, scrapie incidence was 64% in the progeny of free sires and a similar 66% in the progeny of scrapied sires.

A total of 244 sheep (127 Suffolk, 59 Rambouillet, and 58 Targhee) were removed from scrapie exposure within a few hours of birth or at 4, 9, or 20 months of age and placed in isolation pens. Removal of sheep from exposure at these ages was selected as being representative of usual flock operations when sheep might be sold from an infected flock at weaning, the first fall or the second fall after their birth.

Table 5 reflected the fate of such animals. Four of the 6 scrapied sheep which had been isolated at birth were Suffolks and the 2 older animals were Targhees. The first case in the group isolated at birth was a Targhee, progeny of a ewe that did not develop clinical scrapie. The scrapie incidence in 36 at risk Suffolks removed from exposure at birth was 11%, con- siderably less then that expected had these animals remained in an infected environment.

TABLE 3 SCRAPIE - IN PREVIOUSLY UNEXPOSED SHEEP OR GOATS BROUGHT TO MISSION, AND IN THEIR PROGENY BORN AT MISSION

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Table 6 reflected the status of 51 goats isolated from scrapie exposure at birth, and at 6, 8 to 10, 20, 32 to 59 and 60 to 82 months of age.

None of the goats removed at birth developed scrapie, although all 5 of those alive at 5 years of age had scrapied dams and 1 also had a scrapied sire. The sire of the remaining 4 had sired 7 scrapied progeny. Under such circumstances, had they remained in an infected environment nearly all of these goats would have been expected to develop scrapie. With the exception of the 20 month group, scrapie occurred at an incidence of 25 to 100% in all other groups and at the expected age. A further observation was that 4 of the progeny of these dairy goats, born and kept apart from any sheep, developed scrapie which suggested that goats were not "dead- end hosts" insofar as scrapie was concerned.

Table 7 recorded the fate of progeny of certain selected scrapied or free Suffolk sheep or dairy goat dams.

Suffolk ewe G298 was scrapied at 46 months of age. She had twin lambs in 1969 and 1 lamb in 1970. All 3 lambs developed scrapie. Suffolk ewe G27a was scrapied at 39 months. Her lamb born in 1966 was serapied at 53 months; however, her lambs born in 1967 and 1968 remained free--l*lived to 102 months of age.

Suffolk ewe G25a died at 131] months of age and was nega- tive clinically and histologically. Mice remained negative following intracerebral inoculation of brain, spleen, and lymph nedes from this ewe. This ewe had 9 progeny at risk, of which 4 developed scrapie and 5 did not. There was no dis- cernible pattern to the cases. In two instances, 1 twin was scrapied and 1 remained free.

Goat B259 was scrapied when 43 months old. All of her 6 progeny at risk developed scrapie.

Goat B14a remained free and died at 101 months of age. Of her 11 progeny at risk, 7 were scrapied and 4 were not.

It was observed at the Station that when scrapied dams had several progeny at risk, 1 or more progeny usually developed the disease. However, many such scrapied dams also had progeny which lived, or are living, considerably beyond the age of their dams and beyond the age animals born at the Station manifested the disease.

It was also observed that individual free dams had free progeny in earlier years followed by scrapied progeny when they were older, or had scrapied progeny when young followed by free progeny when older, or scrapie and free progeny dis- persed throughout the dam's breeding life. The same situation occurred in progeny of scrapied dams; however, the pattern was less irregular due to the smaller number of progeny from each scrapied dam and the higher incidence of scrapie in such progeny. Circumstances prevented breeding all ewes every year

TABLE 6 SCRAPIE IN GOATS REMOVED AT VARIOUS AGES FROM EXPOSURE TO SHEEP

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Table 8 reflected the difference in age scrapied of - sheep brought to the Station compared to the age scrapied of those born there. Although the average age of previously exposed sheep (Suffolks) brought to the Station did not differ greatly from the overall average, several animals brought to the Station developed the disease at quite advanced ages. The previously unexposed scrapied animals brought to the Station were also considerably older than animals born there. Progeny of scrapied dams developed the disease at a slightly younger age than did progeny of free dams. The average age was nearly the same for males and females.

DISCUSSION

Observations of natural outbreaks of scrapie indicated that the disease spread from flock to flock by the movement of infected, but apparently normal, sheep which were incubating the disease.

There was no evidence that the disease spread to adjacent flocks in the absence of such movements or that vectors or other host species were involved in the spread of scrapie to sheep or goats; however, these possibilities should be kept open.

In countries where scrapie occurred, it was difficult to know with certainty that sheep or goats were not incubating the disease and would not manifest the disease at some future time. This concept was supported when sheep removed from scrapie exposure at birth, and at 4, 9, or 20 months of age developed scrapie at the expected ages. Thus, sheep born in a contaminated environment had been sufficiently infected so as to develop the disease when they reached the age of manifestation. Unpublished data at the Station demonstrated that scrapie virus could be isolated by intracerebral inocula- tion of mice from an apparently normal Suffolk sheep as young as 4 months and goats as young as 11 months of age. The dams of both such animals had been scrapied. Attempts to isolate scrapie virus from younger progeny or fetal tissues from scrapied dams had been negative. Histological evidence of natural scrapie in apparently normal sheep had been reported in lambs as young as 11 months, Dickinson et al., 1965 (3). Natural scrapie virus was recovered in Cheviot sheep 8 months old. Renwick and Zlotnik, 1965 (30) claimed to have isolated the agent from apparently normal 4 1/2 month old Bord Leicester lam.. (not readable...tss) of a scrapied dam.

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Goats removed from exposure at birth had not developed scrapie at 5 years of age, although all had scrapied dams. Had they remained with their dams in the infected environment, nearly all of these 5 goats would have been expected to develop scrapie. However, goats isolated at 6 months of age or older developed scrapie at the expected age. Goats born and kept apart from all sheep, but in contact with scrapied goats, developed scrapie suggesting goats were not dead-end hosts.

When previously unexposed animals 3 to 9 months old were placed on premises where clinical cases were occurring, a small number of such test sheep developed clinical scrapie at rather advanced ages of 73 to 102 months. However, 14 to 61% of the progeny of such sheep or goats developed scrapie at the customary 30 to 60 months of age. This was observed when progeny of previously unexposed Suffolk, Rambouillet, Targhee, or Hampshire sheep or Angora or dairy goats were exposed to scrapied sheep, mainly Suffolks.

Suffolk sheep showed definite familial patterns, sug- gesting an inherited component and/or maternal transmission of scrapie. Morbidity in the progeny born on infected premises of free sires and free dams was 25% with 105 at risk (58% for dairy goats with 24 at risk) and increased to about 80% or more if both parents were scrapied.

The overall incidence in 283 Suffolk progeny at risk was 36%. Although the incidence was 62% in the progeny of scrapied and 34% in the progeny of free dams, the latter contributed a much greater number of progeny at risk and actually had a larger number of scrapied progeny.

Under similar exposure, the incidence in mixed dairy goats was 61% in 72 progeny at risk. Morbidity was 58% in progeny of free dams and free sires, 44% if the sire only was scrapied, 71% if the dam only was scrapied, and 89% if both sire and dam were scrapied.

Limited attempts to isolate scrapie virus from materials which might provide clues for animal to animal spread have been largely negative at the Mission Station. Tissues from scrapied sheep or goats or other materials inoculated intracerebrally or subcutaneously or fed to swiss white outbred mice included feces, urine, saliva, milk, semen, testes, colostrum, and ovary. Mice were also exposed to grass from pastures and manure from sheds believed to be contaminated. Preliminary results were negative. In only 2 instances did inoculated mice develop scrapie, This involved 1 cage of mice inoculated with internal parasites, Haemonchus contortus, and 1 cage of mice inoculated with fetal cotyledon from scrapied goats.

The average age of previously exposed scrapied sheep brought to the Mission Station did not differ greatly from the overall average. However, several of these animals showed clinical evidence of the disease at advanced ages, up to 142 months. Previously unexposed animals brought to Mission also developed clinical signs at 73 to 102 months of age, con- siderably older than their progeny born at Mission.

In the United States, sheep with natural scrapie have on rare occasions shown clinical signs as young as 18 months.of age, Scrapied ewes as old as 142 months and scrapied rams as old as 102 months of age were recorded at the Mission Station; however, the great majority of scrapied sheep and goats were from 30 to 60 months of age. Field cases in younger animals were more likely to be seen when the disease was firmly established in a flock, Clinical natural scrapie was not observed in sheep or goats less than 18 months of age and rarely in animals that young; however, Katiyar, 1962 (31) and Joubert et al., 1972 (32) reported natural scrapie in India and in France in sheep as young as 10 to 12 months of age.

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16. Thorp, F., Jr., Judd, A. W., Gray, M. L., and Sholl, L. B. (1952). "Scrapie in Sheep." Michigan State Coll Vet, 13, pp. 36-37.

17. Stuart, J. E,, Allen, R. K., Shultz, G., De Lay, P. D. and Rosenberger, A. C. (1952}. "An Outbreak of Scrapie. in California Sheep." California Vet, 6, pp. 22.

18. Wagner, A. R., Goldstein, H. E., Doran, J. E., and Hay, J. R. (1954), “"NSerapie -A Study in Ohio." JAVMA, 124, pp. 136-140.

19. Klingsporn, A. L., and Hourrigan, J. L. (in print). "Scrapie Report." 82nd Annual Meeting, U. S, Animal Health Assn (1978).

20. Chellé, P. L. (1942). "Un Cas Tremblante Chez la Chevre." Bull de lL'Academle Veterinaire de France, 15, pp. 294-295.

21. Brotherston, J. G., Renwick, C. C., Stamp, J. T., Zlotnik, I., and Pattison, I. H. (1968). "Spread of Scrapie by Contact to Goats and Sheep." J Comp Path & Therap, 78, pp. 9-17.

22. Stamp, J. T. (1962). "Scrapie: A Transmissible Disease of Sheep." Vet Rec, 74, pp. 357-362,

23. Hourrigan, J. L., Klingsporn, A. L., McDaniel, H. A., and Riemenschneider, M. N. (1969). “Natural Scrapie in a Goat." JAVMA, 154, pp. 538-539,

24. Stemshorn, B. W. (1975). "Un Cas De Tremblante Naturelle Chez Une Chevre." Can Vet J, 16, pp. 84-86.

25. Harcourt, R. A., and Anderson, M. A. (1974). "Naturally- Occurring ©-~apie in Goats." Vet Rec, 94, pp. 504,

26. Mackay, J. M. K., and Smith W. (1961). "A Case of Scrapie in an Uninoculated Goat — A Natural Occurrence or a Contact Infection?" Vet Rec, 73, pp. 394-396.

27. Greig, J. R. (1940). “Scrapie: Observations on the Transmission of the Disease by Mediate Contact." Vet J, 96, pp. 203-206.

28. Dickinson, A. G., Stamp, J. T., and Renwick, C. C. (1974). "Maternal and Lateral Transmission of Scrapie in Sheep." J Com Path, 84, pp. 19-25.

29. McDaniel, H. A., and Morehouse, L. G. (1966). "The Diagnosis of Scrapie." Report of Scrapie Seminar, ARS, 91-53, U. S. Dept of Agriculture, Washington, DC, pp 41-52.

30. Renwick, C. ¢., and Zlotnik, I. (1965). "The -Transmission of Scrapie to Mice by Intracerebral Inoculations of Brain from an Apparently Normal Lamb." Vet Rec, 77, pp. 984- 985.

31. Katiyar, R. D. (1962). "A Preliminary Report on the Occurrence of Scrapie in Indian Sheep." Ceylon Vet J, 10, pp. 93-96.

32. Joubert, L., Lapras, M., Gastellu, J., Prave, M., and Laurent, D. (1972). “Un Foyer de Tremblante du Mouton en Provence (An Epidemic of Sheep Scrapie in the Provence}." Bull Soc Sci Vet et Med Comparee, 74, Lyon, France, pp. 165-184.

web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf

BSE: TIME TO TAKE HB PARRY SERIOUSLY

HB Parry Seriously’ (YB88/6.8/4.1)

IF the scrapie agent is generated from ovine DNA and thence causes disease in other species, then perhaps, bearing in mind the possible role of scrapie in CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the notifiable disease.

web.archive.org/web/20030714133556/http://www.bseinquiry.gov.uk/files/yb/1988/06/08004001.pdf

Scrapie-a personal view

l. H. PATTISON

From the ARC Institute for Research on Animal Diseases, Compton, Newbury, Berkshire

J. clin. Path., 25, Suppi. (Roy. Coll. Path.), 6, 110-114

Scrapie-a personal view

l. H. PATTISON

From the ARC Institute for Research on Animal Diseases, Compton, Newbury, Berkshire Scrapie disease of sheep and the closely similar kuru disease of the Fore people of New Guinea have been extensively documented. Preparation of review articles on scrapie and kuru has been a safety valve for workers frustrated by the maddeningly slow pace of research on these diseases; the literature on both has been exhaustively analysed and summarized. Anyone seeking up-to-date information should consult the excellent reviews by Field (1969) and Thormar (1971).

When the organizers of this Symposium very kindly invited me to speak about scrapie, I wondered what on earth I could present that had not already been recorded, again and yet again. Had I any unique contribution? Perhaps so. It happens that I have baen associated with research on scrapie for twice as long as anyone else still active in the field, and three times as long as most. This does not make me more knowledgeable than other people, but it means that I have been privileged to be personally involved, as participant or onlooker, in a long and still unfinished story. At the risk of being dubbed a bore, I would like to tell that story.

My first contact with scrapie was in 1939 when I was still a veterinary student, working part time at Moredun Institute in Edinburgh. I learned that the disease was a slowly progressive, fatal, non-inflammatory degeneration of the central nervous system, characterized clinically by incoordination of the hind-quarters, a bewildered expression, and, in many cases, compulsive rubbing (scraping) against fixed objects. It was impossible not to become involved with scrapie at Moredun Institute at that time, because large-scale experiments were in progress to confirm the exciting claim by Cuille and Chelle (1936) from France that the disease had been reproduced by intraocular inoculation of healthy sheep with a preparation of spinal cord from an affected sheep. When first made, this claim had been viewed with a scepticism that has from time to time been applied to observations made by scrapie research workers since the days of Roche-Lubin (1848) who suggested that the cause of the disease was sexual excess or lightning. Scepticism in 1936 was not unreasonable, because Cuille and Chelle had reported that the disease had not appeared until between 14 and 22 months after inoculation-and that took some believing.

By the time I arrived at Moredun Institute, Cuille and Chelle were riding high. Not only had they again reproduced scrapie after a long incubation period, but they had also shown that material passed through an antibacterial Chamberland L3 filter would reproduce the disease. In 1938 they suggested that the cause of scrapie was a virus. I was just in time to help with the histological diagnosis of scrapie in the experiments at Moredun Institute that proved beyond doubt that what Cuille and Chelle had claimed was correct. The occasion was unique. For the first and last time, scrapie workers were unanimous. The disease, they said, was caused by a virus.

In the early 19403 all of those involved in scrapie research at Moredun Institute except the late D. R. Wilson went their various ways. Wilson remained at the Institute and during the next 10 years carried out pioneer work on the disease. Wilson's achievements have been greatly undervalued. He was a shy, reticent person, incapable of exaggeration, honest to a rare degree. At that time scrapie was of limited economic importance (compared with many other sheep diseases), and of no special scientific interest. Wilson accepted the conclusion reached by Cuille and Chelle that it was a virus disease, and he set about looking for the virus. He published very little: a paper in 1950, and a brief general article on scrapie in 1952, but Stamp, Brotherston, Zlotnik, Mackay, and Smith (1959) and Stamp (1960) have recorded a good deal of his unpublished work.

Wilson's achievements were remarkable when one remembers that his only method of detecting the transmissible agent of scrapie was by inoculating sheep only about 25 % of which were susceptible to the disease after up to a year's incubation period. By carrying the disease through nine serial passages he showed beyond doubt that scrapie is an experimentally transmissible disease. He was first to demonstrate the high resistance of the transmissible agent to heat (I00'C for 30 minutes), formalin, phenol, and chloroform. He showed that it would pass filters of APD 650 mu and 410 my, that it could

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not be completely sedimented by centrifugation at 40 000 rpm for two hours, and that it remained viable in dried brain for at least two years, and he noted resistance to a considerable dose of ultraviolet light. He found that the disease could be transmitted not only by the intracerebral and intraocular routes, but also subcutaneously, intravenously, and intradermally. He searched extensively for, but was unable to find, antibodies in scrapie-affected or scrapie-inoculated sheep. He could find no abnormality in the cerebrospinal fluid of affected animals, and he noted that the characteristic vacuolated nerve cells of serapie in sheep were less numerous in experimental than in field cases. He recognized the enormous difficulties of working exclusively with sheep, and in 1952 he wrote wistfully. 'The inability to infect a small laboratory animal greatly increases the difficulties of scrapie investigation . . . ' Not that he had not tried to infect laboratory animals; he had done so extensively, but his luck was out. That advance was still nine years into the future.

Scrapie was first diagnosed in Canada in 1939 and the United States of America in 1947, and an extensive programme aimed at complete eradication of the disease was started in the USA in 1952. It is highly likely that scrapie in Canada and the USA was related to importation of sheep from Britain. The disease was diagnosed in Australia in 1952, in sheep imported from Britain some 12 months earlier. Not surprisingly these countries, together with New Zealand, placed a complete embargo on the importation of sheep from Britain unless they could be guaranteed free from scrapie. That embargo is still in force, and more recently has been applied also by South Africa. This sudden closure of export markets for British sheep created a new importance for scrapie research. In 1953 the Agricultural Research Council decided that investigation of the disease must be intensified, and that the work should be done at Moredun Institute and at the Institute for Research on Animal Diseases (at that time called the 'ARC Field Station') at Compton. The late W. S. Gordon, who had worked with scrapie in the prewar days at Moredun Institute, was by this time Director at Compton. And this was when I again became actively involved. Wilson visited Compton in 1953 to inoculate sheep and start our experiments.

The strain of scrapie agent that we-and many others-still use is often called the 'Compton' strain, but in fact it is Wilson's strain, established by his technical skill, not ours. Our first experiments at Compton were aimed at extending Wilson's observations, and it was ieally fortuitous that as early as 1954 we examined further an observation recorded in 1939 by Cuille and Chelle that both of two goats had developed scrapie

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26 months after intraocular inoculation with a homogenate of lumbar cord from a scrapie-affected sheep. I happened to be inoculating a batch of sheep with scrapie on a day when 12 goats were available; I inoculated these animals also, intracerebrally with the suspension of scrapie sheep brain I was putting into sheep. To my surprise, all these 12 goats developed scrapie b2tween 15 and 22 months after inoculation (Pattison, Gordon, and Millson, 1959). This 1000% take was entirely unexpected, because we had become resigned to being unable to produce the disease in more than about 25 % of inoculated sheep. When this high susceptibility was recognized, goats were used for more and more experiments, both by ourselves and others, and a lot of information was obtained that would have been difficult to acquire with sheep because of the large numbers of animals that would have had to be involved.

Looking back to the period 1953 to 1960, at Compton and elsewhere, I recall it as a time of steady but unspectacular progress. Some might call it pedestrian. But the fact remains that many of the original observations out of which the facts of scrapie have emerged were made during that time. The disease was passed from sheep to goats and back to sheep again, and the high take in goats was confirmed; the disease was shown to be non-febrile throughout its course; the presence of the transmissible agent in various body tissues was followed from the time of inoculation onwards, and its very wide distribution in cellular tissues in the advanced clinical disease was recognized; transmission of the disease was achieved by many routes of inoculation, and by oral dosing; the remarkable resistance of the agent to many adverse physical and chemical treatments was confirmed, including heat, formalin, repeated freezing and thawing, and DNase and RNase; also confirmed was an earlier observation, reported by Gordon (1957), that the agent was active in the brain to a dilution of at least 10-6, and a clear indication was obtained of a relationship between length of incubation period and amount of agent in an inoculum. The pathology of the disease in the sheep and goat was studied by several people, myself included, but it turned out that the pathology of goat scrapie was very similar to that of sheep scrapie, and all we did really was to dot a few is and cross a few ts, because the detailed obseivations on the pathology of sheep scrapie by Besnoit and Morel (1898), Stockman (1926), Bertrand, Carre, and Lucam (1937), and Brownlee (1940) left little new to be discovered. During this period, also, extensive but unsuccessful attempts were made (especially at Moredun Institute) to grow the transmissible agent in tissue culture, and to find antibodies in the natural and experimental disease. Also, the first attempts

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were made to detect the agent by electron microscopy, and a great deal of work was done on the epidemiology of the disease. Two distinct types of clinical syndrome, called at that time 'nervous' and 'scratching', were noted in scrapie-affected goats (Pattison and Millson, 1961), and these subsequently played an important role in the transfer of scrapie to mice by Chandler (1961).

The late W. S. Gordon, Director at Compton for 25 years, was an investigator in the grand manner, only marginally interested in experiments with fewer than 50 animals and rejoicing to work with hundreds. But even he excelled himself with what has come to be known as the '24-breed experiment', an audacious plan that established once and for all the importance of genetic make-up in susceptibility to experimental scrapie. Gordon assembled at Compton between 30 and 57 sheep of each of 24 different breeds (1.027 in all), and on a balmy day in July 1957 all were inoculated with a suspension of scrapie sheep brain. I have cause to remember that day, because over a period of 12 hours I injected 250 animals intracerebrally; the remainder were inoculated subcutaneously. The sheep were held under observation for two years, and the occurrence of scrapie was noted. The results of this experiment (Gordon, 1966) are given in the Table. The differences in incidence of scrapie between breeds represented differences in genetic make-up, and detailed analysis of the results showed that within breeds there were resistant and susceptible families.

I still feel an urge to genuflect as I pass the spot at our Institute, beside the boiler house, where my colleague R. L. Chandler paused one day in 1960 to suggest to me that he might inoculate three strains of mice with brain material from the two clinical types of goat scrapie that G. C. Millson and I had called 'nervous' (now usually called 'sleepy' or 'drowsy') and 'scratching'. Chandler had found a difference in susceptibility between C57, CBA, and Swiss mice to the slowly progressive disease caused by Mycobacterium johnei; might these strains show different susceptibilities to scrapie? So he injected C57, CBA, and Swiss mice intracerebrally with 'drowsy' goat scrapie brain, or with 'scratching' goat brain. Seven months later Swiss mice inoculated with 'drowsy' brain developed scrapie (Chandler, 1961). Some weeks later C57 and CBA mice inoculated with 'drowsy' brain also developed scrapie; mouse-tomouse passage was achieved with 100 % susceptibility and an incubation period of about four months (Chandler, 1962). Thus occurred the greatest single advance in scrapie research since experimental transmission of the disease to sheep by Cuille and Chelle in 1936. It had now become possible to carry out experiments involving large numbers of animals, particularly titration experiments that had been virtually impossible with sheep or goats. Above all it was now possible for people with only limited animal accommodation to become involved in scrapie research.

Over almost the same period of time as that covering transfer of scrapie from goat to mouse, other highly significant events occurred that brought scrapie into the medical field, and again Compton was privileged to be intimately involved. Early in 1958 the Agricultural Research Service of the United States Department of Agriculture assigned a veterinary pathologist, W. J. Hadlow, to Compton to create close liaison on scrapie research between the two countries. In September 1959 a letter written by Hadlow, entitled 'Scrapie and Kuru', was published in The Lancet. In this letter Hadlow drew attention to close epizootiological, aetiological, clinical, and pathological similarities between scrapie and kuru. He concluded by saying, 'Thus it might be profitable, in view of veterinary experience with scrapie, to examine the possibility of the experimental induction of kuru in a laboratory primate, for one might surmise that the pathogenetic mechanisms involved in scrapie-however unusual they may be-are unlikely to be unique in the province of animal pathology.' What a prophetic statement! Seldom can medical research workers have received so valuable a directive from a veterinary colleague! D. C. Gajdusek, already deeply interested in kuru, visited Compton in June 1961 to learn about scrapie. We gave him a 'drowsy' goat brain, and in due course he confirmed Chandler's finding by successfully producing scrapie in mice with this brain (Morris and Gajdusek, 1963). With great diligence, he and his colleagues at the National Institutes of Health then followed Hadlow's suggestion that an attempt should be made to induce kuru in a laboratory primate. After a long incubation period, success was achieved with the chimpanzee (Gajdusek, Gibbs, and Alpers, 1966).

Scrapie research in 1961 and 1962 was largely devoted to establishing that Chandler's disease in mice was indeed scrapie. This was done by passing it back to sheep and goats, and onwards through mice, and by studying the clinical and pathological features of the mouse disease in detail. By 1963 the mouse was ready to play its full part. So began the modem era of scrapie research, and I daresay no one at that time believed that the problem of scrapie would be still unsolved in February 1972. Helpful though the mouse has been, however, its use in assaying scrapie activity still leaves much to be desired, and there have been many attempts to find an alternative method, especially by tissue culture techniques. Gustafson and Kanitz (1965), Field and Windsor (1965), and Haig and Pattison (1967) observed abnormal properties in cells from some

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tissues of scrapie-affected animals, and these studies stimulated further work on culture in vitro of scrapie tissues. Within the past two years my colleagues at Compton, D. A. Haig and M. C. Clarke, have established a cell line from scrapie mouse brain in which the agent apparently multiplies in synchrony with, and as an integral part of, the cells; apparently there is only one active site in each affected cell. Very recently Haig and Clarke have suggested that the 'target cells' in scrapie may be of reticuloendothelial origin (Haig and Clarke, 1971). These studies have opened up new lines of research on scrapie that bid fair to become of increasing importance in the future.

As was said at the beginning of this paper, published work on scrapie has been extensively summarized. This applies particularly to the modern era. What may not be immediately obvious to the casual reader, however, is why there should be such a wide divergence of opinion on the nature of scrapie itself and of the transmissible agent. After all, the same experimental evidence is available to everyone; why should its interpretation be so widely different? In particular, why should some authors refer to the transmissible factor as a 'virus', and others studiously avoid the word-and substitute 'agent'? Authors who support a more or less conventional virus aetiology have been influenced by the necessity to explain apparent multiplication of the agent in terms of nucleic acid. Those who have abandoned a virus theory believe that the physicochemical properties of the agent are inconsistent with the presence of nucleic acid.

The first published reference to the transmissible agent as something other than a virus was by Parry (1962), who called it a provirus, defined as something that was formed inside an affected animal but had no independent outside existence. The next published suggestion that the scrapie agent might be odd was my own (Pattison, 1965) when I said that ' . . . if the transmissible agent of scrapie is a living virus, it is a virus of a kind as yet unrecognized.' This conclusion was based on a long series of unsuccessful attempts to inactivate the scrapie agent by heroic methods, including treatment with 12% formalin for 28 months. But what is a 'virus'? If by 'virus' is meant something that will negotiate an antibacterial filter and can be passed indefinitely through animals, apparently increasing in quantity as it goes, then the scrapie agent is a virus. If, however, a virus has to contain nucleic acid, then I believe that D. A. Haig and M. C. Clarke at Compton and their collaborator Tikvah Alper at the Hammersmith Hospital have shown beyond reasonable doubt by their studies with ultraviolet irradiation that the scrapie agent does not contain nucleic acid and is not a virus (Alper, Haig, and Clarke, 1966; Alper, Cramp, Haig, and Clarke,

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1967; Haig, Clarke, Blum, and Alper, 1969; Latarjet, Muel, Haig, Clarke, and Alper, 1970).

Scrapie is one of four closely similar diseases, the others being kuru, Jakob-Creutzfeldt disease, and transmissible mink encephalopathy, all of which will be discussed at this Symposium. All are difficult to handle experimentally, because their undefined transmissible agents can be detected only by animal inoculation after an incubation period of many months. The common link between them is the clinicopathological one of a slowly progressive, fatal, spongiform encephalopathy. Research on scrapie was responsible for recognition of this group of diseases, to which others may be added in due course, and knowledge of the vagaries of scrapie has been of great value in planning research on them all, for in planning a complicated journey it is reassuring to know that similar ground has already been covered.

References

Alper, T., Cramp, W. A., 1faig, D. A., and Clarke, M. C. (1967). Does the agent of scrapie replicate without nucleic acid? Nature (Lond.), 214, 764-766.

Alper. T., Haig, D. A., and Clarke, M. C. (1966). The exceptionally small size of the scrapie agent. Biochem. biophys. Res. Comnmun., 22, 278-284.

Bertrand, I., Carre, ff., and Lucam, F. (1937). La 'tremblante' du mouton. Ann. Anat. path. med.-chir., 14, 565-586.

Besnoit, C., and Morel, C. (1898). Note sur les lesions nerveuses de Ia tremblante du mouton. Rev. vet. Toulouse, 23, 397-400.

Brownlee, A. (1940). Histopathological studies of scrapie, an obscure disease of sheep. Vet. J., 96, 254-264.

Chandler, R. L. (1961). Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet, 1, 1378-1379.

Chandler, R. L. (1962). Encephalopathy in mice. (Letter). Lancet, 1, 107-108.

Cuille, J., and Chelle, P. L. (1936). La maladie dite tremblante du mouton est-elle inoculable? C.R. Acad. Sci. (Paris), 203, 1552-1554.

Cuille, J. and Chelle, P. L. (1938). La tremblante du mouton est-elle determinee par un virus filterable? C.R. Acad. Sci. (Paris), 206, 1687-1688.

Cuille, J., and Chelle, P. L. (1939). Transmission experimentale de la tremblante a la chevre. C.R. Acad. Sci. (Paris), 208, 1058-1060.

Field, E. J. (1969). Slow virus infections of the nervous system. Int. Rev. exp. Path., 8, 129-239.

Field, E. J., and Windsor, G. D. (1965). Cultural characters of scrapie mouse brain. Res. vet. Sci., 6, 130-132.

Gajdusek, D. C., Gibbs, C. J., Jr., and Alpers, M. (1966). Experimental transmission of a kuru-like syndrome to chimpanzees. Nature (Lond.), 209, 794-796.

Gordon, W. S. (1957). Discussion to Palmer, A. C. Studies in scrapie. Vet. Rec., 69, 1324-1327.

Gordon, W. S. (1966). Review of work on scrapie at Compton, England, 1952-1964. In Report of Scrapie Seminar, Washington D.C., ARS 91-53, pp. 19-36.

Gustafson, D. P., and Kanitz, C. L. (1965). Evidence of the presence of scrapie in cell cultures of brain. In Slow, Latent and Temperate Virus Infections (NINDB Monograph No. 2), pp. 221-236, edited by D. C. Gajdusek, C. J. Gibbs, Jr., and M. Alpers, National Institute of Health, Washington D.C.

Hadlow, W. J. (1959). Scrapie and kuru. Lancet, 2, 289-290.

Haig, D. A., and Clarke, M. C. (1971). Multiplication of the scrapie agent. Nature (Lond.), 234, 106-107.

Haig, D. A., Clarke, M. C., Blum, E., and Alper, T. (1969). Further studies on the inactivation of the scrapie agent by ultraviolet light. J. gen. Virol., 5, 455-457.

Haig, D. A., and Pattison, I. H. (1967) In-vitro growth of pieces of brain from scrapie-affected mice. J. Path. Bact., 93, 724-727.

Latarjet, R., Muel, B., 1-faig, D. A., Clarke, M. C., and Alper, T. (1970). Inactivation of the scrapie agent by near monochromatic ultraviolet light. Nature (Lond.), 227, 1341-1343.

Morris, J. A., and Gajdusek, D. C. (1963). Encephalopathy in mice following inoculation of scrapie sheep brain. Nature (Lond.), 197, 1084-1086.

Parry, H. B. (1962). Scrapie: a transmissible and hereditary disease of sheep. Heredity, 17, 75-105.

Pattison, I. H. (1965). Resistance of the scrapie agent to formalin. J. comp. Path., 75, 159-164.

Pattison, I. H., Gordon, W. S., and Millson, G. C. (1959). Experimental production of scrapie in goats. J. comp. Path., 69, 300-312.

Pattison, 1. H., and Millson, G. C. (1961). Scrapie produced experimentally in goats with special reference to the clinical syndrome. J. comp. Path., 71, 101-108.

Roche-Lubin (1848). Memoire pratique sur la maladie des b8tes a laine connue sous les noms de prurigo lombaire, maladie convulsive, trembleuse, tremblante, etc. Rec. Med. vet. Ser 3, 5, 698-7 14.

Stamp, J. T. (1960). Scrapie and scrapie research at Animal Diseases Research Association, Moredun Institute, Edinburgh. In U.S. Department of Agriculture Special Meetings on Scrapie, ARS 91-22, pp. 13-22.

Stamp, J. T., Brotherston, J. G., Ziotnik, I., Mackay, J. M. K., and Smith, W. (1959). Further studies on scrapie. J. comp. Path., 69, 268-280.

Stockman, S. (1926). Contribution to the study of the disease known asscrapie. J. comp. Path., 39, 42-71.

Thormar, H. (1971). Slow infections of the central nervous system. Z. Neurol., 199, 1-23 and 151-166.

Wilson, D. R. (1952). Scrapie. Vet. Rec., 64, 468.

Wilson, D. R., Anderson, R. D., and Smith, W. (1950). Studies in scrapie. J. comp. Path., 60, 267-282.

jcp.bmj.com/content/jclinpath/s3-6/1/110.full.pdf

1988: Letter entitled ‘Scrapie, Time to take HB Parry Seriously’ (YB88/6.8/4.1) 24. In this letter I stated that BSE had been officially confirmed as a TSE (when much of the veterinary profession still favoured a variety of alternate hypotheses). I also suggested that scrapie should be made a notifiable disease, and drew attention to the work of HB 'James' Parry and the possibility that natural scrapie in sheep might be of genetic origin. 25. I withdrew the letter following advice from Professor Barlow (who as far as I can recall had been contacted by MAFF and the Veterinary Record) that it might not be in my interests to pursue publication at that moment in time. 26. I received a letter from the then editor, Edward Boden, questioning my permission to release the information that BSE was indeed a proven TSE. I had no permission, though was unaware that any was needed, to inform my profession of this urgent and important fact.

1992: McGill and Wood 27. This paper summarises views as to why an open debate on TSEs and in particular scrapie were and remain essential. We drew attention to the work of Parry, Prusiner and others, and outlined novel explanations for recent research findings in light of such work. We suggested that not all the relevant questions were being asked in the interpretation of data. In particular, the possibility that the infectious agent was being generated de novo from the genome (the PrP gene) in certain families of sheep, was still not being considered, despite a body of scientific data going back over 30 years. It was to be a further 5 years before publications from Government laboratories would start to cite Parry’s work as a possibly correct theory. 28. The refereeing process for this work was at the time not transparent, and I have yet to be informed as to why this remains unpublished.

SNIP...SEE;

webarchive.nationalarchives.gov.uk/ukgwa/20080102155239/http://www.bseinquiry.gov.uk/files/ws/s067.pdf

www.tandfonline.com/doi/full/10.1080/19336896.2016.1163048?journalCode=kprn20

www.nature.com/articles/srep11573

***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***

Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.

www.nature.com/articles/srep11573

O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations

Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France

Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).

Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.

*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,

***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),

***is the third potentially zoonotic PD (with BSE and L-type BSE),

***thus questioning the origin of human sporadic cases.

We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.

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

***thus questioning the origin of human sporadic cases***

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

***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.

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

prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.

***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.

***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.

www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20

PRION 2016 TOKYO

Saturday, April 23, 2016

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online

Taylor & Francis

Prion 2016 Animal Prion Disease Workshop Abstracts

WS-01: Prion diseases in animals and zoonotic potential

Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.

These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.

www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20

Title: Transmission of scrapie prions to primate after an extended silent incubation period)

*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS.

*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated.

*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains.

www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160

Commentaries and Views

Sheep scrapie and deer rabies in England prior to 1800

Anthony Ness,Judd Aiken &Debbie McKenzie

Pages 7-15 | Received 16 Nov 2022, Accepted 19 Dec 2022, Published online: 18 Jan 2023

Download citation doi.org/10.1080/19336896.2023.2166749

ABSTRACT

Eighteenth-century England witnessed the emergence of two neurological diseases in animals. Scrapie, a transmissible spongiform encephalopathy, is a fatal neurodegenerative disease of sheep and goats that appears in classical and atypical forms. Reports of classical scrapie in continental Europe with described symptoms date back to 1750 in what is now western Poland. However, two major outbreaks of scrapie appeared in England prior to the 1800s. References to a sheep disease with a resemblance to scrapie first appear in Southwestern England between 1693 and 1722 and in the East Midlands between 1693 and 1706. Concurrent with the descriptions of scrapie in sheep was a neurological disease of deer first appearing in the East of England. Two 18th-century writers remarked on the symptomatic similarities between the sheep and deer neurological diseases. Multiple outbreaks of the unknown deer disease existing as early as 1772 are examined and are identified as rabies.

www.tandfonline.com/doi/full/10.1080/19336896.2023.2166749


1: J Infect Dis 1980 Aug;142(2):205-8

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

snip...

The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.

PMID: 6997404

www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract

Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.

snip...

76/10.12/4.6

web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf

Nature. 1972 Mar 10;236(5341):73-4.

Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).

Gibbs CJ Jr, Gajdusek DC.

Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0

Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)

C. J. GIBBS jun. & D. C. GAJDUSEK

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland

SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).

www.nature.com/nature/journal/v236/n5341/abs/236073a0.html

Although the current U.S. feed ban is based on keeping tissues from TSE infected cattle from contaminating animal feed, swine rations in the U.S. could contain animal derived components including materials from scrapie infected sheep and goats. These results indicating the susceptibility of pigs to sheep scrapie, coupled with the limitations of the current feed ban, indicates that a revision of the feed ban may be necessary to protect swine production and potentially human health.

2. Determined that pigs naturally exposed to chronic wasting disease (CWD) may act as a reservoir of CWD infectivity. Chronic wasting disease is a naturally occurring, fatal, neurodegenerative disease of cervids. The potential for swine to serve as a host for the agent of CWD disease is unknown. The purpose of this study was to investigate the susceptibility of swine to the CWD agent following experimental oral or intracranial inoculation. Pigs were assigned to 1 of 3 groups: intracranially inoculated; orally inoculated; or non-inoculated. At market weight age, half of the pigs in each group were tested ('market weight' groups). The remaining pigs ('aged' groups) were allowed to incubate for up to 73 months post inoculation (MPI). Tissues collected at necropsy were examined for disease-associated prion protein (PrPSc) by multiple diagnostic methods. Brain samples from selected pigs were bioassayed in mice expressing porcine prion protein. Some pigs from each inoculated group were positive by one or more tests. Bioassay was positive in 4 out of 5 pigs assayed. Although only small amounts of PrPSc were detected using sensitive methods, this study demonstrates that pigs can serve as hosts for CWD. Detection of infectivity in orally inoculated pigs using mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity. Currently, swine rations in the U.S. could contain animal derived components including materials from deer or elk. In addition, feral swine could be exposed to infected carcasses in areas where CWD is present in wildlife populations. The current feed ban in the U.S. is based exclusively on keeping tissues from TSE infected cattle from entering animal feeds. These results indicating the susceptibility of pigs to CWD, coupled with the limitations of the current feed ban, indicates that a revision of the feed ban may be necessary to protect swine production and potentially human health.


www.ars.usda.gov/research/publications/publication/?seqNo115=353091

www.ars.usda.gov/research/project/?accnNo=432011&fy=2017

www.ars.usda.gov/research/publications/publication/?seqNo115=337105

www.ars.usda.gov/research/publications/publication/?seqNo115=326166

CONFIDENTIAL

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

LINE TO TAKE

3. If questions on pharmaceuticals are raised at the Press conference, the suggested line to take is as follows:-

"There are no medicinal products licensed for use on the market which make use of UK-derived porcine tissues with which any hypothetical “high risk" ‘might be associated. The results of the recent experimental work at the CSM will be carefully examined by the CSM‘s Working Group on spongiform encephalopathy at its next meeting.

DO Hagger RM 1533 MT Ext 3201

web.archive.org/web/20030822054419/www.bseinquiry.gov.uk/files/yb/1990/09/21009001.pdf

While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...

web.archive.org/web/20031026000118/www.bseinquiry.gov.uk/files/yb/1990/08/23004001.pdf

we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.

web.archive.org/web/20030822031154/www.bseinquiry.gov.uk/files/yb/1990/09/10007001.pdf

May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ...

web.archive.org/web/20030822052332/www.bseinquiry.gov.uk/files/yb/1990/09/11005001.pdf

3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ...

web.archive.org/web/20030822052438/www.bseinquiry.gov.uk/files/yb/1990/09/12002001.pdf

But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ...

web.archive.org/web/20030518170213/www.bseinquiry.gov.uk/files/yb/1990/09/13004001.pdf

Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....

web.archive.org/web/20030822054419/www.bseinquiry.gov.uk/files/yb/1990/09/21009001.pdf

(x.) There was concern over the exemption for sausage casings/sutures;[13]

bseinquiry.blogspot.com/2017/08/dfa-15-monitoring-and-enforcement-of.html

www.mad-cow.org/00/sep00_news.html#hhh

Other US BSE risks: the imported products picture 24 Jul 00 Trade Statistics: UK to US Compiled by Terry S.Singeltary Sr of Bacliff, Texas [Opinion (webmaster): The US has focused for years on tracing, containing, and eradicating live animal imports from the UK or other countries with acknowledged BSE like Belgium, including some 499 cattle and the Vermont sheep. This strategy does not acknowledge imports of rendered bovine products from England during the BSE period nor secondary products such as surgical catgut, which is to say surgical cowgut, or dairy cattle embryos, vaccines for veterinarian and human medicines. What has become of these? Mr. Singeltary, who lost his mother to CJD of unexplained origin a few years back and went on to became a well-known TSE activist, has tracked down voluminous pertinent import data through correspondence with UK officials and searches of government web sites. Imports of such products are frequently cited by Europeans in rating BSE risks in the US and in shutting out US exports.

Many people's eyes glaze over when reviewing reams of sometimes older trade statistics. There is no proof that any of the imported products was contaminated with BSE nor if so, any evidence that any BSE product lead to infection in US livestock, surgical patients, or what not. Nonetheless, the data obtained by Mr. Singeltary establish that an appalling variety and tonnage of products that were imported by the US from the UK and othr BSE-affected countries during the peak of the BSE epidemic years.]

10 January 1990 COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION

COMMITTEE ON SAFETY OF MEDICINES

WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY

SURGICAL CATGUT SUTURES

2.1 At the first meeting of the Working Party on Bovine Spongiform Encephalopathy on 6 September 1989, detailed consideration was given to XXXXX Surgical Catgut. This arose from the Company's response to the Letter to Licence Holders, indicating that the bovine small intestine source material was derived from UK cattle, unlike 8 other licenced catgut sutures. In contrast XXXXX Surgical Catgut was stated to hold over 90% share of the market for catgut sutures, and to constitute approximately 83% of all sutures used in U.K.

IMPORTS OF SUTURES FROM THE KNOWN BSE COUNTRY;

3006.10.0000: STERILE SURGICAL CATGUT, SIMILAR STERILE SUTURE MATERIALS AND STERILETISSUE ADHESIVES FOR SURGICAL WOUND CLOSURE; AND SIMILAR STERILE MATERIAL

U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date

(Customs Value, in Thousands of Dollars) (Units of Quantity: Kilograms)

snip...see;

www.mad-cow.org/00/jul00_dont_eat_sheep.html#hhh

see original bse inquiry link;

www.bseinquiry.gov.uk/files/yb/1990/01/10008001.pdf

suture concerns;

bseinquiry.blogspot.com/2017/08/bse-inquiry-dfa-17-medicines-and.html

CATTLE BY-PRODUCTS AND BSE

webarchive.nationalarchives.gov.uk/ukgwa/20080102185236mp_/http://www.bseinquiry.gov.uk/files/yb/1989/07/03004001.pdf

Small Intestines - Sutures (I thought the source was ovine, but you are checking on this)

webarchive.nationalarchives.gov.uk/ukgwa/20080102185236mp_/http://www.bseinquiry.gov.uk/files/yb/1989/07/03004001.pdf

mad dogs and Englishmen

DEER BRAIN SURVEY RED DEER ATAXIA OR CWD???

web.archive.org/web/20090506025229/http://www.bseinquiry.gov.uk/files/yb/1991/11/20004001.pdf

webarchive.nationalarchives.gov.uk/ukgwa/20080102232755/http://www.bseinquiry.gov.uk/files/yb/1992/11/04002001.pdf

web.archive.org/web/20161027181651/http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1982/07/05001001.pdf
web.archive.org/web/20161027182246/http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1982/07/28001001.pdf
web.archive.org/web/20161027181712/http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1983/03/01001001.pdf

MAD DOGS AND ENGLISHMEN

bseinquiry.blogspot.com/2019/02/mad-dogs-and-englishmen-bse-scrapie-cwd.html

EPIDEMIOLOGY OF SCRAPIE IN THE UNITED STATES

web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf

WEDNESDAY, FEBRUARY 03, 2021

Scrapie TSE Prion United States of America a Review February 2021 Singeltary et al

scrapie-usa.blogspot.com/2021/02/scrapie-tse-prion-united-states-of.html

WEDNESDAY, MARCH 16, 2022

SHEEP BY-PRODUCTS AND WHAT ABOUT Scrapie TSE PrP and Potential Zoonosis?

transmissiblespongiformencephalopathy.blogspot.com/2022/03/sheep-by-products-and-what-about.html

TUESDAY, DECEMBER 13, 2022

Scrapie and CJD, Suspect Symptoms, Like Lambs To the Slaughter 2001, a review 2022

transmissiblespongiformencephalopathy.blogspot.com/2022/12/scrapie-and-cjd-suspect-symptoms-like.html_

Terry S. Singeltary Sr.