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From: TSS ()
Subject: SEAC New forms of Bovine Spongiform Encephalopathy 1 August 2007
Date: August 5, 2007 at 10:41 am PST

Position Statement


New forms of Bovine Spongiform Encephalopathy


1. SEAC considered the implications of scientific research on recently identified novel forms of bovine spongiform encephalopathy (BSE).

2. Very low numbers of cattle with abnormal prion proteins (PrPsc) with different biochemical properties from those normally associated with BSE have been detected in active surveillance programmes in a number of countries. SEAC considered (SEAC 97, May 2007) published and unpublished research relating to these putatively new forms of BSE.

Characterisation of cases

3. Different forms of BSE were initially identified and distinguished from classical BSE on the basis of their PrPsc profiles in biochemical tests. All BSE cases identified to date conform to one of three different PrPsc profiles on western blot tests. The European Union (EU) Community Reference Laboratory has suggested that cases be classified on the basis of these profiles as classical, L- or H-type BSE. The key distinguishing features in western blot tests are the lower concentration of the diglycosylated band and the slightly lower molecular mass of unglycosylated band of PrPsc in L-type BSE, and the higher molecular mass of the unglycosylated band in H-type BSE, compared with classical BSE. A western blot method to discriminate between the three types of BSE has been developed .

4. All the reported cases of L-4,5,6,7 and H-type7,9,8,9 BSE have been detected during active surveillance of healthy slaughtered animals or fallen stock. In the majority of cases, retrospective investigations indicated that these animals either showed no clinical signs of BSE or showed non-specific signs such as ataxia and recumbency. As these cases have been detected following active rather than passive surveillance, it has not been possible to observe the clinical signs associated with L- or H-type BSE in sufficient detail to assess whether there are differences in the clinical features between L-type, H-type and classical BSE. However, a significant distinction between classical BSE and L- and H-type BSEs is the age distribution of cases as L- and H-type BSE are found in older cattle with an age range of 5.5 to 19 years. One putative L-type BSE case was aged two years6, however the BSE typing of this case has not been verified. Around 85% of L- or H-type BSE cases have been found in animals more than 10 years old, which is much older than most cases of classical BSE.

5. Neuropathological investigations suggest that PrPsc may be more widely distributed, with a different brain distribution pattern for L- and H-type BSE, compared with classical BSE. However, these investigations are limited by the very low number of animals for which a complete brain has been available for analysis. There are no data on the peripheral distribution of PrPsc or infectivity of L- and H-type BSE or on the pathogenesis of these diseases. However, studies to assess the tissue distribution of infectivity and PrPsc in animals throughout the incubation period following intracerebral challenge are underway.


6. As there is no regulatory requirement to specify the type of BSE when notifying the EU or the World Organisation of Animal Health of BSE cases, it is not possible to accurately quantify the number of H- or L-type BSE cases that have occurred world-wide. Information presented to SEAC indicated that at least 37 cases of L- and H-type BSE have been identified world-wide to date. These cases are widely distributed geographically with L-type cases identified in a number of European countries and Japan, and H-type cases identified in a number of European countries and North America.

7. Due to the different approaches to surveillance between countries, proportions of animals tested and methods used, which do not necessarily include systematic molecular typing, these surveillance systems are not equally capable of detecting L- and H-type BSE. Furthermore, surveillance procedures, including the most appropriate brain region to sample, have not been optimised for the detection of L- and H-type BSE. Therefore, it is not possible to accurately assess and compare the prevalence of L- and H-type BSE in different countries. Origins and Causes

8. It is not known whether L- or H-type BSE are newly emerging forms of BSE or whether they have existed for some time and have only come to light following extensive active surveillance programmes in the EU and elsewhere, together with the introduction and development of new biochemical tests. Studies using historic frozen brain samples from cattle collected from passive surveillance during the early years of the UK BSE epidemic are underway to investigate whether L- and H-type BSE existed in the UK in the past. However, if the prevalence of these BSE types was low, these studies may not identify many, if any, cases.

9. Genetic analyses of a few L- and H-type BSE cases4,5,8,9 have not identified associations between the occurrence of such cases and known genetic polymorphisms in the prion protein gene. There are no mutations in the prion protein gene open reading frame in all, but one, sequenced case. However, the analyses conducted to date are limited by the small number of cases and controls analysed. Thus, a genetic cause of the disease cannot be ruled out.

10. No detailed epidemiological investigations have been conducted to investigate the possible causes for, or links between, L- and H-type BSE cases. No geographical clusters of L- and H-type BSE cases have been found to date. Therefore, it is not possible to rule out feed related, environmental or spontaneous causes for these types of cases.

Transmission studies

11. Transmission studies5,10,11 have demonstrated that both L- and H-type BSE are transmissible to other species by the intracerebral route. No studies have assessed the transmissibility by the oral route. Thus, the available information shows that it is possible for species other than cattle to develop these diseases upon infection. However, these data do not allow an assessment of the susceptibility to infection from the most likely natural route of exposure.

12. L-type BSE has been transmitted to wild-type, bovinised, ovinised and humanised mice as well as to cattle and a cynomolgus macaque by intracerebral inoculation. Incubation periods, clinical signs, neuropathology as well as the neurological distribution of PrPsc were distinct from classical BSE13,12. With the exception of transmissions to wild-type mice, primary transmissions resulted in clinical disease. Although primary transmission to wild-type mice did not result in clinical disease, secondary transmissions from some of these animals resulted in clinical disease. Sub-passage of L-type BSE in wild-type12 and ovinised mice13 suggests that L-type BSE may be converted to an infection of a similar phenotype to classical BSE. However, further experiments using serial sub-passages of infections in a range of species are required to more fully investigate whether L-type BSE may convert to a disease with a classical BSE phenotype.

13. H-type BSE has been transmitted to wild type, bovinised and ovinised mice by intracerebral inoculation with incubation periods, neuropathology and neurological distribution of PrPsc distinct from classical and L-type BSE.

14. Studies of intracerebral transmission of H-type BSE to cattle and cynomolgus macaques . To date, clinical disease has developed from one intracerebral inoculation of H-type BSE to cattle. Oral transmissions of L- and H-type to cynomolgus macaques are underway.

Human and animals health implications
15. There are too few data to enable an assessment of the natural transmissibility of L- and H-type BSE between cattle, or to sheep or goats. The present feed control measures which prevent feeding of mammalian meat and bone meal to ruminants would limit the spread of these forms of BSE to cattle, sheep and goats should they be transmissible to these species by the oral route.

16. Similarly, the lack of data on the oral transmissibility of L- or H-type BSE to humanised mice or non-human primates does not allow an assessment of the human health implications of ingestion of meat from animals infected with L- or H-type BSE. The differing clinical features of L-type and classical BSE in the cynomolgus macaque suggest that if L-type BSE were ever to be transmitted to humans, its clinical presentation may differ from that of vCJD. It is possible, therefore, that, if transmitted to humans, it could be identified by continuing surveillance of unusual neurological conditions in place in the UK.


17. L- and H-type BSE have not yet been fully characterised, however data from biochemical, neuropathological and transmission studies suggest that L- and H-type and classical BSE may be distinct strains of prion disease. In contrast to classical BSE, L- and H-type BSE infections are mostly detected in animals of older age with most of the infected animals identified to date over 10 years of age. Although L- and H-type BSE may be diseases that predominantly affect older cattle, it is possible that infections may occur at a young age and develop over a long period of time. The origins and possible routes of transmission, if transmissible under natural conditions, of L- and H-type BSE are not known. Due to the older age of the cases identified, wide geographical distribution and their apparent low number, it is possible they may have arisen spontaneously, however feed borne or environmental transmission cannot be ruled out.

18. As data on the oral transmissibility of L- and H-type BSE are lacking, it is not possible to fully assess the animal and human health implications. However, as the occurrence of L- and H-type BSE appears to be low, and due to the feed control measures in place, the risk of spread to other cattle, sheep and goats is likely to be very low assuming that, as with classical BSE, environmental transmission is negligible. For these reasons, and because of the BSE control measures in place to protect the food supply, assuming that the specific risk material controls are similarly effective for L- and H-type and classical BSE, the risk to human health is likely to be very low to negligible. However, given the paucity of data on L- and H-type BSE, a close watching brief should be maintained on the findings of research in this area.

SEAC July 2007


1SEAC 97 discussion papers available at

2Published and unpublished data from the Institute for Novel and Emerging Infectious Diseases, Germany presented by Dr M. Groschup, the Instituto Nazionale Neurologico, Italy presented by Dr F. Tagliavini, the Unite Agents Transmissibles Non Conventionnels, France presented by Dr T. Baron, the Istituto Zooprofilattico Sperimentale del Piemonte, Italy presented by Dr P. Acutis, the National Animal Disease Centre, USA presented by Dr J. Richt, the National Veterinary Services Laboratories, USA presented by Dr M. Hall, the Commissariat à L’Energie Atomique, France presented by Professor C. Lasmezas, the Veterinary Laboratories Agency, UK presented by Dr. L. Terry and the National Institute of Infectious Diseases, Japan provided by Dr Y. Yamakawa.

3Jacobs et al. Molecular discrimination of atypical bovine spongiform encephalopathy strains from a geographical region spanning a wide area in europe. J Clin Microbiol. 2007;45(6):1821-9.

4Casalone et al. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A. 2004;101(9):3065-70.

5 Buschmann et al. Atypical BSE in Germany--proof of transmissibility and biochemical characterization. Vet Microbiol. 2006;117(2-4):103-16.

6Yamakawa et al. Expert Committee for BSE Diagnosis, Ministry of Health, Labour and Welfare of Japan. Atypical proteinase K-resistant prion protein (PrPres) observed in an apparently healthy 23-month-old Holstein steer. Jpn J Infect Dis. 2003;56(5-6):221-2.

7Brown et al. On the question of sporadic or atypical bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Emerg Infect Dis. 200;12(12):1816-21.

8Biacabe et al. Distinct molecular phenotypes in bovine prion diseases. EMBO Rep. 2004;5(1):110-5.

9Richt et al. Identification and characterisation of two bovine spongiform encephalopathy cases diagnosed in the United States. J Vet Diagn Invest 2007;19:142-54

10Capobianco et al. Conversion of the BASE Prion Strain into the BSE Strain: The Origin of BSE? PLoS Pathog. 2007;3(3):e31

11Baron et al. Transmission of new bovine prion to mice. Emerg Infect Dis. 2006;12(7):1125-8.

12Beringue et al. Isolation from cattle of a prion strain distinct from that causing bovine spongiform encephalopathy. PLoS Pathog. 2006;2(10):e112.

13Beringue et al. A bovine prion acquires an epidemic bovine spongiform encephalopathy strain-like phenotype on interspecies transmission. J Neurosci. 2007;27(26):6965-71.

Page updated: 1 August, 2007

Bovine spongiform encephalopathy: the effect of oral exposure dose on attack
rate and incubation period in cattle
G. A. H. Wells1, T. Konold1, M. E. Arnold1, A. R. Austin1,, S. A. C.
Hawkins1, M. Stack1, M. M. Simmons1, Y. H. Lee2, D. Gavier-Widén3, M.
Dawson1, and J. W. Wilesmith1,

1 Veterinary Laboratories Agency, Woodham Lane, New Haw, Addlestone, Surrey
KT15 3NB, UK
2 National Veterinary Research and Quarantine Service, Anyang, Republic of
3 National Veterinary Institute (SVA), SE-75189 Uppsala, Sweden

G. A. H. Wells

The dose–response of cattle exposed to the bovine spongiform encephalopathy
(BSE) agent is an important component of modelling exposure risks for
animals and humans and thereby, the modulation of surveillance and control
strategies for BSE. In two experiments calves were dosed orally with a range
of amounts of a pool of brainstems from BSE-affected cattle. Infectivity in
the pool was determined by end-point titration in mice. Recipient cattle
were monitored for clinical disease and, from the incidence of
pathologically confirmed cases and their incubation periods (IPs), the
attack rate and IP distribution according to dose were estimated. The dose
at which 50 % of cattle would be clinically affected was estimated at 0.20 g
brain material used in the experiment, with 95 % confidence intervals of
0.04–1.00 g. The IP was highly variable across all dose groups and followed
a log-normal distribution, with decreasing mean as dose increased. There was
no evidence of a threshold dose at which the probability of infection became
vanishingly small, with 1/15 (7 %) of animals affected at the lowest dose (1

Present address: Oak Farm, Harpsden Bottom, Henley-on-Thames, Oxon RG9 4HY,

Present address: NSPAC, Defra, Whittington Road, Worcester WR5 2SU, UK.

Present address: Defra, 1a Page Street, London SWIP 4PQ, UK, and Department
of Infectious and Tropical Diseases, London School of Hygiene and Tropical
Medicine, University of London, Keppel Street, London WC1E 7HT, UK.

Volume 2: Science
3. The nature and cause of BSE
Dose-related experiments (including the attack rate experiment)

Transmission of BSE and scrapie to sheep and goats by intracerebral and oral
3.165 Initiated in June 1988 at the NPU, this experiment set out to compare
transmission of both BSE and scrapie to two breeds of sheep, one
susceptible, the other resistant to scrapie infection, and to goats which
are rarely susceptible to natural scrapie. Its aim was to determine,
firstly, if BSE behaved differently from scrapie in these animals and,
secondly, if BSE transmission was influenced by the route of challenge.

3.166 Sheep of both breeds and goats were inoculated either intracerebrally
with 0.05 g of infected BSE brain material, or orally with 0.5 g of infected
material. The size of the intracerebral inoculations was based on that used
for standard scrapie transmissions and was effectively limited by the volume
of material that could be introduced into the brain. 6 Amounts used for oral
administration were limited by the physical quantity of bovine material
available, and so, in order to inoculate several animals, it was necessary
to use a smaller quantity of inoculum (0.5 g) than if the available material
had been administered to one animal.

3.167 BSE was found to transmit to both scrapie-resistant and susceptible
sheep breeds as well as to goats following intracerebral inoculation. This
result was significant in that it showed that BSE transmitted to animals
which were not susceptible to scrapie infection. BSE was also found to
transmit orally to these animals, showing that the amount of infectivity
contained in 0.5 g of brain material was sufficient to cause disease. The
results also showed that the two inoculation routes were similarly efficient
in transmitting disease, when it had been commonly accepted that the
intracerebral route was much more efficient than the oral route.

3.168 Results of positive oral transmission to scrapie-susceptible sheep
were known to scientists conducting the experiment by November 1990, 7
although it was not clear if the sheep had succumbed to infection with
natural scrapie or BSE. This was more than a year before the start of the
attack rate experiment. Oral transmission of BSE to negative-line sheep was
not recorded until October 1991. 8

3.169 It is not clear when MAFF officials became aware of the oral
transmission of BSE to sheep, let alone the amount of material that was
sufficient to cause disease. Results were supplied periodically by the NPU
to the CVL in the form of a data sheet which contained updates of all NPU
experiments. It is not clear who received these reports, though it appears
that they were distributed prior to the NPU/CVL R&D meetings. 9 The quantity
of material administered orally to the animals was not recorded on these
data sheets, so those not familiar with the design of the experiment would
not necessarily have appreciated the significance of the oral transmission.
Interim results of this experiment were published in the Veterinary Record
in 1993. 10

3.170 These results showed that a small amount of infectious material
administered orally was sufficient to cause BSE, even across a species
barrier. This information could have usefully guided decisions made on the
design of the attack rate experiment in cattle.

look at the table and you'll see that as little as 1 mg (or 0.001 gm) caused 7% (1 of 14) of the cows to come down with BSE;

Risk of oral infection with bovine spongiform encephalopathy agent in primates

Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys
Summary The uncertain extent of human exposure to bovine spongiform encephalopathy (BSE)--which can lead to variant Creutzfeldt-Jakob disease (vCJD)--is compounded by incomplete knowledge about the efficiency of oral infection and the magnitude of any bovine-to-human biological barrier to transmission. We therefore investigated oral transmission of BSE to non-human primates. We gave two macaques a 5 g oral dose of brain homogenate from a BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months after exposure, whereas the other remained free of disease at 76 months. On the basis of these findings and data from other studies, we made a preliminary estimate of the food exposure risk for man, which provides additional assurance that existing public health measures can prevent transmission of BSE to man.


BSE bovine brain inoculum

100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg

Primate (oral route)* 1/2 (50%)

Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%) 1/15 (7%)

RIII mice (ic ip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)

PrPres biochemical detection

The comparison is made on the basis of calibration of the bovine inoculum used in our study with primates against a bovine brain inoculum with a similar PrPres concentration that was

inoculated into mice and cattle.8 *Data are number of animals positive/number of animals surviving at the time of clinical onset of disease in the first positive animal (%). The accuracy of

bioassays is generally judged to be about plus or minus 1 log. ic ip=intracerebral and intraperitoneal.

Table 1: Comparison of transmission rates in primates and cattle infected orally with similar BSE brain inocula

Published online January 27, 2005

It is clear that the designing scientists must also have shared Mr Bradley’s surprise at the results because all the dose levels right down to 1 gram triggered infection.


18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7
December 2006 are now available.


64. A member noted that at the recent Neuroprion meeting, a study was
presented showing that in transgenic mice BSE passaged in sheep may be more
virulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the


3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve

Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain
discovered recently in Italy, and similar or different atypical BSE cases
were also reported in other countries. The infectivity and phenotypes of
these atypical BSE strains in humans are unknown. In collaboration with
Pierluigi Gambetti, as well as Maria Caramelli and her co-workers, we have
inoculated transgenic mice expressing human prion protein with brain
homogenates from BASE or BSE infected cattle. Our data shows that about half
of the BASE-inoculated mice became infected with an average incubation time
of about 19 months; in contrast, none of the BSE-inoculated mice appear to
be infected after more than 2 years.

***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than
classical BSE in humans.***

6:30 Close of Day One

1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

If, on the other hand, atypical BSE continues to occur as typical BSE
disappears, this would be a strong indication that it is indeed sporadic,
and if in addition at least 1 form of what is presently considered as
sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot
signature like BASE) were to increase, this would suggest (although not
prove) a causal relationship (Figure 5).

The Lancet Infectious Diseases 2003; 3:463


Tracking spongiform encephalopathies in North America

Xavier Bosch

“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.”


adding that, “the cases that we know about are reassuring, because they do not suggest the appearance of a new variant of CJD in the USA or atypical features in patients that might be exposed to CWD. However, until we establish a system that identifies and analyses a high proportion of suspected prion disease cases we will not know for sure”. The USA should develop a system modelled on that established in the UK, he points out....snip...END

1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.





MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to

comment on the CDC's attempts to monitor the occurrence of emerging

forms of CJD. Asante, Collinge et al [1] have reported that BSE

transmission to the 129-methionine genotype can lead to an alternate

phenotype that is indistinguishable from type 2 PrPSc, the commonest

sporadic CJD. However, CJD and all human TSEs are not reportable

nationally. CJD and all human TSEs must be made reportable in every

state and internationally. I hope that the CDC does not continue to

expect us to still believe that the 85%+ of all CJD cases which are

sporadic are all spontaneous, without route/source. We have many TSEs in

the USA in both animal and man. CWD in deer/elk is spreading rapidly and

CWD does transmit to mink, ferret, cattle, and squirrel monkey by

intracerebral inoculation. With the known incubation periods in other

TSEs, oral transmission studies of CWD may take much longer. Every

victim/family of CJD/TSEs should be asked about route and source of this

agent. To prolong this will only spread the agent and needlessly expose

others. In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?

Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under-
counts CJD, Schonberger conceded that the current surveillance system
has errors but stated that most of the errors will be confined to the older




By Terry S Singeltary

Bacliff, Texas USA Jan 24, 07


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