Scientific Opinion on the risk of transmission of classical scrapie via in vivo derived embryo transfer in ovine animals
EFSA Journal 2013;11(2):3080 [15 pp.]. doi:10.2903/j.efsa.2013.3080 EFSA
Panel on Biological Hazards (BIOHAZ) SCIENTIFIC OPINION
Scientific Opinion on the risk of transmission of classical scrapie via in
vivo derived embryo transfer in ovine animals1
EFSA Panel on Biological Hazards2, 3
European Food Safety Authority (EFSA), Parma, Italy Panel Members Olivier
Andreoletti, Dorte Lau Baggesen, Declan Bolton, Patrick Butaye, Paul Cook,
Robert Davies, Pablo S. Fernandez Escamez, John Griffin, Tine Hald, Arie
Havelaar, Kostas Koutsoumanis, Roland Lindqvist, James McLauchlin, Truls
Nesbakken, Miguel Prieto Maradona, Antonia Ricci, Giuseppe Ru, Moez Sanaa,
Marion Simmons, John Sofos and John ThrelfallAcknowledgment The Panel wishes to
thank the members of the Working Group on the risk of transmission of classical
scrapie via in vivo embryo transfer in ovine animals: Olivier Andreoletti, Nora
Hunter and Ciriaco Ligios for the preparatory work on this scientific opinion
and the hearing experts: Michel Thibier and Pascale Chavatte-Palmer, and EFSA
staff: Pablo Romero Barrios for the support provided to this scientific
opinion.Possible conflict of interest One member of the Panel did not
participate in the discussion on the subject referred to above because of
potential conflicts of interest identified in accordance with the EFSA policy on
declarations of interests.Contact biohaz@efsa.europa.eu
Type: Opinion of the Scientific Committee/Scientific Panel On request from:
European Commission Question number: EFSA-Q-2012-00647 Adopted: 24 January 2013
Published: 08 February 2013 Affiliation: European Food Safety Authority (EFSA),
Parma, Italy Article(0.3 Mb) Send Print Cite
Abstract
The risk of transmission of classical scrapie via the transfer of in vivo
derived embryo in ovines was assessed, taking into account the scientific
information made available since the last EFSA opinion on this topic (2010) (see
http://www.efsa.europa.eu/en/efsajournal/pub/1429.htm).
The potential impact of PrP genotype of the embryo and/or of the ram and donor
ewe on this risk was also assessed. The new data made available over the last
three years further reinforce the view that classical scrapie could be
vertically transmitted in sheep. Since the possibility of such vertical
transmission was already considered in the previous opinion, its conclusions and
recommendations relating to the risk of classical scrapie transmission via
embryo transfer remain valid. In ovines, the susceptibility to classical scrapie
infection in sheep is strongly influenced by certain polymorphisms of the PrP
gene. Under natural exposure conditions, animals that are heterozygous or
homozygous A136R154R171 display respectively a low or negligible risk of being
infected. The genetic control of the susceptibility to classical scrapie is also
likely to impact on the risk of transmitting the disease via embryo transfer.
Irrespective of the embryo’s genotype, embryos derived from rams and dams
carrying at least one ARR allele would significantly decrease this risk
(compared to an embryo from parents of unknown genotypes). The use of homozygous
ARR embryos would provide the highest level of safety regarding the risk of
transmitting classical scrapie through embryo transfer (in vivo derived
embryos). The use of heterozygous ARR embryos would ensure a higher level of
safety compared to Q171/Q171 embryos. Finally, it was concluded that, providing
the OIE recommendations and procedures relating to embryo transfer are adhered
to, the risk of transmitting classical scrapie due to the transfer of homozygous
or heterozygous ovine ARR embryos can be considered negligible.
© European Food Safety Authority, 2013
Summary Following a request from the European Commission, the Panel on
Biological Hazards (BIOHAZ) was asked to deliver a scientific opinion on the
risk of transmission of classical scrapie via in vivo derived embryo transfer in
ovine. The Panel was requested to provide an updated scientific opinion on the
risk of transmission of classical scrapie via in vivo derived embryo transfer in
ovine animals, taking into account any new scientific information made available
since its last assessment on this issue in 2010. In addition, the Panel was
requested to elaborate on this risk of transmission according to the PrP
genotype of the embryo and/or of the ram and donor ewe.
The Panel reviewed the scientific literature published since the adoption
of the previous Opinion covering this issue in 2010 and concluded that relevant
findings available further reinforce the view that classical scrapie in small
ruminants could be vertically transmitted. Since the possibility of vertical
transmission was already considered in the previous opinion, these new findings
do not make it necessary to revise the conclusions related to the risk of
classical scrapie transmission via embryo transfer.
With regard to the effect of genotype, the susceptibility to classical
scrapie infection in sheep is strongly influenced by certain polymorphisms of
the PrP gene. Under natural exposure conditions, animals that are heterozygous
or homozygous A136R154R171 show respectively a low or negligible risk of being
infected by classical scrapie. This genetic control of the susceptibility to
classical scrapie infection directly influences the risk of transmitting the
disease via embryo transfer in that, irrespective of the embryo’s genotype, the
use of embryos derived from rams and dams carrying at least one ARR allele would
significantly decrease the risk of transmitting classical scrapie via embryo
transfer (by comparison to an embryo from parents of unknown genotypes).
Furthermore, the use of homozygous ARR embryos would provide the highest
possible level of safety with regard to minimising the risk of transmitting
classical scrapie through embryo transfer (in vivo derived embryos). The use of
heterozygous ARR embryos would ensure a higher level of safety by comparison
with homozygous Q171 (A/V136, R/H154) embryos.
Providing that the OIE recommendations and procedures relating to embryo
transfer are adhered to, the risk of transmitting classical scrapie by the
implantation of homozygous or heterozygous ARR ovine embryos can be considered
negligible.
The Panel indicated that the recommendations relating to the risk of
transmitting classical scrapie via embryo transfer that were formulated in the
2010 opinion remain valid. In particular, the presence of infectivity in ovine
embryos collected from scrapie infected dams bearing susceptible genotypes needs
to be assessed before a definitive assessment of the risk of transmitting
classical scrapie via the use of embryos bearing a susceptible genotype can be
made.
Keywords Classical scrapie, ovine, sheep, embryo transfer, transmission
risk
snip...
CONCLUSIONS AND RECOMMENDATIONS
CONCLUSIONS Since the 2010 opinion only two relevant studies have been
published. None of them suggest a need to revise the previous conclusion adopted
by the BIOHAZ Panel in January 2010 i.e ‘Based on the data currently available
the risk of TSE transmission associated with embryos collected from Classical
scrapie incubating ewes and she-goats ranges from negligible to low. However,
data are insufficient to conclude that such a risk is negligible.’ In sheep the
susceptibility to classical scrapie infection is strongly influenced by the
polymorphisms of the PrP gene. Under natural exposure conditions, animals that
are heterozygous or homozygous ARR show respectively a low or negligible risk of
being infected by classical scrapie. This genetic control of the susceptibility
to classical scrapie infection directly influences the risk of transmitting the
disease via embryo transfer:
– Irrespective of the embryo’s genotype, the use of embryos derived from
rams and dams carrying at least one ARR allele would significantly decrease the
risk of transmitting classical scrapie via embryo transfer (by comparison to an
embryo from parents of unknown genotypes).
– The use of homozygous ARR embryos would provide the highest possible
level of safety with regard to the risk of transmitting classical scrapie
through embryo transfer (in vivo derived embryos).
– The use of heterozygous ARR embryos would ensure a higher level of safety
by comparison with Q171/Q17110 embryos.
– The risk of transmitting classical scrapie by implantation of a Q171/Q171
embryo collected from a dam with an unknown classical scrapie status cannot be
considered negligible. Providing that the OIE recommendations and procedures
relating to embryo transfer are adhered to, the risk of transmitting classical
scrapie by the implantation of homozygous or heterozygous ovine ARR embryos can
be considered negligible.
RECOMMENDATIONS
The recommendations relating to the risk of transmitting classical scrapie
via embryo transfer that were formulated in the 2010 opinion remain valid.
In particular, the presence of infectivity in ovine embryos collected from
scrapie infected dams bearing susceptible genotypes needs to be assessed before
a definitive assessment of the risk of transmitting classical scrapie via the
use of embryos bearing a susceptible genotype can be made.
10 By convention Q171 refers to ARQ, VRQ, and AHQ alleles.
SEMEN AND TSE INFECTIVITY
USDA
Chronic Wasting Disease
Program Standards
July 2012
At this time there is no scientific evidence that germplasm (embryos or
semen) may transmit CWD. However, there is no scientific evidence that embryos
or semen from positive animals do not serve as a route of transmission for CWD.
Because of the lack of scientific information on transmission potential, APHIS
recommends that germplasm from known CWD-positive animals should not be used. If
more definitive evidence of the role of embryos or semen in the transmission of
CWD should become available, this guidance will be changed.
Envt.18:
Mother to Offspring Transmission of Chronic Wasting Disease
Candace K. Mathiason,† Amy Nalls, Kelly Anderson, Jeanette Hayes-Klug,
Jenny G. Powers, Nicholas J. Haley and Edward A. Hoover Colorado State
University; Fort Collins, CO USA†Presenting author; Email: ckm@lamar.colostate.edu
We have developed a new cervid model in small Asian muntjac deer (Muntiacus
reevesi) to study potential modes of vertical transmission of chronic wasting
disease (CWD) from mother to offspring. Eight of eight (8/8) muntjac doe orally
infected with CWD tested PrPCWD lymphoid positive by four months post infection.
Ten fawns were born to these CWD-infected doe— four of the fawns were viable,
five were non-viable and one was a first trimester fetus harvested from a
CWD-infected doe euthanized at end-stage disease. The viable fawns have been
monitored for CWD infection by immunohistochemistry and sPMCA performed on
serial tonsil and rectal lymphoid tissue biopsies. PrPCWD has been detected in
one fawn by IHC as early as 40 days of age. Moreover, sPMCA performed on rectal
lymphoid tissue has yielded positive results on another fawn at ten days of age.
In addition, sPMCA assays have demonstrated amplifiable prions in fetal
placental or spleen tissue of three non-viable fawns and mammary tissue of the
dams. Additional pregnancy related fluids and tissues from the doe as well as
tissue from the nonviable fawns are currently being probed for the presence of
CWD. In summary, we have employed the muntjac deer model, to demonstrate for the
first time the transmission of CWD from mother to offspring. These studies
provide the foundation to investigate the mechanisms and pathways of maternal
prion transfer.
PPo3-18:
A Possible Case of Maternal Transmission of the BSE Agent within Captive
Cheetah Affected with Feline Spongiform Encephalopathy
Anna Bencsik, Sabine Debeer, Thierry Petit and Thierry Baron Afssa; Unité
ATNC; Lyon, France; Zoo de la Palmyre; Les Mathes, France
Key words: BSE, FSE, vertical transmission
Introduction. Feline spongiform encephalopathy (FSE) is considered to be
related to bovine spongiform encephalopathy (BSE). It has been reported in
domestic cats as well as in captive wild cats including cheetahs, first in the
United Kingdom (UK) and then in other European countries. In France, several
cases were described in cheetahs either imported from UK or born in France. Here
we report details of two other FSE cases in captive cheetah. These cases are of
particular interest since the 2nd case of FSE in a cheetah born in France,
appears most likely due to maternal transmission.1
Results. Complete PrPd study showed the close likeness between the two
cheetah cases. The TgOvPrP4 mouse brains infected with cattle BSE and cheetah
FSE revealed similar vacuolar lesion profiles, PrPd brain mapping with
occurrence of typical florid plaques.
Materials and Methods. Using immunohistochemistry (IHC), pathological form
of PrP(PrPd) was analyzed in the brains and peripheral organs of these two
cheetahs. Transmission studies to the TgOvPrP4 mouse line were also performed,
for comparison with the transmission of cattle BSE. Lesion profiles of the
infected transgenic mice were analyzed as well as type and brain distribution of
PrPd.
Conclusion. Collectively, these data indicate that both FSE cases harbor
the same strain of agent as the cattle BSE agent. Because this is most probably
a case of maternal transmission of the disease, this new observation may have
some
impact on our knowledge of vertical transmission of BSE agent-linked TSEs
such as in human variant Creutzfeldt Jakob disease.
References
1. Bencsik et al. PLoS One 2009; 4:6929.
PRION 2011
landesbioscience.com
International Prion Congress: From agent to disease September 8–11, 2010
Salzburg, Austria
Saturday, February 11, 2012
PrPSc Detection and Infectivity in Semen from Scrapie-Infected Sheep
PrPSc Detection and Infectivity in Semen from Scrapie-Infected Sheep
Friday, December 23, 2011
Detection of PrPres in Genetically Susceptible Fetuses from Sheep with
Natural Scrapie
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely
create alarm in some circles even if the result could not be interpreted for
man. I have a view that all these agents could be transmitted provided a large
enough dose by appropriate routes was given and the animals kept long enough.
Until the mechanisms of the species barrier are more clearly understood it might
be best to retain that hypothesis.
snip...
R. BRADLEY
Wednesday, February 16, 2011
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
Sunday, December 12, 2010
EFSA reviews BSE/TSE infectivity in small ruminant tissues News Story 2
December 2010
Sunday, April 18, 2010
SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010
Thursday, December 23, 2010
Molecular Typing of Protease-Resistant Prion Protein in Transmissible
Spongiform Encephalopathies of Small Ruminants, France, 2002-2009
Volume 17, Number 1 January 2011
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
Monday, April 25, 2011
Experimental Oral Transmission of Atypical Scrapie to Sheep
Volume 17, Number 5-May 2011
Friday, February 11, 2011
Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues
Thursday, March 29, 2012
atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012
NIAA Annual Conference April 11-14, 2011San Antonio, Texas
Wednesday, April 4, 2012
20120402 - Breach of quarantine/Violation de la mise en quarantaine of an
ongoing Scrapie investigation
Michigan and California have had a high spike in Goat Scrapie cases,
compared to elsewhere ???
Tuesday, February 01, 2011
Sparse PrP-Sc accumulation in the placentas of goats with naturally
acquired scrapie
(Figure 6) including five goat cases in FY 2008 that originated from the
same herd in Michigan. This is highly unusual for goats, and I strenuously urge
that there should be an independent investigation into finding the common
denominator for these 5 goats in the same herd in Michigan with Scrapie. ...
Thursday, February 23, 2012
Atypical Scrapie NOR-98 confirmed Alberta Canada sheep January 2012
RESEARCH
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
Experimental Oral Transmission of Atypical Scrapie to Sheep
Marion M. Simmons, S. Jo Moore,1 Timm Konold, Lisa Thurston, Linda A.
Terry, Leigh Thorne, Richard Lockey, Chris Vickery, Stephen A.C. Hawkins,
Melanie J. Chaplin, and John Spiropoulos
To investigate the possibility of oral transmission of atypical scrapie in
sheep and determine the distribution of infectivity in the animals’ peripheral
tissues, we challenged neonatal lambs orally with atypical scrapie; they were
then killed at 12 or 24 months. Screening test results were negative for
disease-specifi c prion protein in all but 2 recipients; they had positive
results for examination of brain, but negative for peripheral tissues.
Infectivity of brain, distal ileum, and spleen from all animals was assessed in
mouse bioassays; positive results were obtained from tissues that had negative
results on screening. These fi ndings demonstrate that atypical scrapie can be
transmitted orally and indicate that it has the potential for natural
transmission and iatrogenic spread through animal feed. Detection of infectivity
in tissues negative by current surveillance methods indicates that diagnostic
sensitivity is suboptimal for atypical scrapie, and potentially infectious
material may be able to pass into the human food chain.
SNIP...
Although we do not have epidemiologic evidence that supports the effi cient
spread of disease in the fi eld, these data imply that disease is potentially
transmissible under fi eld situations and that spread through animal feed may be
possible if the current feed restrictions were to be relaxed. Additionally,
almost no data are available on the potential for atypical scrapie to transmit
to other food animal species, certainly by the oral route. However, work with
transgenic mice has demonstrated the potential susceptibility of pigs, with the
disturbing fi nding that the biochemical properties of the resulting PrPSc have
changed on transmission (40). The implications of this observation for
subsequent transmission and host target range are currently unknown.
How reassuring is this absence of detectable PrPSc from a public health
perspective? The bioassays performed in this study are not titrations, so the
infectious load of the positive gut tissues cannot be quantifi ed, although
infectivity has been shown unequivocally. No experimental data are currently
available on the zoonotic potential of atypical scrapie, either through
experimental challenge of humanized mice or any meaningful epidemiologic
correlation with human forms of TSE. However, the detection of infectivity in
the distal ileum of animals as young as 12 months, in which all the tissues
tested were negative for PrPSc by the currently available screening and confi
rmatory diagnostic tests, indicates that the diagnostic sensitivity of current
surveillance methods is suboptimal for detecting atypical scrapie and that
potentially infectious material may be able to pass into the human food chain
undetected.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
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
http://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
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).
IT is of my opinion, that the OIE and the USDA et al, are the soul reason,
and responsible parties, for Transmissible Spongiform Encephalopathy TSE prion
diseases, including typical and atypical BSE, typical and atypical Scrapie, and
all strains of CWD, and human TSE there from, spreading around the globe.
I have lost all confidence of this organization as a regulatory authority
on animal disease, and consider it nothing more than a National Trading
Brokerage for all strains of animal TSE, just to satisfy there commodity. AS i
said before, OIE should hang up there jock strap now, since it appears they will
buckle every time a country makes some political hay about trade protocol,
commodities and futures. IF they are not going to be science based, they should
do everyone a favor and dissolve there organization.
JUST because of low documented human body count with nvCJD and the long
incubation periods, the lack of sound science being replaced by political and
corporate science in relations with the fact that science has now linked some
sporadic CJD with atypical BSE and atypical scrapie, and the very real threat of
CWD being zoonosis, I believed the O.I.E. has failed terribly and again, I call
for this organization to be dissolved. ...
Tuesday, July 17, 2012
O.I.E. BSE, CWD, SCRAPIE, TSE PRION DISEASE Final Report of the 80th
General Session, 20 - 25 May 2012
Thursday, December 20, 2012
OIE GROUP RECOMMENDS THAT SCRAPE PRION DISEASE BE DELISTED AND SAME OLD BSe
WITH BOVINE MAD COW DISEASE
TSS
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