From: TSS ()
Subject: Profile of the vCJD epidemic AND IMPLICATIONS OF RECENT RESEARCH ON MODELS OF THE vCJD EPIDEMIC
Date: February 25, 2005 at 9:29 am PST
Profile of the vCJD epidemic:
• Cover paper- J. W. Ironside (February 2005) Human Prion
• Parchi et al. (1999) Classification of sporadic Creutzfeld-Jakob
disease based on molecular and phenotypic analysis of 300
subjects. Ann. Neurol.
• Clarke & Ghani (2005) Projections of future course of the
primary vCJD epidemic in the UK: inclusion of subclinical
infection and the possibility of wider genetic susceptibility R.
J. Soc. Interface.
• Lasmezas et al. (2005) Risk of oral infection with bovine
spongiform encephalopathy agent in primates. Lancet.
Human Prion Diseases JW Ironside, February 2005
An ever- widening spectrum of human prion diseases has been reported since
Creutzfeldt-Jakob disease (CJD) was initially described in the 1920s (Table
1). This includes sporadic, familial and acquired diseases, the commonest of
which is sporadic CJD (1,2). The naturally occurring polymorphism at codon
129 of the prion protein gene (PRNP) influences susceptibility to sporadic
CJD (Table 2). In comparison with normal population there is an excess of
homozygotes at codon 129 in the PRNP in sporadic CJD (particularly
methionine homozygotes), with a reduction in the percentage of
The clinical and neuropathological features of sporadic CJD are both
this variability is substantially influenced by the PRNP codon 129 genotype
and the isotype of PrPSc in the brain as determined by Western blotting
studies (1,3). PrPSc occurs in 2 major biochemical isoforms in sporadic CJD
(type 1 and type 2), so there are at least 6 different possible
PrPSc isotype and PRNP codon 129 genotype: MM1, MM2, MV1, MV2 VV1
and VV2, each of which appears to be associated with distinctive
pathological features in sporadic CJD (1). Whether these different isoforms
represent different strains of the transmissible agent in sporadic CJD
to be established; the agent strain in variant CJD is similar to bovine
spongiform encephalopathy (BSE), but different from sporadic CJD (4).
To date, all patients with variant CJD who have been tested genetically are
methionine homozygotes at codon 129 in the PRNP, and variant CJD exhibits
a striking uniformity of clinical, pathological and biochemical features in
contrast to sporadic CJD (2,3). It remains to be seen whether BSE infection
will manifest as a clinical disease in individuals with a MV or VV codon 129
PRNP genotype, and if so, whether these cases will have similar or different
clinical and pathological features to variant CJD. Subclinical infection
vCJD by blood transfusion has been reported in an individual who was MV at
codon 129 in the PRNP, but showed no neurological disease or brain
pathology at the time of death (5).
The PRNP codon 129 polymorphism also appears to influence disease
incubation period in other acquired forms of human prion diseases, including
kuru (6) and the cases of iatrogenic CJD following growth hormone therapy in
France (7). In both diseases, individual who are heterozygous (MV) at codon
129 in the PRNP had a longer disease incubation period (which in kuru may
be over 40 years) than MM or VV homozygotes. If this is also the case for
BSE infection in humans, we might expect to see other codon 129 genotypes
affected over an unknown timescale in the future. The results of the
retrospective tonsil and appendix study has suggested that more cases of
BSE infection may have occurred in the UK than the numbers of clinical cases
of variant CJD would so far indicate (8). This study raises the
some BSE infections may have occurred in individuals with VV or MV codon
129 PRNP genotype who have not yet (or perhaps may never) manifest a
clinical disease. Continuing surveillance for all forms of CJD is
required in the
UK to address this possibility.
Members are invited to note particularly references 1 and 2 below:
al 1999, which is provided to members) and the NCJDSU Annual Report
“Creutzfeldt-Jakob disease surveillance in the UK”. www.cjd.ed.ac.uk
1. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O,
Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A,
Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P,
Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease
based on molecular and phenotypic analysis of 300 subjects. Ann
2. Creutzfeldt-Jakob disease surveillance in the UK. The National CJD
Surveillance Unit. www.cjd.ed.ac.uk
3. Head MW, Bunn TJ, Bishop MT, McLoughlin V, Lowrie S, McKimmie
CS, Williams MC, McCardle L, MacKenzie J, Knight R, Will RG,
Ironside JW. Prion protein heterogeneity in sporadic but not variant
Creutzfeldt-Jakob disease: UK cases 1991-2002. Ann Neurol
4. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A,
McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock
CJ. Transmissions to mice indicate that 'new variant' CJD is caused by
the BSE agent. Nature1997;389:498-501.
5. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW.
Preclinical vCJD after blood transfusion in a PRNP codon 129
heterozygous patient. Lancet 2004;364:527-9.
6. Goldfarb LG, Cervenakova L, Gajdusek DC. Genetic studies in relation
to kuru: an overview. Curr Mol Med 2004;4:375-84.
7. Huillard d'Aignaux J, Costagliola D, Maccario J, Billette de Villemeur T,
Brandel JP, Deslys JP, Hauw JJ, Chaussain JL, Agid Y, Dormont D,
Alperovitch A. Incubation period of Creutzfeldt-Jakob disease in
human growth hormone recipients in France. Neurology 1999;53:1197-
8. Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Ritchie D,
Penney M, Hegazy D, Ironside JW. Prevalence of lymphoreticular prion
protein accumulation in UK tissue samples. J Pathol 2004; 203:733-9.
Table 1. Classification of human prion diseases
Idiopathic: Sporadic Creutzfeldt-Jakob disease
Sporadic fatal insomnia
Inherited: Familial Creutzfeldt-Jakob disease
Fatal familial insomnia
Acquired: Human source: Iatrogenic Creutzfeldt-Jakob disease
Bovine source: Variant Creutzfeldt-Jakob disease
Table 2. Codon 129 PRNP polymorphisms in CJD and normal
population in UK
methionine/methionine methionine/valine valine/valine
Normal 39% 50% 11%
Sporadic CJD 66% 17% 17%
Variant CJD 100% - -
IMPLICATIONS OF RECENT RESEARCH ON MODELS OF THE
1. Recent horizon scanning identified the hypothetical risk of a
secondary epidemic of vCJD as a result of lateral transfer of the
BSE prion between individuals (for example through blood
transfusion) a key issue to assess. In addition, DH requested that
SEAC considers the implications of recent research on models of
the profile of the vCJD epidemic. These two issues are related.
2. Trends in the incidence of BSE in cattle show that the control
measures introduced to prevent recycling of mammalian meat
and bone meal have resulted in dramatic decline in the number of
cases of the disease1. Control measures have also been
introduced which significantly limit the potential risk of primary
infection of humans from consumption of food contaminated with
the BSE agent.
3. Recent numbers of vCJD cases show a decline in the incidence
of vCJD2. To date, all the affected individuals have been found to
be methionine homozygous (M/M) at codon 129 of the prion
protein (PrP) gene, suggesting that this PrP genotype may be
relatively susceptible to vCJD compared with other PrP
4. Projections of the profile of the vCJD epidemic based on data
from the BSE and vCJD epidemics, together with assumptions on
parameters such as vCJD phenotype and incubation period, have
suggested that the numbers of vCJD cases will be relatively
small3. However, a number of recent experimental and
1 BSE Update. Item 2 SEAC 84 minutes.
2 vCJD Update. Item 3 SEAC 84 minutes.
3 e.g. Ghani et al. Updated projections of future vCJD deaths in the UK.
BMC Infect Dis. 2003
epidemiological research findings suggest that the profile of the
epidemic may be more complex. For example:
• A survey to detect abnormal prion protein (PrP) in tonsil and
appendix4 has indicated that the prevalence of infection may
be higher than suggested by the number of clinical vCJD
• A case of probable blood transfusion associated
transmission of vCJD was found to be heterozygous (M/V) at
codon 129 of the PrP gene raising the possibility that
genotypes other than M/M may also be susceptible to
infection. However, the patient was asymptomatic for vCJD
before dying of an unrelated cause5.
• Findings from a study of transgenic mouse models
expressing human forms of the PrP gene6 suggest that the
PrP genotype may strongly influence the clinical phenotype
of BSE and vCJD infection.
• An analysis of the age distribution of vCJD cases suggests
that susceptibility to vCJD could be related to age, with a
higher susceptibility to vCJD in younger people7.
5. The potential for secondary (human to human) infection as a
result of medical procedures (e.g. use of contaminated
surgical/dental instruments, blood transfusions and tissue
transplants) is a further factor that may influence the profile of the
6. SEAC has considered the profile of the vCJD epidemic on
numerous occasions and has also considered the potential for
secondary infections as a result of medical procedures or
maternal transmission. However, in light of new information
about the prevalence of the disease as well as the possible
relationships between age and susceptibility and PrP genotype
and disease phenotype, DH has asked the committee to reassess
4 Hilton et al. Prevalence of lymphoreticular prion protein accumulation
in UK tissue samples.
J Pathol. 2004 203, 733-739.
5 SEAC statement on the second presumed case of blood
with vCJD. (2004)
6 Wadsworth et al. Human prion protein with valine 129 prevents
expression of variant CJD
phenotype. Science. 2004 306, 1793-1796.
7 Boelle et al. Epidemiological evidence of higher susceptibility to
vCJD in the young. BMC
Infect Dis. 2004 4, 26.
current models of the profile of the vCJD epidemic and consider
the possible impact of secondary infections on the epidemic.
7. The SEAC CJD epidemiology subgroup has recently been
disbanded and will be reconvened as the SEAC epidemiology
subgroup with new terms of reference to cover both the animal
and human epidemiology of prion diseases. The new terms of
reference for the subgroup are:
To report to SEAC on the significance of emerging and published
epidemiological data about human and animal TSEs, and on such
specific epidemiological questions as SEAC refers to it for advice.
8. Detailed epidemiological analyses, together with new modelling
work, will be required to address this issue comprehensively.
Thus, it is envisaged that SEAC could task the reconvened SEAC
epidemiology subgroup to address the request and report back to
the committee at a later date.
9. To inform the subgroup considerations, SEAC is asked to
consider the issues and identify key questions for the subgroup to
address. A list of possible key and subsidiary questions is given
at the end of this paper. DH has agreed to consider support for
some modelling work.
10. To facilitate consideration of the key issues and questions by
SEAC, a number of experts have been invited to make
presentations to the committee and some of the key pieces of
research are also provided in annexes as below:
• the most recent data on the clinical profile of vCJD and sCJD
cases, projections of the course of the vCJD epidemic and
an estimation of the risk of primary infection (see Annex 1).
• information on genotype-phenotype relationships from
transgenic mouse models and the Kuru epidemic (see
• research on measures to reduce potential vCJD
transmission through the use of surgical instruments (Annex
• models of age-related susceptibility to infection (Annex 4).
11. Note that parts of Annexes 3 and 4 have not been circulated outside
the committee as these annexes contain new scientific data that have
not yet been published in a scientific journal. However, the content can
be discussed by the committee in the public meeting.
ADVICE SOUGHT FROM THE COMMITTEE
12. The committee is asked to:
• agree that the reconvened SEAC epidemiology subgroup be
tasked with a detailed consideration of the issues identified.
• suggest possible sources of additional information that could
inform the subgroup’s considerations.
• develop key questions for the subgroup to consider to
enable it to address the issues identified.
13. Suggested key and subsidiary questions are as follows:
Q1 What are the implications of recent research for current
models of the vCJD epidemic?
(a) Do recent data on age- and genotype-related effects alter
the predicted profile of the vCJD epidemic and the potential
number of infective carriers?
(b) Are there likely to be 'carriers' of infectivity who do not
develop clinical vCJD within their lifetime, or who present
with clinical features not currently recognised as vCJD, and if
so, what are the limits on the possible prevalence / age
distribution / genotype of such individuals?
Q2 What new evidence would lead SEAC to believe that the size
of the vCJD epidemic is likely to be larger or smaller than current
estimates (i.e. what new data would lead SEAC to believe that
current estimates may be incorrect)?
(a) Are the current and expected data from population level
studies (i.e. tonsil and appendix and other tissue surveys)
sufficient to enable estimation of the age / genotype
distribution of infection, and what further information would
help inform predictions of the profile of the vCJD epidemic?
(b) What are the information barriers to determining the
potential risks to public health from carriers of vCJD
Q3 Is there a significant risk of a self-sustaining human vCJD
epidemic through secondary transmission of BSE between
(a) What are the relative risks of secondary transmission
through medical procedures (transfusion, transplantation,
(b) Taking all these potential routes of transmission and their
interactions into account, how likely is a self-sustaining
(c) If a self-sustaining epidemic is possible, what factors
determine its scale?
Q4 What are the key points at which modification of practice
could significantly reduce the risk of a self-sustaining epidemic?
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