Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain

Understanding the epidemiology and aetiology of new–variant Creutzfeldt–Jakob (vCJD) disease in humans has become increasingly important given the scientific evidence linking it to bovine spongiform encephalopathy (BSE) in cattle and hence the wide exposure of the population of Great Britain (GB) to potentially infectious tissue. The recent analysis undertaken to determine the risk to the population from dorsal route ganglia illustrated the danger in presenting point estimates rather than ranges of scenarios in the face of uncertainty. We present a mathematical template that relates the past pattern of the BSE epidemic in cattle to the future course of any vCJD epidemic in humans, and use extensive scenario analysis to explore the wide range of possible outcomes given the uncertainty in epidemiological determinants. We demonstrate that the average number of humans infected by one infectious bovine and the incubation period distribution are the two epidemiological factors that have the greatest impact on epidemic size and duration. Using the time–series of the BSE epidemic and the cases seen to date, we show that the minimum length of the incubation period is approximately nine years and that at least 20% of the cases diagnosed to date were exposed prior to 1986. We also demonstrate that the current age distribution of vCJD cases can only arise if younger people were either exposed to a greater extent, more susceptible to infection, or have shorter incubation periods. Extensive scenario analyses show that given the information currently available, the very high degree of uncertainty in the future size of the epidemic will remain for the next 3–5 years. Furthermore, we demonstrate that this uncertainty is unlikely to be reduced by mass screening for late–stage infection.

[1]  R. Hassler,et al.  Experimental kuru in the spider monkey. Histopathological and ultrastructural studies of the brain during early stages of incubation. , 1975, Brain : a journal of neurology.

[2]  J. Zajicek,et al.  Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease , 1998, The Lancet.

[3]  M. Alpers,et al.  The Natural Incubation Period of Kuru and the Episodes of Transmission in Three Clusters of Patients , 1984 .

[4]  Arieyeh J Austin,et al.  Infectivity in the ileum of cattle challenged orally with bovine spongiform encephalopathy , 1994, Veterinary Record.

[5]  N. Hunter,et al.  PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. , 1994, The Journal of general virology.

[6]  H. Fraser,et al.  Transmission of bovine spongiform encephalopathy and scrapie to mice. , 1992, The Journal of general virology.

[7]  Richard J. Beckman,et al.  A Comparison of Three Methods for Selecting Values of Input Variables in the Analysis of Output From a Computer Code , 2000, Technometrics.

[8]  M. D. McKay,et al.  A comparison of three methods for selecting values of input variables in the analysis of output from a computer code , 2000 .

[9]  P. Brown,et al.  Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  A. Ghani,et al.  Analysis of dam–calf pairs of BSE cases: confirmation of a maternal risk enhancement , 1997, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[11]  Solomon H. Snyder,et al.  Diurnal variation in mRNA encoding serotonin N-acetyltransferase in pineal gland , 1995, Nature.

[12]  J. Wilesmith,et al.  A cohort study to examine maternally-associated risk factors for bovine spongiform encephalopathy , 1997, Veterinary Record.

[13]  D. J. Middleton,et al.  Dietary transmission of bovine spongiform encephalopathy to mice , 1990, Veterinary Record.

[14]  H. Fraser,et al.  Detection of BSE infectivity in brain and spleen of experimentally infected sheep , 1996, Veterinary Record.

[15]  D. J. Middleton,et al.  Failure to transmit bovine spongiform encephalopathy to mice by feeding them with extraneural tissues of affected cattle , 1993, Veterinary Record.

[16]  M. Jeffrey,et al.  A novel progressive spongiform encephalopathy in cattle , 1987, Veterinary Record.

[17]  DavidJ. Evans,et al.  Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy , 1997, The Lancet.

[18]  R H Kimberlin,et al.  Pathogenesis of experimental scrapie. , 1988, Ciba Foundation symposium.

[19]  M. Stein Large sample properties of simulations using latin hypercube sampling , 1987 .

[20]  M. Smits,et al.  Preclinical test for prion diseases , 1996, Nature.

[21]  M. Palmer,et al.  Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease , 1991, The Lancet.

[22]  Christl A. Donnelly,et al.  Analysis of the Bovine Spongiform Encephalopathy Maternal Cohort Study: Evidence for Direct Maternal Transmission , 1997 .

[23]  M. Zeidler,et al.  Codon 129 genotype and new variant CJD , 1997, The Lancet.

[24]  A. Dickinson,et al.  Maternal and lateral transmission of scrapie in sheep. , 1974, Journal of comparative pathology.

[25]  Hoinville Lj A review of the epidemiology of scrapie in sheep. , 1996 .

[26]  C. Donnelly,et al.  Transmission dynamics and epidemiology of BSE in British cattle , 1996, Nature.

[27]  M. Palmer,et al.  Unaltered susceptibility to BSE in transgenic mice expressing human prion protein , 1995, Nature.

[28]  R. G. Will,et al.  Predicting the CJD epidemic in humans , 1997, Nature.

[29]  Andrew F. Hill,et al.  The same prion strain causes vCJD and BSE , 1997, Nature.

[30]  R. Anderson,et al.  Estimation of the number of people incubating variant CJD , 1998, The Lancet.

[31]  M. Beekes,et al.  Effect of repeated oral infection of hamsters with scrapie. , 1998, The Journal of general virology.

[32]  A. Hofman,et al.  A new variant of Creutzfeldt-Jakob disease in the UK , 1996, The Lancet.

[33]  Andrew F. Hill,et al.  Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD , 1996, Nature.

[34]  L. Hoinville A review of the epidemiology of scrapie in sheep. , 1996, Revue scientifique et technique.

[35]  D. Dormont,et al.  Genotype at codon 129 and susceptibility to Creutzfeldt-Jakob disease , 1998, The Lancet.

[36]  S. Cousens,et al.  Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent , 1997, Nature.

[37]  G. Wells,et al.  Preliminary observations on the pathogenesis of experimental bovine spongiform encephalopathy (BSE): an update. , 1998, The Veterinary record.

[38]  Pandu R. Tadikamalla,et al.  A Probability Distribution and its Uses in Fitting Data , 1979 .

[39]  N M Ferguson,et al.  The epidemiology of BSE in cattle herds in Great Britain. II. Model construction and analysis of transmission dynamics. , 1997, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[40]  P. Lansbury,et al.  Molecular assessment of the potential transmissibilities of BSE and scrapie to humans , 1997, Nature.

[41]  N. Hunter,et al.  Linkage of the gene for the scrapie-associated fibril protein (PrP) to the Sip gene in Cheviot sheep , 1989, Veterinary Record.

[42]  J. Collinge,et al.  Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy , 1997, The Lancet.

[43]  T. Crow,et al.  Codon 129 changes in the prion protein gene in Caucasians. , 1990, American journal of human genetics.