Abstract Despite low case numbers the variant Creutzfeldt-Jakob disease epidemic poses many challenges for public health planning due to remaining uncertainties in disease biology and transmission routes. We develop a stochastic model for variant CJD transmission, taking into account the known transmission routes (food and red-cell transfusion) to assess the remaining uncertainty in the epidemic. We use Bayesian methods to obtain scenarios consistent with current data. Our results show a potentially long but uncertain tail in the epidemic, with a peak annual incidence of around 11 cases, but the 95% credibility interval between 1 and 65 cases. These cases are predicted to be due to past food-borne transmissions occurring in previously mostly unaffected genotypes and to transmissions via blood transfusion in all genotypes. However, we also show that the latter are unlikely to be identifiable as transfusion-associated cases by case-linking. Regardless of the numbers of future cases, even in the absence of any further control measures, we do not find any self-sustaining epidemics.

Citation: Garske T, Ghani AC (2010) Uncertainty in the Tail of the Variant Creutzfeldt-Jakob Disease Epidemic in the UK. PLoS ONE 5(12): e15626. https://doi.org/10.1371/journal.pone.0015626 Editor: Mike B. Gravenor, Swansea University, United Kingdom Received: August 12, 2010; Accepted: November 18, 2010; Published: December 23, 2010 Copyright: © 2010 Garske, Ghani. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Medical Research Council Centre funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.

Introduction The incidence of variant Creutzfeldt-Jakob disease (vCJD) in the UK has declined considerably since the epidemic peaked in 2000, with currently less than 5 cases arising each year [1]. However, 15 years after the identification of the first vCJD case [2], there are still huge uncertainties governing many aspects of the epidemiology. Exposure via the primary route of infection – namely BSE-infected cattle entering the human food supply – remains at very low levels given the declining BSE epidemic in cattle and the remaining controls in place [3]. However, there remains concern about the possibility of future cases arising both from past exposure in previously unaffected genotypes and through person-to-person transmission. The latter is warranted given that 3 of the 171 cases due to definite, probable or possible vCJD to the end of 2009 have been linked to blood transfusions [4], [5], [6] and hence these could herald the start of a potential secondary wave of cases of unknown scale. Furthermore, it is thought that surgery and dentistry could potentially also harbour a risk of vCJD transmission as current decontamination methods might not be sufficient to remove infectivity from surgical and dental instruments [7], [8]. However, to date there is no evidence that any transmissions via these transmission routes have actually occurred. The scale of any future waves depends in part on the existing prevalence of infection in the population. There is currently no simple diagnostic test for infection that can provide unambiguous estimates of prevalence. However, there have been several studies which have provided estimates of the prevalence of vCJD infection in appendix and tonsil tissues. In risk assessments, a positive tissue sample is taken as equivalent to that person being infectious [9], [10], [11], [12]. However, while this is the prudent approach, it is not clear how these tests correlate with infectiousness. Furthermore, it is still not known when in the incubation period detectable levels of PrPSc, the abnormal form of the prion protein, begin to accumulate in different tissues. The prevalence of infection found in the British population [13], [14] is much higher than would be expected from the case data alone, indicating the existence of a subclinical carrier state, during which individuals may or may not be infectious, but will never develop clinical disease [15]. If these sub-clinically infected people are indeed infectious, they might play an important role in onward transmission via blood transfusion. However, as they may never present as cases, any transmissions caused by a sub-clinically infected donor cannot be linked to the blood-borne transmission route. It is therefore possible that some of the past cases that are currently attributed to food-borne transmission were indeed caused by human-to-human transmission. The genotype of codon 129 of the Prion protein appears to be important for transmission dynamics, with the two alleles Methonine (M) and Valine (V) occurring in the population. All probable and definite cases to date that were genotyped were homozygous for MM, a genotype shared by about 40% of the British population. However, in 2009 a possible case was identified in a person of MV genotype [16]. Unfortunately, no post-mortem was performed on this person, precluding definite diagnosis. One explanation for the observed excess of cases in individuals with the MM genotype is that those with MV and VV genotypes are substantially less susceptible to vCJD disease than MMs. Under this scenario we would not expect to see many cases in these genotypes in the future. However, other hypotheses are conceivable, including very long incubation periods in non-MM genotypes, potentially resulting in a substantial number of cases arising in the future [17]. These large uncertainties in the tail of the epidemic pose a problem for public health planning as the expected magnitude of the future epidemic will have implications for the effort and resources needed to control it. Here we develop a stochastic model for vCJD spread via primary transmission through the consumption of BSE contaminated beef and secondary human-to-human transmission through red cell transfusions (but ignoring other blood components and transmissions via surgery or dentistry), taking into account the genetic structure of the population at codon 129 of the PrP protein. We fit the model to the available epidemiological data accounting for unobserved infections (pre-clinical and sub-clinical) and unobserved transmission via red cell transfusion to obtain the range of future scenarios consistent with the observed epidemic to date in order to quantify the uncertainty in the future risk of vCJD transmission in the UK and provide appropriate inputs for public health planning.

Discussion When the first vCJD cases were reported in the late 1990s, the small numbers combined with lack of knowledge of both the potential transmission routes and key epidemiological parameters meant that projections of the future epidemic were highly uncertain [24], [32]. Following the peak in cases in 2000, and their subsequent decline to low numbers, it has for several years been possible to characterise the oral transmission route in the MM genotype and estimate associated epidemiological parameters with a reasonable degree of precision [28], [31]. However, with small numbers of cases now arising in different genotypes and via other transmission routes (3 cases of MM genotype attributed to blood transfusions since 2003 and reports of a possible vCJD case in a person of MV genotype), there remain concerns about the potential for a second epidemic wave. Building on previous work [10], [17], we have used a stochastic model in a Bayesian framework, combining the transmission via food-borne and red cell transfusion associated transmission with a differentiation with respect to genotype. Our results indicate that we can expect only a small number of future cases to arise in both the MV and VV genotypes through primary transmission. This is because the infection risk is assumed to have been very low indeed for several years and so efficient primary transmission to these genotypes is now only possible in combination with rather long incubation periods, such that a substantial proportion of those infected would reach the end of their natural life span before succumbing to clinical disease. Larger numbers of future cases are possible in all genotypes if efficient transmission occurs though red-cell transfusion. However, even these numbers are limited by the numbers of individuals and the age-profile of those that receive transfusions [10], [33]. Our results suggest that if a second epidemic does arise, this is likely to evolve over a number of decades. Our best estimate for the annual incidence is low with up to 10 cases occurring annually, although the credibility intervals are wide due to large uncertainties in many of the key parameters governing transmission. Despite the rather long time-scale of this potential second wave, we did not find any scenarios which led to a self-sustaining epidemic as classified by the basic reproduction number . In fact, the values are so low that even if both leuko-depletion and the donor ban were totally ineffective they would reach values of less than 0.5. This is in contrast with previous work [10], which found the potential for a self-sustaining epidemic for some combination of parameter values in the absence of any control measures. These results were based on fitting to 2 transfusion associated cases up to 2006, whereas here we are fitting to 3 cases up to 2009, taking into account a number of years during which no transfusion associated cases have been observed. Furthermore, some of the assumptions underlying the earlier work were more pessimistic, whereas here we have refined the model to be more realistic, such as allowing for a delay between infection and the onset of infectivity, a lower susceptibility in non-MM genotypes and the use of several red cell units in a single transfusion, reducing the values of the basic reproduction number further. One assumption implicit in our model simulations concerns the age dependence of susceptibility/exposure to infection. To fit the age distribution of the primary epidemic, as in previous work [27], [28], we fit a strong age dependence in susceptibility/exposure. To date there have been too few secondary cases to fit a distribution to this age profile and we have therefore assumed that for blood-borne transmission susceptibility is independent of age. This might be the case if the age-distribution of cases via primary transmission occurred due to differences in exposure rather than biological susceptibility per se, although evidence for this is limited [34]. Furthermore, animal studies have suggested that one mechanism for biological susceptibility may be age-related changes in the gut [35] and thus it is possible that all ages would be equally susceptible to transmission via blood transfusion. Regardless, even if biological susceptibility did occur via all transmission routes, this remains a reasonable assumption if the infectivity in a single red cell unit is very high. However, for lower transmissibility, including age-dependent susceptibility would reduce the secondary peak considerably given the lack of overlap between those that appear most susceptible to date (teenagers and young adults) and the age distribution of transfusion recipients [25]. We also investigated sensitivity to our assumptions regarding the effectiveness of the control policies in place (see Supplementary Material S1). None of the alternative assumptions investigated changed the overall dynamics significantly, however, the upper limit of the credibility intervals of the projected future epidemic size varied for different scenarios. If leuko-depletion is ineffective in preventing transmissions via red cell transfusions we would expect the secondary outbreak to be up to twice as large, whereas a less effective donor ban had very little effect on the outbreak size. This is because the majority of red cell transfusion cases are caused by people who were themselves infected via the oral transmission route and are therefore not subject to the donor ban. If the test sensitivity of the prevalence test is lower, the true population prevalence is higher than measured in the appendix study, leading to more secondary transmission and therefore potential for a larger secondary outbreak. In summary, given that there are no further known transmission routes efficient enough that they could lead to a self-sustaining epidemic, the variant CJD epidemic in the UK is likely to continue with a low level annual incidence for a lengthy period of years to decades. Whilst any projections of future case numbers are highly uncertain, reflecting the current uncertainties in key transmission parameters for the genotypes and transmission routes in which we have not seen many cases as yet, the timescales involved are fairly insensitive to these highly uncertain parameters. Despite the inherent large uncertainty our results are important for public health planning: The current low level of annual incidence appears to suggest that the epidemic is nearly over. However, while this might be the case, a secondary peak remains a possibility, and this has to be taken into account when decisions are made about the introduction or withdrawal of control measures.

Acknowledgments We would like to thank Robert G Will for the provision of data and Peter Bennett for constructive comments on the manuscript. Imperial College High Performance Computing Service (http://www.imperial.ac.uk/ict/services/teachingandresearchservices/highperformancecomputing) was used for the simulations.

Author Contributions Analyzed the data: TG. Wrote the paper: ACG TG. Designed the model: ACG TG. Implemented the model: TG.