Variant Creutzfeldt–Jakob disease (vCJD) is a disorder caused by the aggregation and deposition of a pathologic isoform of the cellular prion protein (PrP^C), denoted as PrP^Sc. vCJD emerged clinically in the United Kingdom (UK) in 1994 and was first reported in 1996 (1). This disorder was not fully unexpected, as an ad-hoc surveillance system was set up in the UK in the early 1990s and later on in a few other EU member countries as a research activity to unveil potential consequences of dietary exposure to bovine spongiform encephalopathy (BSE) (2). vCJD garnered considerable attention and concern in Europe due to fears that the presence of the first patients could signal the beginning of an outbreak of unpredictable magnitude secondary to local BSE exposure after an incubation time of approximately 10 years. Twenty-five years later, as a result of surveillance and research regarding human transmissible spongiform encephalopathy (HTSE), the natural history of sporadic, genetic, and acquired prion disorders has been thoroughly reported, which provided a unique context for vCJD public health work in the 21st century (3).

vCJD, now a rare disorder due to significant public health interventions, has been extensively studied (4, 5). Dating back to 2 May 2022, 233 vCJD deaths had been recorded in 12 countries. Of these, the United Kingdom and France stand out, with 178 and 29 cases, respectively (6). In the UK, two persons with the M129V codon structure died with vCJD, one clinical case and a subclinical case in a person with hemophilia. The results of three national surveys of abnormal prion prevalence in archived appendix specimens showed that potential vCJD carriers may still exist (7). The etiological underlying factors appeared to be dietary exposure to BSE products by residence or travel to the UK, import of cattle raised in the UK or fed with meat and bone meal imported from the UK, as well as transmission by blood and blood products in a few cases (5). Recently, cases have been reported in laboratory workers, one in Italy, who died in 2016 (8), and two in France (9), who died in 2019 and 2021. In Spain, five cases have been reported during the 1993–2018 period, with three of them clustered by time and place of residence, and two of them were first-degree relatives with shared dietary habits (3, 10).

The purpose of this study was to describe three separate aspects of vCJD surveillance in Spain for the period 1993–2021: (1) surveillance procedures particularly relevant for vCJD, (2) surveillance outcomes for vCJD, and (3) response after surveillance, i.e., the preventive measures determined by the potential transmissibility of each vCJD case.

As follows, we report on the public health structures and surveillance work relevant to vCJD in Spain.

Spain's population, 46 million in 2008 (the midpoint of the studied period), is served by a health care system that has an important public component, including pediatric and neurological diagnosis and care, as well as public health services progressively decentralized to 17 regions since 2001. However, it was an international network of researchers, rather than public health institutions, that took up the study of CJD in the early 1990s. Country-based CJD surveillance started in a few European Union (EU) member countries, formally as a Concerted EU Action coordinated from centers in Edinburgh, Scotland, and Rotterdam, The Netherlands, in the early 1990s, and crystalized as an extended EU public health network supported by the European Centre for Disease Prevention and Control as of 2007 (11). Spain joined the network in 1995. The basic features and outcomes of the Spanish HTSE surveillance system for the period 1993–2018 have recently been reported (3). Variation in the effectiveness of vCJD surveillance over the period probably existed, i.e., in part due to alarms in 1996 and 2001 secondary to the first vCJD cases in the UK and the BSE cases reported in Spain, respectively, as well as important technical advances in HTSE diagnosis introduced at specific time points and countries (3). An overall, structured view of surveillance methods during the 1993–2021 period is given in reference 3. The following is a summary of the characteristics mentioned in two publications from 2000 to 2010 covering the first two-thirds of the period (12, 13), and scientific reports on diagnostics (12).

As shown in Table 1, of 2,257 suspected cases reported during the period 1995–2021, five were diagnosed as post-mortem neuropathologically confirmed vCJD, while none of the others were ultimately classified as probable vCJD (Figure 2) (13). Table 1 summarizes the rather heterogeneous most relevant clinical and laboratory findings, including prion protein isoforms (18). There were three cases in the province of León, two of them mother and son with almost simultaneous clinical onset, and a third case, which had met the criteria of probable sCJD with triphasic EEG complexes, was finally diagnosed as vCJD after a detailed re-evaluation of her post-mortem examination. The age at clinical onset of confirmed vCJD cases ranged from 25 to 64 years, with a mean of 45.60 and a standard deviation (SD) of 13.95 years. Transmission to humanized mice with tissue from the two family-related cases showed, despite differences in patient age at clinical onset and disease manifestations, the same properties of the strain in these patients as in the UK vCJD cases (19).

Figure 3 shows the annual number of vCJD deaths in Spain together with the vCJD outbreaks in European countries during the period 1995–2019. vCJD in Spain appeared late after the UK and France epidemics, and the vCJD peak in France fits the first vCJD death in Spain. We lack information to interpret the temporal patterns of other countries.

Since 2009, no new vCJD has been identified in Spain for 15 years.

Surveillance of HTSE in Spain for more than 25 years shows that the five vCJD cases had particular characteristics. Compared to other countries, particularly the UK and France (1), Spain's peak calendar period, age at onset, and death, spatiotemporal clustering, family aggregation, and dietary habits showed some significant differences, with all the reservations stemming from the few affected cases. While the vCJD cases reported in the UK and France hardly differed in age and survival time, and the two cases in northern Portugal had a lower age of onset (25), the Spanish vCJD cases had a higher age at onset/death and a shorter survival time. On the other hand, some clinical parameters, such as the triphasic complex at EEG and a rapid course, mimicked sCJD characteristics.

To better understand the outbreak of vCJD cases in Spain, we must first consider the potential dietary exposures to BSE in Spain. Figure 4 shows the BSE exposure of the Spanish population, expressed by imports of beef from the UK, and the number of BSE cases diagnosed annually throughout the country and recorded up to 2010. Imports of beef from the UK into Spain started in 1993, peaked in 1995, and fell sharply to very low values in 1996, when vCJD was reported in the UK. The beef carcasses imported from the UK contained spinal cord. During the whole period, national annual beef production did not change over time (an annual average of 530 000 tons between 1989 and 1998) and was several hundred times higher than beef imports from the UK at any time. By contrast, the local BSE epidemic in Spain could have started in 2000, reached its peak in 2003, and almost disappeared in 2006. While beef consumption in Spain was almost constant, BSE dietary exposure appeared to have been limited and bimodal, first imported and then related to domestic BSE. The distribution of lesions found in the BSE cases in Spain suggested that the phenotype of the BSE strain found in the Spanish cases was the same as that reported in the British and Portuguese epidemics (26).

Based on ecological data and case reports from international surveillance, we could hypothesize etiological clues in a few cases. Approximately 10 years before the onset of case 1 (roughly the estimated incubation period for vCJD in the United Kingdom and France), imports of UK cattle carcasses containing spinal cord reached their peak in Spain, coinciding with the patient's occupational and dietary exposure. Her clinical profile, low age at onset, and particularly her dietary history might fit better with a causal exposure to imported BSE from the UK, a hypothesis for vCJD suggested in local BSE-free populations (27). The first vCJD case in the Netherlands, a 26-year-old woman at the time of her death with an occupational history of several years working and eating in a processed meat restaurant (28), resembles the first Spanish case, and both would fit the hypothesis of BSE meat imported from the UK.

For cases 3 and 4, the PrP strain present in the mother and son matched that seen in the UK humanized mouse models (19), suggesting a link between both cases and BSE arising in the UK. The clustering of cases 2, 3, and 4 in the province of León suggests that they shared a common etiology. The mother and son had a history of dietary exposure to beef brain and offal, potentially related to BSE, as it coincided with the onset of the BSE epizootic in Spain. The ultimate origin of BSE in León, where it was prevalent, could have been the meat and bone meal imported from Portugal, where UK exports were important. The province of León is close to northern Portugal, the region where two cases of vCJD were detected. Furthermore, in the province of León, domestic slaughtering of cattle and other animals existed at the turn of the century (Badiola J pers. comm.) and could have implicated cattle with BSE before BSE surveillance. Although the transmission of BSE from sheep in central Spain has been proposed (29), we believe that the León cluster is related to BSE. Unfortunately, we do not have any etiological clues regarding case 5 who is from Cantabria, a neighboring region to León. In summary, we suggest two etiological sources: one from beef with BSE imported from the UK (case 1) and one from local beef with BSE (cases 2, 3, and 4).

Prevention efforts derived from vCJD surveillance is a public health action distinct from food and feed control, and these efforts have been reflected in policies to increase safety in blood donation and the pharmaceutical industry (30), as well as in preventive measures implemented in hospitals. In response to surveillance results, we took measures to prevent the spread of the disease in three of the five cases (3). In order to ensure preventive action, this response requires an early, sustained, and strong commitment from national and regional institutions. However, we barely succeeded in this endeavor. The fact that at the time of diagnosis, patients may have transmitted the disease to others through their blood, fluids, or medical devices, due to the long incubation period before clinical onset, hinders prevention. Once a diagnosis of vCJD has been made, retrospective intervention is necessary to prevent further harm and to monitor all patients already exposed.

Our study has limitations. The surveillance system may have had low sensitivity to detect cases. Case 4 was initially misdiagnosed as probable sCJD. The post-mortem findings precluded this bias, but there were a few cases, especially in recent years, where post-mortem examinations were not performed, such as in the patient diagnosed with probable sCJD with a history of occupational laboratory exposure to prion disorders. Consequently, our surveillance might have underestimated the true number of cases. The clinical differences in the Spanish cases compared to cases from Portugal, France, and the UK, where young patients predominated, could have led to misdiagnosing other cases as sCJD. Another limitation has been the delay in reporting cases to the central hub, sometimes taking months, especially since 2020 with the COVID-19 pandemic, which could have hampered proper preventive and public health decision-making.

To recapitulate, we found five cases of vCJD in Spain during a short period of time, from 2005 to 2008. The absence of new vCJD cases since 2010 may primarily be due to the cessation of beef imports from the UK and effective control of the local BSE epidemic. We cannot rule out that response measures to surveillance might have helped to control vCJD. Due to the considerable plasticity of vCJD, the potential shift to an upward trend in the annual number of vCJD referrals determined by occupational exposures from laboratory research since 2016 (31) should act as a warning signal for surveillance of all forms of HTSE and encourage strategic causal research taking into account a broad view of rapidly progressing conformational proteinopathies.