Heterogeneous transfusion risk linked to variant Creutzfeldt-Jakob disease in a non-human primate model
Jessica Rontard,Jacqueline Mikol,Florian Almela,Daisy Bougard,Christelle Jas-Duval,Olivier Andreoletti,Jérôme Delmotte,
Mohammed-Amin Madoui,Jean-Philippe Deslys,Emmanuel E. Comoy
Published: November 10, 2026
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Abstract
Among the 178 cases of variant Creutzfeldt-Jakob disease (v-CJD) in the UK, three were reported between 2003 and 2007 to be linked to a probable transmission through blood transfusion. With no further primary or iatrogenic cases observed worldwide since 2016, several countries are lifting – or have already lifted - deferrals for blood donors who have lived in the UK or, more broadly, Europe, to reduce the threat of supply shortages. However, the high prevalence of silent infection according to abnormal PrP in lymphoid tissues (potentially 100 times higher than for clinical cases in the UK) remains a concern in assessing the potential iatrogenic risk associated with long-term silent carriers for a disease whose incubation periods can extend over decades. In the present study, after experimental intravenous contamination of cynomolgus macaques with v-CJD prions, a relevant model of the human disease, we observed a highly heterogeneous intra- and inter-individual distribution of apparent peripheral prion replication in lymphoid organs that appears to correspond largely to the prion load in blood, the highest levels of which are detectable by amplification-based detection assay. In addition, several primates have developed unexpected incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to mice in the absence of a functional immune system. The peculiar prion strains associated with these atypical phenotypes would involve peripheral mechanisms independent of the immune system, different from those of v-CJD. According to our observations, conventional lymphoid organ prevalence studies may underestimate the true extent of healthy v-CJD carriers, and blood transmission risk assessment should not be based on epidemiological data alone.
Author summary
Variant Creutzfeldt-Jakob disease (v-CJD) is considered a transfusion-transmissible infectious agent. In the absence of cases since 2016, several countries are lifting geographical restrictions on blood donation to reduce supply shortages. However, appendix studies have revealed a high prevalence of silent infection that questions the iatrogenic risk associated with long-term carriers (incubations extend over decades). Here, intravenously-contaminated macaques exhibited a highly heterogeneous distribution of v-CJD prion replication in lymphoid organs corresponding largely to the prion load in blood, whose highest levels are detectable by amplification-based detection assay. In addition, several primates developed incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to immunodeficient mice: the corresponding cryptic prion strains would involve immune-independent mechanisms, unlike v-CJD. According to our observations, the heterogeneity of peripheral prion replication observed in experimentally-infected macaques questions the actual prevalence of asymptomatic v-CJD carriers and the assessment of blood transmission-related risks in the human population.
snip…
These results suggest that the atypical prion strains linked to incomplete prion phenotypes and macaque myelopathy would not need a functional immune system to replicate before neuroinvasion after peripheral exposure, opposite to v-CJD. Either direct neuroinvasion may occur, as is partially the case in different immunodeficient models [49–51], or peripheral replication would occur elsewhere. This point has not yet been elucidated.
In conclusion, this study revealed that peripheral replication of v-CJD prions is widely heterogeneous and cannot be considered as an ultimate criterion for v-CJD diagnosis, whereas blood-related atypical prion strains rely on different peripheral mechanisms prior to neuroinvasion. At least three epidemiological consequences can be drawn here: (i) the prevalence of silent infected people might be wider than expected when using conventional techniques; (ii) the transfusion v-CJD risk would be limited to the highly infectious samples, which might be detected with current diagnostic techniques; (iii) atypical prions are uncontrollable with current techniques to date and would follow different pathophysiological mechanisms. As deferral measures are lifted in some countries, new tools are needed to analyze and circumvent these newly described novel prion strains.
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very concerning…terry
Jessica Rontard,Jacqueline Mikol,Florian Almela,Daisy Bougard,Christelle Jas-Duval,Olivier Andreoletti,Jérôme Delmotte,
Mohammed-Amin Madoui,Jean-Philippe Deslys,Emmanuel E. Comoy
Published: November 10, 2026
Only registered and activated users can see links., Click Here To Register...
Abstract
Among the 178 cases of variant Creutzfeldt-Jakob disease (v-CJD) in the UK, three were reported between 2003 and 2007 to be linked to a probable transmission through blood transfusion. With no further primary or iatrogenic cases observed worldwide since 2016, several countries are lifting – or have already lifted - deferrals for blood donors who have lived in the UK or, more broadly, Europe, to reduce the threat of supply shortages. However, the high prevalence of silent infection according to abnormal PrP in lymphoid tissues (potentially 100 times higher than for clinical cases in the UK) remains a concern in assessing the potential iatrogenic risk associated with long-term silent carriers for a disease whose incubation periods can extend over decades. In the present study, after experimental intravenous contamination of cynomolgus macaques with v-CJD prions, a relevant model of the human disease, we observed a highly heterogeneous intra- and inter-individual distribution of apparent peripheral prion replication in lymphoid organs that appears to correspond largely to the prion load in blood, the highest levels of which are detectable by amplification-based detection assay. In addition, several primates have developed unexpected incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to mice in the absence of a functional immune system. The peculiar prion strains associated with these atypical phenotypes would involve peripheral mechanisms independent of the immune system, different from those of v-CJD. According to our observations, conventional lymphoid organ prevalence studies may underestimate the true extent of healthy v-CJD carriers, and blood transmission risk assessment should not be based on epidemiological data alone.
Author summary
Variant Creutzfeldt-Jakob disease (v-CJD) is considered a transfusion-transmissible infectious agent. In the absence of cases since 2016, several countries are lifting geographical restrictions on blood donation to reduce supply shortages. However, appendix studies have revealed a high prevalence of silent infection that questions the iatrogenic risk associated with long-term carriers (incubations extend over decades). Here, intravenously-contaminated macaques exhibited a highly heterogeneous distribution of v-CJD prion replication in lymphoid organs corresponding largely to the prion load in blood, whose highest levels are detectable by amplification-based detection assay. In addition, several primates developed incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to immunodeficient mice: the corresponding cryptic prion strains would involve immune-independent mechanisms, unlike v-CJD. According to our observations, the heterogeneity of peripheral prion replication observed in experimentally-infected macaques questions the actual prevalence of asymptomatic v-CJD carriers and the assessment of blood transmission-related risks in the human population.
snip…
These results suggest that the atypical prion strains linked to incomplete prion phenotypes and macaque myelopathy would not need a functional immune system to replicate before neuroinvasion after peripheral exposure, opposite to v-CJD. Either direct neuroinvasion may occur, as is partially the case in different immunodeficient models [49–51], or peripheral replication would occur elsewhere. This point has not yet been elucidated.
In conclusion, this study revealed that peripheral replication of v-CJD prions is widely heterogeneous and cannot be considered as an ultimate criterion for v-CJD diagnosis, whereas blood-related atypical prion strains rely on different peripheral mechanisms prior to neuroinvasion. At least three epidemiological consequences can be drawn here: (i) the prevalence of silent infected people might be wider than expected when using conventional techniques; (ii) the transfusion v-CJD risk would be limited to the highly infectious samples, which might be detected with current diagnostic techniques; (iii) atypical prions are uncontrollable with current techniques to date and would follow different pathophysiological mechanisms. As deferral measures are lifted in some countries, new tools are needed to analyze and circumvent these newly described novel prion strains.
Only registered and activated users can see links., Click Here To Register...
very concerning…terry