Heterogeneous transfusion risk linked to variant Creutzfeldt-Jakob disease in a non-human primate model

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.