The Generative Brain

Comoy EE et al. 2015, Transmission of scrapie prions to primate after an extended silent incubation period (Sci Rep 5:11573)

The second evidence line, next to Cassard 2014, for the idea that sheep scrapie might in principle reach people. A long running primate programme at the CEA prion unit in Fontenay-aux-Roses reported that one cynomolgus macaque, inoculated into the brain with 25 mg of brain material from a sheep with classical scrapie, fell ill after about 110 months of silence and was euthanised at 118 months, with spongiform change, heavy PrPSc deposits and a western blot pattern unlike the BSE pattern seen in the same colony. The authors present it as a case report rather than a transmission series, note that no oral challenge was done, and say risk managers should be aware of a long term potential risk from at least some scrapie isolates. The same paper carries the clearest published reading of the limits of the 2014 humanised mouse work: transmissions in an extreme minority of mice, only a marginal increase on second passage, no clinical signs for up to 750 days, mice that overexpress human prion protein and live about two years, and strain adaptation as an alternative explanation for a successful second passage. Published in Scientific Reports on 30 June 2015, open access under CC BY. This entry is information only and is not a statement about risk to any individual.

Key facts

  • Fifteen authors, first author Comoy EE and last author Deslys JP, across six institutions: the CEA iMETI prion unit (SEPIA) at Fontenay-aux-Roses, INRA-ENVT Toulouse, the Istituto Zooprofilattico Sperimentale del Piemonte in Turin, the USDA ARS National Animal Disease Center at Ames in Iowa, ANSES Lyon, and the Norwegian Veterinary Institute in Oslo.
  • The paper is Scientific Reports 5:11573, doi 10.1038/srep11573, PMID 26123044, PMC4485159, received 16 February 2015, accepted 28 May 2015, published 30 June 2015, gold open access under CC BY.
  • The animals were captive bred male cynomolgus macaques aged 2 to 5 years at inoculation, all homozygous for methionine at codon 129 of PRNP, challenged intracerebrally with brain material from naturally infected sheep (classical scrapie and atypical Nor98), cattle (classical BSE, L-type and H-type) and CWD sources; some animals also received an intratonsillar inoculation to model oral exposure.
  • The reported case is a single macaque given 25 mg brain equivalent of a classical scrapie isolate. Neurological signs appeared at about 110 months, with anxiety, hyperesthesia, stiff gait, tremor, progressive weakness and ataxia, and the animal was euthanised at 118 months.
  • Post mortem findings were brain atrophy most marked in the temporal lobes, widespread spongiform change, severe Purkinje cell loss, a marked thalamic lesion, and heavy PrPSc staining in cortex, striatum and cerebellum. Western blot gave a type 1 profile with a 21 kDa unglycosylated band, against the type 2 19 kDa profile of the BSE infected macaques in the same colony. No PrPres was found in lymph nodes, spleen or tonsils of this animal.
  • Comparison groups in the same programme: 17 macaques inoculated with classical BSE developed disease at roughly 3 to under 8 years depending on dose, L-type BSE gave about 2 years at the lowest doses tested, and the animals exposed to Nor98 scrapie, to CWD (three animals) and to H-type BSE (one animal) showed no clinical signs at follow-up of 7 to more than 10 years.
  • The authors state the limits themselves: one animal, described as a case report, no duplicate intracerebral exposures and no oral challenge, and confirmation that could take more than a decade. They say the lesion profile is reminiscent of MM2c and VV1 sporadic CJD but that interspecies comparison of lesion profiles needs caution, and they argue against a sporadic origin because the animal was 14 years old at onset, about 40 percent through its expected lifetime, against a peak sporadic CJD incidence at 60 to 65 years in people.
  • On the 2014 humanised mouse work they write that transmission occurred in an extreme minority of mice with only a marginal increase in attack rate on second passage, that no clinical signs appeared for up to 750 days, that the roughly two year life of a mouse limits what a negative result can show, and that a successful second passage may reflect strain adaptation to the species barrier rather than zoonotic potential of the original isolate.
  • The food chain argument in the discussion rests on sheep data, not on this animal: infectivity has been reported in blood, milk and skeletal muscle of asymptomatic infected small ruminants, and in sheep lymphoid organs from 3 months of age and from 2 months in gut associated lymph nodes, which the authors read as potential dietary exposure for consumers. The macaque itself, challenged intracerebrally, had no detectable peripheral PrPres.
  • The policy ask is modest and explicit: no premature conclusions from negative transmission studies observed for under a decade, awareness among risk managers of a long term potential risk from at least certain scrapie isolates, a note that classical BSE control measures were being relaxed at the time, and a call for long term studies of CWD and atypical Nor98 scrapie, whose zoonotic potential the data cannot settle.
  • Uptake, as counted on 17 October 2026: Europe PMC lists 64 citing records and OpenAlex 88 citations with a field weighted citation impact of 3.99. Neither record lists a funder or grant for the study.
  • A 2019 Scientific Reports study from CISA-INIA with this CEA group tabulates the macaque work and records this transmission as 118 months, 1 of 1. In its own mouse experiments the French scrapie isolate PS21 gave no positives in human PrP mice (0 of 6 Hu-Tg340) but 2 of 6 positives in macaque PrP mice at 273 and 392 days post inoculation, which the authors use to argue that the macaque is a reasonable stand-in for human susceptibility to sheep scrapie.
  • A 2023 age period cohort analysis of French sporadic CJD mortality cites this paper together with Cassard 2014 for the sentence that these observations highlight the possibility of a causal link between exposure to sheep scrapie and sporadic CJD in some cases, stated as a possibility rather than a finding.
  • The atlas already summarised this result inside the CEA unit entry, as a 2015 Scientific Reports paper transmitting a classical scrapie isolate to a cynomolgus macaque after about ten years of silent incubation, read by the authors as an argument for long term primate studies of other animal prion diseases.

Timeline

  1. 2015Manuscript received by Scientific Reports.
  2. 2015Manuscript accepted.
  3. 2015Published as Scientific Reports 5:11573 under CC BY.
  4. 2019A CISA-INIA and CEA study lists this transmission in its macaque table and reports 0 of 6 human PrP mice against 2 of 6 macaque PrP mice for a French scrapie isolate.
  5. 2023A French age period cohort study of sporadic CJD mortality cites it with Cassard 2014 when discussing a possible scrapie link.
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