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Published on: December 23, 2016
Blood reference materials from macaques infected with variant Creutzfeldt-Jakob disease agent
Kristy L McDowell1, Nabanita Nag, Zulmarie Franco
1Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Food and Drug Administration, Silver Spring, Maryland.
Insights
Researchers developed crucial variant Creutzfeldt-Jakob disease (vCJD) blood panels using infected macaques. These panels will aid in developing and validating new vCJD blood tests for early detection.
Area of Science:
- Neuroscience
- Infectious Diseases
- Biomedical Research
Background:
- Variant Creutzfeldt-Jakob disease (vCJD) is a fatal, transmissible neurodegenerative disorder.
- Current diagnostic limitations include the absence of a validated antemortem blood screening test for vCJD.
- Developing reliable blood tests requires validation using disease-relevant reference panels.
Purpose of the Study:
- To generate well-characterized vCJD-infected macaque blood reference materials.
- To support the development and validation of novel vCJD blood screening assays.
- To investigate vCJD infectivity in blood during preclinical and clinical disease stages.
Main Methods:
- Infection of cynomolgus macaques with a macaque-adapted vCJD agent.
- Serial blood collection throughout the disease course, with plasma and whole blood processing.
- Detection of PrP(TSE) in plasma using protein misfolding cyclic amplification (PMCA).
- Titration of vCJD agent infectivity in mouse models.
Main Results:
- Generation of liters of vCJD-infected macaque blood over 29 months.
- Confirmation of vCJD in all inoculated macaques.
- Detection of PrP(TSE) in plasma from infected macaques, but not controls, via PMCA.
- Demonstration of higher sensitivity of mouse models to macaque-adapted vCJD agent.
Conclusions:
- The generated macaque vCJD blood panels represent a valuable resource for assay development.
- These panels will facilitate the characterization of vCJD infectivity in blood.
- The study supports the advancement of diagnostic tools for vCJD.
Background:
Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative infection that can be transmitted by blood and blood products from donors in the latent phase of the disease. Currently, there is no validated antemortem vCJD blood screening test. Several blood tests are under development. Any useful test must be validated with disease-relevant blood reference panels.
Study Design And Methods:
To generate blood reference materials, we infected four cynomolgus macaques with macaque-adapted vCJD brain homogenates. Blood was collected throughout the preclinical and clinical phases of infection. In parallel, equivalent blood was collected from one uninfected macaque. For each blood collection, an aliquot was stored as whole blood and the remainder was separated into components. Aliquots of plasma from terminally ill macaques were assayed for the presence of PrP(TSE) with the protein misfolding cyclic amplification (PMCA) method. Infectivity of the macaque brain homogenate used to infect macaques was titrated in C57BL/6 and RIII J/S inbred wild-type mice.
Results:
We sampled blood 19 times from the inoculated monkeys at various stages of the disease over a period of 29 months, generating liters of vCJD-infected macaque blood. vCJD was confirmed in all inoculated macaques. After PMCA, PrP(TSE) was detected in plasma from infected monkeys, but not from uninfected animals. Both mouse models were more sensitive to infection with macaque-adapted vCJD agent than to primary human vCJD agent.
Conclusion:
The macaque vCJD blood panels generated in this study provide a unique resource to support vCJD assay development and to characterize vCJD infectivity in blood.
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