Cynomolgus macaque model for pneumonic plague
Richard Warren1, Hank Lockman, Roy Barnewall
1Battelle Biomedical Research Center, 505 King Ave., Columbus, OH 43201, USA.
Abstract:
A recombinant vaccine (rF1V) is currently being developed for protection against pneumonic plague. An essential component in evaluating efficacy of the rF1V vaccine is the development of a well-understood animal model that shows similarity to human disease. The objective of this study was to determine the inhaled median lethal dose (LD₅₀), evaluate the pathophysiology of disease and identify appropriate study endpoints in a cynomolgus macaque (CM) model of pneumonic plague. Eighteen CMs were challenged by head-only aerosol exposure with seven dosages of Yersinia pestis CO92. An LD₅₀ of 24 colony forming units was estimated using Probit analysis. Disease pathology was evaluated by blood culture, clinical pathology, histopathology and telemetry. CMs that died became febrile following challenge and died 34-92 h after onset of fever. Bacteremia, increased respiration and heart rate, decreased blood pressure and loss of diurnal rhythm were also observed in conjunction with onset of fever. Histopathological examinations revealed significant findings in the lungs (intra-alveolar neutrophils and fibrinous pleuritis) consistent with pneumonic plague. These data indicate that the disease pathology observed in CMs following aerosol exposure to Y. pestis CO92 is similar to that of pneumonic plague in humans. Thus, the CM is an appropriate model to evaluate efficacy of a recombinant F1V vaccine candidate.
Insights
A cynomolgus macaque model for pneumonic plague was established to test a new vaccine. This model accurately mimics human disease, showing similar pathology and enabling vaccine efficacy studies.
Area of Science:
- Infectious Diseases
- Vaccinology
- Primate Models
Background:
- Pneumonic plague poses a significant public health threat.
- A recombinant F1V vaccine is under development for protection.
- A relevant animal model is crucial for vaccine efficacy evaluation.
Purpose of the Study:
- To establish a cynomolgus macaque (CM) model for pneumonic plague.
- To determine the inhaled median lethal dose (LD₅₀) of Yersinia pestis CO92.
- To characterize disease pathophysiology and identify study endpoints in CMs.
Main Methods:
- Eighteen CMs were exposed to aerosolized Yersinia pestis CO92 across seven dosages.
- Median lethal dose (LD₅₀) was calculated using Probit analysis.
- Disease was assessed via blood culture, clinical pathology, histopathology, and telemetry.
Main Results:
- The inhaled LD₅₀ was estimated at 24 colony forming units.
- CMs developed fever, bacteremia, and cardiorespiratory changes preceding death (34-92 hours post-fever onset).
- Histopathology revealed lung inflammation (neutrophils, fibrinous pleuritis) consistent with pneumonic plague.
Conclusions:
- The cynomolgus macaque model replicates key aspects of human pneumonic plague.
- This model is suitable for evaluating the efficacy of the rF1V vaccine candidate.
- The established model provides a foundation for further pneumonic plague research and countermeasures.
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