Abstract: Neither licensed vaccines nor antiviral therapeutics with proven efficacy exist to protect against the equine encephalitis viruses (EEVs), specifically Eastern, Western, and Venezuelan Equine Encephalitis Viruses. Due to rigorous ethical, regulatory, and scientific considerations, animal models that can faithfully demonstrate aspects of clinical disease must be established for testing of countermeasure candidates. Such models must satisfy the Animal Rule promulgated and enforced by the United States Food and Drug Administration and capture key aspects of equine encephalitis virus presentation in humans, especially with respect to encephalitic disease, whose manifestations include fever and neurological signs.
This study seeks to establish and study a model of human equine encephalitis virus infection via the aerosol route in the nonhuman primate, the cynomolgus macaque (Macaca fascicularis) with a focus on the natural history of disease through examination of radiofrequency electrocardiography data, and evaluates the feasibility of the use of such data to prognosticate severe disease courses which include encephalitis. Twelve nonhuman primate subjects, grouped four per type of equine encephalitis virus, were challenged with aerosol exposures of the alphaviruses in various doses.Macaques infected with a sufficient dose of Eastern Equine Encephalitis Virus (>1.1x108 PFU) became febrile three days post-challenge, and were euthanized in concordance with the humane study endpoint at six days post-challenge after becoming moribund on the fifth day after infection. Significant metrics for EEEV consisted of: HR, PCt, P-Width, PR-I, QRS, QRSA, QT- I, R-H, and RR-I. Heart rate exhibited an increase during the onset of febrile illness, with covariant metrics displaying the same trends. QRS-interval widened in subjects that became ill, compared to subjects that did not become ill.
The macaque who presented with febrile illness in Western Equine Encephalitis Virus became febrile on the second day post-challenge and reached the humane study endpoint at seven days post-challenge. Significant metrics for WEEV consisted of HR, MxdV, Noise, PCt, P-H, PR- I, QRS, QRSA, QT-I, RR-I, ST-I, and T-H. Again, HR displayed an increase during the febrile period, with concomitant changes in covariant metrics. QRS-interval narrowed in subjects that became ill compared to subjects that did not display signs of disease.
Venezuelan Equine Encephalitis Virus-infected nonhuman primates manifested with no fatal illness; all subjects survived the aerosol challenge and displayed similar disease profiles, becoming febrile at approximately one day post-challenge, with a biphasic febrile illness that resolved by seven days post-infection, ushering in a recovery period. As none of the subjects displayed significant within-subject changes in electrocardiography metrics, one-way ANOVAs that compared period-level data within the same subjects found significant effects in all metrics. QRS-interval exhibited increases in two subjects and decreases in two subjects, following a dichotomy between subject sex, body weight, and dose received.
The variables discussed herein form a core set of metrics that can be used to track the progression of disease; frequency spectrum analysis conducted on these metrics can be used to distinguish different periods of disease, if not distinguish between diseases, and Poincare plots of heart rate variability data can be used to track the progression of illness.
Last Updated On Thursday, April 6, 2017 by Malenka, Judith Ann
Created On Thursday, April 6, 2017
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