The threat of bioterrorism requires that researchers evaluate highly infectious pathogens, particularly those that can be aerosolized and transmitted by inhalation. The Rift Valley Fever Virus (RVFV) is one such agent. RVFV causes Rift Valley Fever (RVF), a veterinary and human disease endemic to Sub-Saharan Africa and the Middle East. Transmitted by mosquito bites, direct contact, and inhalation, humans typically develop a febrile disease that resolves in 1-2 weeks. However, some develop a form of RVF characterized by liver disease with hemorrhagic complications or encephalitis. Approximately 1% of RVF patients die from this severe form of the disease.
Currently, there are no licensed vaccines or therapeutics for humans with the most severe cases of RVF. To develop these medical countermeasures, researchers need to further explore how the disease works. As a first step, animal models for RVF must be established in accordance with the FDA’s Animal Rule, which states that models must be well characterized to the human disease in terms of pathophysiological mechanisms and route of exposure. A study performed by Hartman et al.1 sought to narrow down appropriate animal models for severe RVF in humans. The study focused on non-human primate (NHP) models, which are phylogenetically comparable to humans. NHPs in the study were infected via aerosol dispersion because previous RVF research using rats and NHPs suggests that inhalation may be a particularly lethal route of infection. Also, the virus would most likely be aerosolized in the event of a bioterror attack.
Four types of NHPs were evaluated for the study: adult cynomolgus macaques, rhesus macaques, African green monkeys (AGMs), and common marmosets. Each NHP was implanted with DSI telemetry for monitoring body temperature and activity. Baseline data were collected for 3-5 days. Then, the NHPs were anesthetized and exposed to RVFV; the macaques and AGMs were exposed using a head-only chamber and the marmosets were exposed using a rabbit nose-only exposure chamber modified for marmosets. A Buxco plethysmograph was used to derive minute volume. AGMs were divided into three groups, each of which received a low, medium or high dose. Marmosets also received either a low, medium or high dose. Cynomolgus macaques and rhesus macaques all received similar doses of the virus. (Doses were verified via aerosol samples for reproducibility in future studies.) Body temperature was recorded every 10-15 minutes using DSI acquisition and analysis software. Following the exposure period, all comatose or moribund NHPs were euthanized and tissue samples were analyzed.
All four species exposed to aerosolized RVFV developed fever. Dosage did not appear to affect fever severity among any of the NHPs. In terms of immune response, none of the NHPs in the study had detectable serum antibodies to RVFV prior to infection. After infection, serum antibodies were elevated and antibody levels in the survivors were particularly strong. The virus was only lethal in AGMs and marmosets. Five of six AGMs and four of eight marmosets died from RVF. Results from examinations of those NHPs are outlined below.
Comparison of fever symptoms between AGMs and marmosets
| AGMs |
Marmosets
|
Predominately single-phase fever
|
Biphasic fever
|
Clinical signs of encephalitis, dehydration, anorexia, neurological dysfunction
|
Clinical signs of encephalitis (with high doses), dehydration, anorexia, neurological dysfunction
|
| Elevated white blood cells |
Elevated white blood cells |
Confirmed viralmeningoencephalitis
|
Confirmed viralmeningoencephalitis
|
Signs of thrombosis
|
Signs of thrombosis
|
High levels of RVFV in brain and spinal cord, but not cerebrospinal fluid
|
High levels of RVFV in brain and spinal cord, but not cerebrospinal fluid
|
Virus not detected in most peripheral tissue
|
Virus detected in peripheral tissue |
Overall, the symptoms observed in the NHPs tested suggest AGMs and marmosets have the most potential as models for research on severe RVF in humans. Although knowledge of the disease in humans is limited, fatal encephalitis has now occurred in severe cases of RVF in AGMs, marmosets, and humans. Also, the marmosets experienced early-onset biphasic fever similar to what has been observed in humans. The study also supports the theory that infection via aerosol exposure may result in more lethal cases of RVF (subcutaneous infection of AGMs and marmosets in previous studies were nonlethal), highlighting the importance of developing vaccines and therapies for a potential bioterror attack. Although more research is needed to refine NHP models for RVF in humans, the knowledge gained from this study establishes a solid foundation for further inquiry.
1Hartman, A. L., Powell, D. S., Bethel, L. M., Caroline, A. L., Schmid, R. J., Oury, T. & Reed, D. S. (2014). Aerosolized Rift Valley Fever Virus causes fatal encephalitis in African green monkeys and common marmosets. Journal of Virology, 88 (4): 2235-2245. Doi: 10.1128/JVI.02341-13
To read the complete article, visit: http://www.ncbi.nlm.nih.gov/pubmed/24335307