Development of a safe and efficacious vaccine for Rift Valley fever virus

This application addresses the USDA NIFA "Global Food Security and Hunger" primary societal challenge area by developing a countermeasure against a potential agricultural disease threat - Rift Valley fever virus (RVFV). RVFV is an arthropod-borne pathogen that often results in severe morbidity and mortality in both humans and livestock. RVF manifests itself in the vast majority of individuals that become infected. In fact, unlike a West Nile virus (WNV) infection, which has no clinical manifestation in 80% of infected individuals, approximately 90% of humans infected with RVF virus show clinical signs of the disease. While infections in humans are typically mild and present as self-limiting febrile illnesses, RVFV infections can progress to more severe disease including fulminant hepatitis, encephalitis, retinitis, blindness, or a hemorrhagic syndrome in approximately 2% of affected individuals. However, statistics from recent outbreaks suggest that the case fatality rate from RVFV infection is significantly increasing (up to 45%) in naive populations. Human RVFV infections are usually preceded by transmission from wild to domestic animal hosts, recognized by sudden and devastating impact on livestock. In sheep, mortality in lambs under 2 weeks of age approaches 100%, reaches 30% in older animals and abortions approach 100%. Cattle also show high abortion rates (up to 100%) with adult mortality averaging 10%. As RVFV's geographic range continues to spread, it presents a real threat to naive populations around the world by accidental introduction or a bioterror/agroterror event. The lack of prophylactic and therapeutic measures, the potential for human-to-human and animal-to-animal transmissions, and the significant threat to livestock associated with RVFV make infection with this pathogen a serious public health concern. RVFV epizootics and epidemics might rapidly overwhelm the capacities of the public health and veterinary medical communities to provide rapid diagnostic testing, distribution of countermeasures and adequate medical care. The development of safe and efficacious RVFV vaccines has proven to be quite difficult. Live-attenuated countermeasures have a high potential to revert to the deadly wildtype virus, while subunit candidates usually require several vaccination/boost regimens to initiate immunity. In addition, most of the tested live attenuated vaccine candidates do not follow the DIVA concept which makes it impossible to differentiate infected from vaccinated animals - a crucial feature in outbreak situations. The use of VLPs is a promising alternative approach for the development of a safe and efficient RVFV vaccine. RVF VLPs exhibit morphology similar to that of wild-type viruses and have wild type tropism with comparable cellular uptake and intracellular trafficking. VLPs present viral antigens in a native conformation allowing for effective recognized by the immune system. The VLP-based vaccine candidates against RVFV described in this proposal are safe, show high efficacy in two rodent models, and are therefore a promising concept to combat emerging RVFV.