Durable protection against lethal Rift Valley fever hepatitis and encephalitis following low-dose ΔNSsΔNSm...

Rift Valley fever virus (RVFV) is a zoonotic arbovirus that infects and causes disease in both humans and livestock. In humans, RVFV infection mostly results in febrile illness but has the potential to cause severe complications such as hepatitis and encephalitis. There are currently no licensed vaccines for human use; however, several candidates have been shown to be safe and immunogenic in pre-clinical studies. However, there remain gaps in our knowledge, including the duration of immunity and efficacy of protection from divergent disease manifestations over time. This pilot study investigated the duration of immunity following low-dose vaccination with live-attenuated RVFV ΔNSsΔNSm in two murine models with divergent RVF disease manifestations. Following percutaneous infection with wild-type (WT) RVFV, C57BL/6 mice readily succumb to fulminant hepatitis 3 to 5 days post-infection (dpi). In contrast, CC057/Unc mice from the Collaborative Cross Resource experience self-limiting liver disease and develop late-onset encephalitis. Following ΔNSsΔNSm vaccination, both humoral and cellular immunity decreased over time but were comparable between the two mouse strains at 1 and 3 months. Vaccinated mice were challenged with WT RVFV (ZH501) 6 months later, and 83% of C57BL/6 mice and 100% of CC057/Unc mice survived. Taken together, this study highlights the potential of ΔNSsΔNSm to provide durable protection against lethal RVF hepatitis and encephalitis.IMPORTANCERift Valley fever virus (RVFV) causes both morbidity and mortality in endemic areas of Africa and the Middle East; however, no vaccines are available for humans. Pre-clinical studies have investigated the safety and immunogenicity of ΔNSsΔNSm vaccine (a live-attenuated version of RVFV that has two virulence factors deleted), but the duration of immunity and protection in the context of divergent RVF disease manifestations was unknown. This pilot study demonstrated that a single, low dose of ΔNSsΔNSm provided substantial protection to mice from RVF hepatitis and encephalitis 6 months post-vaccination. These pre-clinical data could support further development of a live-attenuated vaccine based on this platform for human use.