Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on the safety, immunogenicity, and efficacy of the ⌬NSs-⌬NSm recombinant RVFV (rRVFV) vaccine (which lacks the NSs and NSm virulence factors) in a total of 41 sheep, including 29 timed-pregnant ewes. This vaccine was proven safe and immunogenic for adult animals at doses ranging from Rift Valley fever virus (RVFV) (family Bunyaviridae, genus Phlebovirus) is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and the Arabian Peninsula. The virus was first identified following the sudden death of approximately 4,700 lambs and ewes on a single farm along the shores of Lake Naivasha in the Great Rift Valley of Kenya over a 4-week period in 1931 (15). Since then, RVFV has caused numerous economically devastating epizootics often characterized by sweeping "abortion storms," neonatal animal mortality approaching 100%, and significant mortality (ϳ10 to 20%) among adult ruminant livestock, especially sheep and cattle (7,13,14,28,32). Human infections are typically self-limiting febrile illnesses that, in 1 to 2% of affected individuals, can progress to more severe disease that includes fulminant hepatitis, encephalitis, retinitis, blindness, or a hemorrhagic syndrome. Fatality ratios in hospitalized patients are 10 to 20% (22,24).RVFV is uniquely suitable for a one-health approach to prevent both livestock and human disease through animal vaccination. Livestock provide two key ecological links between the transovarially infected Aedes sp. floodwater mosquito and the human population. First, infected livestock rapidly develop high viremias, allowing the spillover of RVFV into secondary vectors (Culex and Anopheles sp. mosquitoes) that are more likely to feed on humans. Second, the high virus loads found in livestock are also a significant risk factor for human infection by direct contact with contaminated blood, tissues, and aborted fetal materials (1). A vaccination strategy targeted at preventing the virus amplification step in livestock could provide a window of opportunity to interrupt nascent RVFV outbreaks by both reducing the potential for secondary vector spillover and eliminating the threat posed by infected livestock tissues.Currently, no RVFV vaccine has been approved for veterinary use outside areas of endemicity, although a variety of vaccines for either human or livestock use have been developed since RVFV was first isolated (9, 29). Problems with prior RVFV vaccines include poor immunogenicity, requiring multiple vaccination doses; difficulties with manufacturing; and