A DNA vaccine candidate provides protection against Rift Valley Fever virus in sheep under natural field conditions.

Rift Valley Fever virus (RVFV) is a mosquito-borne zoonotic pathogen, that causes significant morbidity and mortality in livestock, including high abortion rates in pregnant animals and elevated case fatality in neonates, representing a major threat to both animal and human health. Vaccination is the most effective countermeasure to reduce RVFV's impact. In this study, we designed a veterinary DNA vaccine encoding a consensus RVFV glycoprotein precursor (GPC), optimized for expression in sheep. The construct was evaluated for immunogenicity in mice and sheep and for protective efficacy in sheep raised under natural field conditions in Senegal, West Africa. The vaccine induced robust humoral responses characterized by high neutralizing antibody titers in both mice and sheep. Under natural exposure, vaccinated sheep showed reduced infection rates (3.2%) compared with controls (14.3%), and neutralizing antibody responses persisted for more than one year. Importantly, the vaccine was well tolerated, including in pregnant animals, with no adverse outcomes such as abortions or fetal abnormalities. These findings demonstrate that a DNA-based RVFV vaccine can elicit durable immunity and provide protection in livestock under real-world conditions. This study highlights the potential of DNA vaccines as a safe, effective, and affordable alternative to existing veterinary vaccines and supports their further development as a key strategy to reduce RVFV transmission and improve animal and human health outcomes in endemic regions.