Herein, we report the development and evaluation of a nanoparticle-enhanced inactivatedRift Valley fever (RVF) vaccine aimed at overcoming the critical shortcomings of current vaccineformulations, including safety concerns, high production costs, and the need for frequent boosterdoses. To address these challenges, zinc oxide nanoparticles (ZnNPs) and selenium nanoparticles(SeNPs) were incorporated as co-adjuvants into an aluminum hydroxide gel-based vaccine(ALHV) to enhance immunogenicity and extend the duration of protection. Rigorous testing of thevaccine formulations in sheep, a species relevant to RVF epidemiology and control, demonstratedexcellent sterility and safety, with no adverse reactions observed across all groups. Importantly,the inclusion of ZnNPs and SeNPs significantly improved immune responses, as evidenced byneutralizing antibody titers that surpassed protective thresholds within one week post-vaccination.Furthermore, nanoparticle-enhanced formulations conferred prolonged immunity lasting up to 11months, compared to 10 months for the ALHV-alone vaccine. Notably, the ALHV + ZnNPsformulation emerged as the most promising candidate, eliciting robust humoral and cell-mediatedimmune responses—marked by elevated serum interferon-gamma (IFN-γ) levels—and enhancinggrowth performance in vaccinated sheep, suggesting potential added benefits for livestockproductivity. These findings highlight the transformative potential of nanoparticle-enhancedvaccines as scalable, effective, and durable solutions for RVF prevention in endemic regions.Moreover, this study underscores the broader applicability of nanoparticle-based platforms foradvancing vaccine development against zoonotic and emerging infectious diseases.
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