Opportunities and challenges for countermeasures against Rift Valley fever virus: A quintessential One Health...

Rift Valley fever virus (RVFV) is a zoonotic arbovirus transmitted by a wide range of mosquito vectors present across the African continent. RVFV has resulted in large-scale epidemics in East, West, southern, and northern Africa with additional epidemics affecting the Arabian Peninsula, Mayotte, and Comoros. In some areas, rather than large-scale isolated outbreaks, RVFV causes a fluctuating low-level endemic burden affecting livestock populations by resulting in pregnancy loss and significant production losses. RVFV risk extends into the human population when it is transmitted either by vector-borne transmission or direct contact with infected animals or animal products such as blood, meat, or milk. Following infection, 2%-3% of humans can develop severe disease manifestations including encephalitis/meningitis, hemorrhagic fever, and retinitis, with visual deficits commonly reported among survivors. While RVF cases in animals and humans have been spatially linked, the proportion and risk associated with spillover events is poorly classified. Given RVFV's dual threat to human and livestock health, it has been designated a priority pathogen by WHO for development of countermeasures. This review aims to summarize current knowledge of RVFV epidemiology, infection, and control as well as highlight key recent advances in the understanding of epidemiology and vaccine development. Multiple next-generation vaccine candidates have advanced to phase two clinical trials which offer hope for approved and commercially available human vaccines in the coming decades. However, despite these promising advancements, key gaps in knowledge remain, particularly regarding the total burden and geographic distributions of endemic and epidemic infections, shifting epidemiologic patterns, optimal vaccine use cases, and the effects of RVFV infection on pregnancy in humans living in hyperendemic regions. Many gaps in understanding persist, and RVFV remains a quintessential One Health pathogen requiring coordinated human, animal, and environmental investigation and collaboration to translate scientific advances into effective national public health strategies.