Yellow fever virus (YFV) is an enveloped, positive-sense, single-stranded RNA virus belonging to the genus Flavivirus within the family Flaviviridae, and is the type species of that genus and the family. It is the causative agent of yellow fever, an acute haemorrhagic disease transmitted to humans principally through the bite of infected Aedes and Haemagogus mosquitoes. Yellow fever virus is endemic across sub-Saharan Africa and tropical South America, where it circulates in sylvatic, intermediate, and urban transmission cycles involving non-human primate and human hosts, respectively. The disease ranges in severity from a self-limited febrile illness to a severe syndrome characterised by hepatitis with jaundice (from which the disease takes its name) haemorrhage, acute kidney injury, and a case fatality rate that can exceed 50% in severe cases without supportive care.

The YFV virion is a spherical particle approximately 50 nanometres in diameter, consisting of a host-derived lipid envelope studded with two viral glycoproteins, the envelope (E) protein and the membrane (M) protein, surrounding an icosahedral nucleocapsid formed by the capsid (C) protein and the genomic RNA. The genome is approximately 10,800 nucleotides in length and encodes a single polyprotein that is co- and post-translationally cleaved by viral and host proteases into three structural proteins (C, prM/M, and E) and seven non-structural proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. NS3 functions as a serine protease and RNA helicase, while NS5 encodes the RNA-dependent RNA polymerase responsible for genome replication and a methyltransferase domain involved in capping of viral RNA. The E protein mediates cell attachment and membrane fusion and is the principal target of neutralising antibodies.

YFV enters host cells through receptor-mediated endocytosis, with the E protein undergoing pH-dependent conformational changes within the acidified endosome to drive fusion of the viral and endosomal membranes and release of the nucleocapsid into the cytoplasm. Genome replication and virion assembly occur in close association with the endoplasmic reticulum, with newly assembled virions trafficking through the secretory pathway before release at the cell surface.

Yellow fever 17D refers to the live attenuated vaccine strain of yellow fever virus, derived by Max Theiler and colleagues at the Rockefeller Institute in the 1930s through extensive serial passage of the virulent Asibi strain in mouse brain tissue and, subsequently, in embryonated chicken eggs. The resulting attenuated virus lost neurotropism and viscerotropism while retaining potent immunogenicity, and was first used in humans in 1937. Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951 for this work. Two closely related sub-strains, 17D-204 and 17DD, are in current use worldwide as the basis for all licensed yellow fever vaccines. A single dose of 17D vaccine induces durable protective immunity in over 95% of recipients, with evidence that immunity persists for decades and is likely lifelong in most individuals, which led the World Health Organization to remove the requirement for decennial booster doses in 2013.

Beyond its role as a vaccine, yellow fever 17D has been extensively studied as a model flavivirus and as a vector platform for the development of recombinant chimeric vaccines. The ChimeriVax technology exploits the 17D replication backbone, replacing the prM and E genes with those of a heterologous flavivirus such as dengue, Japanese encephalitis, or West Nile virus, to generate attenuated chimeric vaccine candidates that combine the safety profile of 17D with the antigenic specificity of the target pathogen. The dengue chimeric vaccine Dengvaxia (CYD-TDV) is derived from this platform, though it proved largely unsuccessful, failing to provide reliable protection across all dengue serotypes and, critically, increasing the risk of severe disease in seronegative individuals upon subsequent natural infection, which led to severe restrictions on its use. Yellow fever 17D also continues to be used in basic research as a well-characterised, tractable flavivirus model system for studying viral replication, innate immune interactions, and antiviral drug discovery.

Yellow fever remains a significant public health problem despite the availability of an effective vaccine, with an estimated 200,000 cases and 30,000 deaths annually, largely attributable to gaps in vaccination coverage. Large outbreaks in Angola and the Democratic Republic of the Congo in 2015–2016, and in Brazil from 2016 onwards, highlighted the continuing threat and the logistical challenges of maintaining sufficient global vaccine supply, which depends entirely on embryonated egg-based production.