Yellow fever: a reemerging threat

Abstract

Yellow fever (YF) is a viral disease, endemic to tropical regions of Africa and the Americas, which principally affects humans and nonhuman primates and is transmitted via the bite of infected mosquitoes. Yellow fever virus (YFV) can cause devastating epidemics of potentially fatal, hemorrhagic disease. Despite mass vaccination campaigns to prevent and control these outbreaks, the risk of major YF epidemics, especially in densely populated, poor urban settings, both in Africa and South America, has greatly increased. Consequently, YF is considered an emerging, or reemerging disease of considerable importance. This article comprehensively reviews the history, microbiology, epidemiology, clinical presentation, diagnosis, and treatment of YFV, as well as the vaccines produced to combat YF.

Fig. 1

The yellow fever mosquito. The Aedes aegypti mosquito is the primary vector responsible for the transmission of yellow fever virus (YFV) between humans. Known as the YF mosquito, this vector is responsible for explosive outbreaks of urban yellow fever (YF) in African, South American, and Central American cities. Image from the Public Health Image Library, Centers for Disease Control. Photo, James Gathany; contributor Frank Collins. (Courtesy of the Centers for Disease Control and Prevention; with permission.)

Fig. 2

The yellow fever virus virion. The virus particle is small, icosahedral, and enveloped. (A) Photomicrograph showing multiple YFV virions (original magnification ×234,000). Image from the Public Health Image Library, Centers for Disease Control. (B) The immature (intracellular) and mature (extracellular) infectious virion. The single-stranded, infectious RNA genome is packaged in an icosahedral nucleoside with a lipid envelope and viral spike proteins, prM/M and E. The prM protein is processed to M by furin-mediated cleavage immediately before egress. (Courtesy of the Centers for Disease Control and Prevention; with permission.)

Fig. 3

The yellow fever virus genome. The genome is a single-stranded RNA molecule of positive polarity (ie, can be translated), with highly structured 5′ and 3′ nontranslated regions, a 5′ terminal cap, and a single open reading frame encoding the 10 viral proteins, 3 structural and 7 nonstructural.

Fig. 4

Yellow fever virus replication in a permissive cell. The replication cycle is depicted as a series of temporally regulated steps: (1) Translation of the polyprotein; (2) co- and post-translational processing to produce the structural proteins (C, prM, and E) and the nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5); (3) synthesis of complementary, negative-sense RNA by the RNA-dependent RNA polymerase NS5 and other viral replicase components; (4) synthesis of progeny genomes by transcription of the negative strand; (5) progeny genomes are packaged into nucleocapsids and bud intracellularly to acquire envelope.

Fig. 5

Yellow fever transmission cycles. The yellow fever virus is transmitted between human and nonhuman primate hosts by mosquitoes in 3 cycles: the sylvatic (jungle) cycle in which mosquitoes of the forest canopy transmit virus to monkeys and secondarily to humans entering the jungle; the intermediate cycle (or zone of emergence) in which virus enters rural towns and villages bordering jungle areas; and the urban cycle in which humans serve as the viremic host and virus is transmitted from human to human by the domesticated Aedes aegypti mosquito.

Fig. 6

The yellow fever endemic zone. The maps depict the areas in (A) Africa and (B) the Americas that are at risk for yellow fever virus transmission in 2009. (From Brunette GW, Kozarsky PE, Magill AJ, et al. CDC Health Information for International Travel 2010. Elsevier; 2009.)

Fig. 7

The phases of yellow fever, indicating the clinical symptoms in the periods of infection, remission, and intoxication, alongside the pathogenesis of infection.