Few diseases have attracted more attention from medical historians than yellow fever. It was one of the most feared of epidemic diseases from the 15th to 19th centuries, when large outbreaks in North and South America, Africa, and Europe caused devastating mortality. The landmark studies of Walter Reed in 1900–1901 established that the disease was transmitted between people by the Aedes aegypti mosquito. Within one year of Reed’s discovery, the disease was successfully controlled in Cuba as a result of anti-mosquito campaigns. Twenty-eight years later, yellow fever virus became the first mosquito-borne virus to be identified. Despite this legacy, yellow fever is currently classified as a re-emerging disease and remains a significant cause of morbidity and mortality, with an estimated 200,000 cases and 30,000 deaths each year. Although a highly effective vaccine is available, epidemiological data suggest an alarming resurgence of virus circulation in West Africa over the last 20 years. The failure to implement sustained vaccination and mosquito control programs reflects the problems of poverty, civil war, and the inaccessibility of rural areas where outbreaks of the disease occur.
The causative agent of the disease, yellow fever virus, is a single-stranded, positive-sense RNA virus with a genome of approximately 11 kb. This virus is a member of the Flaviviruses, which contain a number of other important vector-borne pathogens, such as dengue fever, Japanese encephalitis, and West Nile viruses. Studies of virus genome sequences strongly suggest that yellow fever virus originated in Africa. What is less clear is the timing and mechanism by which yellow fever virus was introduced to the Americas and whether descendants of the earliest imported viruses still circulate today. The most commonly cited hypothesis of the origin of yellow fever in the Americas is that the virus was introduced from Africa, along with Aedes aegypti mosquitoes, by sailing ships during the slave trade.
Although this hypothesis is often repeated, it had not been subject to rigorous examination using gene sequence data and modern phylogenetic techniques for estimating divergence times until a recent paper was published in PLoS Pathogens (Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas. PLoS Pathogens 3, 5, e75). To determine the evolutionary history of the virus, the authors carried out a phylogenetic analysis of the largest yellow fever virus data set compiled to date, spanning 133 virus isolates sampled from 22 countries over a period of 76 years. The results of this study suggest that the currently circulating strains of yellow fever virus arose in Africa within the last 1,500 years and emerged in the Americas following the slave trade approximately 300–400 years ago. These viruses then spread westwards across the continent and persist there to this day in the jungles of South America. This molecular approach illustrates how gene sequence data can be used to test hypotheses of viral dispersal and demographics, and to document the role of human migrations in the spread of infectious disease.
Yellow fever provides a powerful historical demonstration of how the establishment of travel and trade routes between countries has been accompanied by the spread of microorganisms and their vectors. Global trade and transportation in the present day allows the movement of pathogens and vectors farther and faster than ever before. During recent decades there have been several documented cases of the human importation of yellow fever virus to non-endemic areas. Since 1964, such episodes have included at least nine documented cases of European and North American tourists who have died as a result of yellow fever virus infection after returning home from countries where the disease is endemic. These examples demonstrate that although yellow fever virus continues to be exported, conditions elsewhere have not been favorable to support secondary transmission. Why yellow fever virus has not successfully dispersed to new regions infested with Aedes aegypti, in particular Asia, remains uncertain, although as with West Nile virus in North America, it is clear that previous geographic barriers that prevented spread of yellow fever in the past are quickly eroding.
- The Panama Puzzle: Play the part of Walter Reed, early 20th century U.S. Army doctor, and try to figure out what’s killing the troops constructing the Panama Canal. You may be surprised to learn the nature of some of the experiments the real Walter Reed conducted in the name of science.
- CDC: Yellow Fever