May 20th 2021
written by Dr. Jaclynn Moskow
What is Yellow Fever?
The yellow fever virus, a flavivirus, is transmitted via the bites of various mosquito species. The disease has an average incubation period of 3 to 6 days. The clinical presentation of yellow fever can vary greatly, ranging from a self-limited flu-like illness to overwhelming hemorrhagic fever – with a case fatality rate of 50%. Approximately 55% of yellow fever infections are asymptomatic, 33% are categorized as mild, and 12% severe (1).
Yellow fever generally manifests with the acute onset of fever, headache, backache, myalgia, and vomiting. Conjunctival infection may be seen, accompanied by facial flushing, relative bradycardia (Faget’s sign), and leukopenia. In some cases, fever and other symptoms may remit for a few hours to several days. Upon return of symptoms, icteric hepatitis and a hemorrhagic diathesis may follow with epistaxis, bleeding from the gums and gastrointestinal tract, and petechial and purpuric hemorrhages. Weakness, prostration, protracted vomiting, and albuminuria may also be noted. At this stage, patients will experience renal failure, myocardial dysfunction, necro-hemorrhagic pancreatitis, and seizures.
Yellow fever has a case fatality rate of 10 to 60% within 7 days of disease onset (1).
The Origin and Spread of Yellow Fever
Phylogenetic analyses indicate that yellow fever originated in Africa within the last 1,500 years. Its spread to the Americas coincided with the trans-Atlantic slave trade that began during the 16th century. It is likely that mosquitoes carrying yellow fever were imported into the Americas via slave ships (2). Significant outbreaks followed as the virus was introduced into populations with no pre-existing immunity. During the 18th and 19th centuries, approximately 25 major outbreaks claimed the lives of hundreds of thousands in New York City, Philadelphia, Baltimore, and New Orleans (3). Yellow fever also arrived in Europe during this time, with notable outbreaks occurring at Spanish, Portuguese, French, and British seaports (4).
It is estimated that for every soldier who died in battle during the Spanish-American War, 13 died of yellow fever (5). Yellow fever also killed many thousands during the construction of the Panama Canal.
Development of a Vaccine for Yellow Fever
Early attempts to develop a vaccine for yellow fever resulted in the deaths of several test subjects and researchers. In 1900, a team led by Major Walter Reed traveled to Cuba to study the disease. At this point, the medical community was largely dismissive of the theory that mosquitos were the vectors of transmission for yellow fever. Working under the assumption that the mosquito theory was indeed incorrect, Reed’s team began experimenting with mosquitos and volunteers. After receiving criticism about using human test subjects, some team members decided to instead experiment on themselves. Unfortunately, this resulted in the death of physician-scientist Dr. Jesse Lazear – but with his death, the mosquito theory began to gain acceptance (6).
Despite the death of Dr. Lazear, yellow fever research on human test subjects continued. The Reed team conducted a second and third set of mosquito experiments, offering financial compensation in the form of gold to study participants (6). After learning that none of these latest Reed study participants had died, Cuban physician Dr. John Guiteras began his own experiments. Unfortunately, three of his 42 test subjects succumbed to the illness, and with this, yellow fever research in Cuba came to a halt (7).
Subsequent efforts to control yellow fever centered on reducing mosquito populations as opposed to vaccine development, until 1918 when the Rockefeller Foundation began conducting yellow fever research. Within a year, Japanese scientist Dr. Hideyo Noguchi, who was working with the Foundation, announced that he had successfully developed a vaccine. Individuals in the United States, Latin America, and the French African colonies began receiving his vaccine, but the legitimacy of the studies leading to its development were soon called into question, and ultimately the vaccine was pulled (7).
The Rockefeller Foundation continued its efforts, and in 1925, they sent investigators to Lagos to determine if the African and South American diseases were caused by the same pathogen. Unfortunately, this trip resulted in three more investigators contracting and dying from yellow fever, including Dr. Noguchi. Nonetheless, the Rockefeller Foundation persisted, and a few years later, another candidate vaccine was developed – this time from efforts led by Dr. Max Theiler (7).
Despite the history of physician deaths related to yellow fever experimentation, Brazilian physician Dr. Bruce Wilson volunteered to receive the first dose of the Theiler vaccine. It was designated a success, and mass production began. Soon after, the Pasteur Institute developed their own vaccine, and for the next several years, the Rockefeller Foundation vaccine was used in the West as well as in England, and the Pasteur Institute vaccine used in France and its African colonies (7).
During World War II, the Rockefeller Foundation vaccine was given to almost all US soldiers. Unfortunately, the vaccine contained blood serum, and vaccination efforts resulted in approximately 330,000 soldiers contracting hepatitis B virus infection (8). Blood serum was subsequently removed as a component of the vaccine, and in 1953 a yellow fever vaccine was licensed for civilian use in the US (9). Use of the Pasteur Institute vaccine eventually ceased due to cases of postvaccinal encephalitis, but a variant of the Rockefeller foundation vaccine is still used today. Dr. Theiler received the Nobel Prize in Physiology or Medicine for his critical role in its development.
Yellow Fever in 2021
Today, the Centers for Disease Control and Prevention (CDC) recommends vaccination against yellow fever for individuals 9 months and older and who are traveling to or living in areas at risk in Africa and South America (10). It is a live attenuated vaccine, and thus contraindicated in patients who are immunocompromised. The vaccine is highly effective, with a median seroconversion rate of 99% (range 81–100%) in clinical trials (11).
Yellow fever is currently estimated to affect 200,000 people each year, resulting in 30,000 deaths, with 90% of cases occurring in Africa (12). Recent outbreaks have occurred in Brazil, Angola, Nigeria, and the Democratic Rep. of Congo. If you have a GIDEON account, click here to explore the Yellow Fever outbreak map. There are ongoing efforts to expand accessibility to the vaccine in these regions, as well as to implement additional vector control programs.
The last outbreak of Yellow Fever in the United States occurred in 1905 (13). Yellow fever outbreaks ceased in Europe after World War II, when, for unknown reasons, the Aedes aegypti mosquito disappeared (14).
The absence of yellow fever in Asia is not fully understood. Some have speculated that differences in mosquito species may play a role. Another theory is that there may be a cross-immunity between yellow fever and other flaviviruses endemic to Asia, such as dengue fever. A third theory is that yellow fever has simply never been introduced into Asia (2).
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(1) “Yellow fever”, GIDEON Informatics, Inc, 2021. [Online]. Available: https://app.gideononline.com/explore/diseases/yellow-fever-12650
(2) Cathey and J. Marr, “Yellow fever, Asia and the East African slave trade”, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 108, no. 5, pp. 252-257, 2014. Available: 10.1093/trstmh/tru043
(3) F. Douam and A. Ploss, “Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe”, Trends in Microbiology, vol. 26, no. 11, pp. 913-928, 2018. Available: 10.1016/j.tim.2018.05.012
(4) M. Morillon, B. Marfart, and T. Matton, “Yellow fever in Europe in 19th Century”, Ecological Aspects of Past Settlement in Europe. P. Bennike, pp. 211-222, 2002.
(5) Staples, “Yellow Fever: 100 Years of Discovery”, JAMA, vol. 300, no. 8, p. 960, 2008. Available: 10.1001/jama.300.8.960
(6) “Politics of Participation: Walter Reed’s Yellow-Fever Experiments”, AMA Journal of Ethics, vol. 11, no. 4, pp. 326-330, 2009. Available: 10.1001/virtualmentor.2009.11.4.mhst1-0904
(7) J. Frierson. “The yellow fever vaccine: a history”, Yale J Biol Med, vol. 83, no. 2, pp. 77-85, 2010
(8) M. Furmanski. “Unlicensed vaccines and bioweapon defense in World War II”, JAMA, vol. 282, no. 9, p. 822, 1999
(9) “Historic Dates and Events Related to Vaccines and Immunization”, Immunize.org, 2021. [Online]. Available: https://www.immunize.org/timeline/
(10)”Yellow Fever Vaccine Recommendations”, Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases (DVBD), 2021. [Online]. Available: https://www.cdc.gov/yellowfever/vaccine/vaccine-recommendations.html
(11) J. Staples, A. Barrett, A. Wilder-Smith and J. Hombach, “Review of data and knowledge gaps regarding yellow fever vaccine-induced immunity and duration of protection”, npj Vaccines, vol. 5, no. 1, 2020. Available: 10.1038/s41541-020-0205-6
(12) “Yellow Fever”, Centers for Disease Control and Prevention, Global Health, 2018. [Online]. Available: https://www.cdc.gov/globalhealth/newsroom/topics/yellowfever/index.html
(13) K. Patterson, “Yellow fever epidemics and mortality in the United States, 1693–1905”, Social Science & Medicine, vol. 34, no. 8, pp. 855-865, 1992. Available: 10.1016/0277-9536(92)90255-o
(14) “Facts about yellow fever”, European Centre for Disease Prevention and Control, 2021. [Online]. Available: https://www.ecdc.europa.eu/en/yellow-fever/facts