Yellow fever

• 1. Introduction

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  Yellow fever kills up to half of the people who reach its most severe stage. That is a startling number for a disease the world has known about since the 17th century, has a safe vaccine against, and has periodically pushed to the edge of elimination. Yet in 2013 alone, yellow fever caused an estimated 78,000 deaths in Africa. Nearly a billion people live in areas where the disease is common today.

  The virus travels through a single bite from an infected mosquito. It can cause nothing more than a bad headache and a few days of fever. In about 15% of cases, however, something shifts. What looked like recovery becomes a relapse, the skin turns yellow from liver damage, and the patient begins to bleed internally. That second phase is what earned the disease one of its Spanish names: vómito negro, meaning black vomit.

  The questions worth sitting with are these: How did a disease rooted in African forests end up reshaping the Americas, toppling a Napoleonic military campaign, and deciding the fate of Louisiana? Why does the first safe vaccine, developed in 1937, still be the one in use today? And why, despite decades of effort, does yellow fever continue to spread?

• 2. The Virus Itself

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  In 1927, scientists isolated the yellow fever virus in West Africa, making it the first human virus ever to be isolated. What they captured was an RNA virus around 40 to 50 nanometres wide, belonging to the family Flaviviridae. Its single-stranded genome runs to approximately 10,862 nucleotides.

  The virus enters the body through a mosquito bite, replicates first in the lymph nodes, and then travels to the liver. There it infects liver cells called hepatocytes, most likely indirectly through a type of immune cell called Kupffer cells. The destruction of those liver cells releases cytokines, triggering a cascade. Distinctive structures called Councilman bodies appear in the damaged cells. When cytokine storm, shock, and multiple organ failure follow, death can result.

  For all its destructive complexity inside the body, the virus depends on an elegantly simple delivery system. A female Aedes aegypti mosquito takes a blood meal from an infected human or primate. The virus multiplies in the mosquito's gut, travels through its blood system, and eventually reaches the salivary glands. The next time the mosquito feeds, it injects the virus directly into a new host. The cycle can also pass from a mother mosquito directly to her eggs, a mechanism that may explain sudden isolated outbreaks with no obvious source.

• 3. Three Cycles of Spread

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  Aedes aegypti is a creature of cities. It breeds in standing water found in tires, cans, and plastic bottles, and it bites during the daytime rather than at dusk, which makes standard mosquito precautions less effective. In urban areas across Africa, A. aegypti sustains what epidemiologists call the urban cycle, responsible for the major outbreaks on the continent.

  Deep in forests, a separate sylvatic cycle runs largely out of human sight. In Africa, the vector is Aedes africanus; in South America, mosquitoes of the genera Haemagogus and Sabethes carry the virus among nonhuman primates. African primates have largely developed tolerance and show few symptoms. South American primates have not, and brown howler monkeys in Brazil serve as a sentinel species, meaning their deaths signal the virus's presence before humans are affected.

  Between these two cycles, Africa has a third pathway: the savannah or intermediate cycle, involving different Aedes species in the zones between forest and city. In recent years, this intermediate cycle has become the most common form of transmission on the continent. The three-way structure of transmission is also the reason yellow fever cannot be eradicated simply by vaccinating people. As long as infected mosquitoes move through wild primate populations, the virus has a reservoir that human medicine cannot reach. The sole exception on record for South America is an outbreak in Bolivia in 1999, the last confirmed urban cycle on that continent.

• 4. Origins and the Slave Trade

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  The evolutionary roots of yellow fever almost certainly lie in East or Central Africa, where the virus originated in nonhuman primates before crossing into humans. Because the disease was endemic there for so long, many African populations developed acquired immunity through childhood exposure. European colonists had no such history and died in vastly greater numbers during outbreaks.

  The first definitive outbreak in the New World appeared in 1647 on the island of Barbados. A year later, Spanish colonists recorded an outbreak in the Yucatan Peninsula, where the indigenous Maya called it xekik, meaning blood vomit. In 1685, Brazil suffered its first epidemic in Recife. The mechanism was the trans-Atlantic slave trade: both the virus and Aedes aegypti were transported from West Africa to the Americas as part of the Columbian exchange, carried on the same ships that forcibly moved millions of people.

  Phylogenetic analysis later confirmed this history at the genetic level. The South American virus genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype is estimated at 1822, though the confidence interval stretches from 1701 to 1911. Genotype I, now responsible for virtually all current infections in Brazil, Colombia, Venezuela, and Trinidad and Tobago, originated in the northern Brazilian region around 1908. Genotype II, which accounts for all cases in Peru, originated in Peru around 1920.

• 5. Epidemics That Moved History

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  Napoleon Bonaparte sent an army under his brother-in-law General Charles Leclerc to Saint-Domingue to suppress a slave revolt and reclaim the sugar trade on Hispaniola. The historian J. R. McNeill estimates that yellow fever inflicted between 35,000 and 45,000 casualties on that French force, leaving only about one-third to return to France. The campaign's failure directly shaped the decision to sell Louisiana to the United States in 1803. The following year, Haiti declared independence, becoming the second republic in the Western Hemisphere.

  In Philadelphia in 1793, then the capital of the United States, a yellow fever epidemic killed more than 9% of the city's population. The dead included James Hutchinson, a physician who had been treating residents. The outbreak was so severe that organs of the federal government, including Congress, fled piecemeal to Trenton, New Jersey, eventually joined by President George Washington. A later outbreak in 1799 led to an official decision to relocate the national government to Trenton for six months.

  The widespread Lower Mississippi Valley epidemic of 1878 caused an estimated 20,000 fatalities. That year, unusual rainfall swelled the mosquito population around Memphis. The steamship John D. Porter took refugees northward, but no port would allow passengers to disembark, and the ship roamed the river for two months. The last urban outbreak in the United States struck New Orleans in 1905. In Shreveport in 1873, 759 people died in an 80-day period; by November, more than 400 additional deaths brought the total to approximately 1,200.

• 6. Proving the Mosquito Connection

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  For most of yellow fever's known history, no one understood how it spread. Josiah C. Nott suggested in 1848 that insects might be involved, based on patterns of transmission. Carlos Finlay, a Cuban-Spanish doctor and scientist, made the decisive theoretical leap in 1881, proposing that previously infected mosquitoes, rather than direct human contact, carried the disease.

  The idea took two more decades to prove. After high casualties in the Spanish-American War in the 1890s, the U.S. Army assigned a team led by Walter Reed, which included doctors James Carroll, Aristides Agramonte, and Jesse William Lazear, to test Finlay's hypothesis. They confirmed it. Reed also made history by using one of the first documented medical consent forms during his experiments in Cuba, an attempt to ensure participants understood they were accepting personal risk.

  Reed was careful to credit Finlay publicly and in his published papers. He cited Finlay's work in his articles and correspondence, and the acceptance of Finlay's research was described as one of the most important effects of the U.S. Army Yellow Fever Commission of 1900. William Gorgas applied the findings to eradicate yellow fever from Havana, then turned his attention to Panama, where a previous French canal-building effort had failed in part because of yellow fever and malaria deaths among workers. His success cleared the way for the Panama Canal's completion.

  In Brazil, Oswaldo Cruz led a parallel campaign starting in 1903, when he became director general of public health. His mosquito inspectors sprayed, exterminated rats, improved drainage, and demolished unsanitary housing across Rio de Janeiro. The campaign reshaped the city physically: poor residents were pushed from city centers to suburbs and eventually to favelas on the outskirts.

• 7. The Vaccine and Global Control

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  Max Theiler developed the attenuated live vaccine strain known as 17D in 1937, and the discovery later earned him the Nobel Prize in Physiology or Medicine. The World Health Organization now states that a single dose confers lifelong immunity. Protection begins by the tenth day after vaccination in 95% of recipients.

  The vaccine is safe for most people, but carries rare risks. In fewer than one in 200,000 to 300,000 cases, it can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of those who develop it. An equally rare neurological side effect can lead to meningoencephalitis and is fatal in less than 5% of cases.

  In 2006, the WHO launched the Yellow Fever Initiative, which vaccinated more than 105 million people across 14 countries in West Africa. No outbreaks were reported during 2015. When outbreaks in Angola in 2015, the Democratic Republic of Congo in 2016, Uganda in 2016, and Brazil and Nigeria in 2017 strained global vaccine supplies, health authorities began exploring fractional dosing. The first practical use of fractional doses was in response to the large 2016 outbreak in the Democratic Republic of Congo. Evidence gathered since shows that fractional doses produce an immune response similar to a full dose.

  In March 2017, the WHO launched a vaccination campaign in Brazil using 3.5 million doses from an emergency stockpile. Brazil then shifted policy in March 2018, announcing plans to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Newer vaccines based on vero cells were in development as of 2018, though the 17D strain developed by Theiler remains the standard.

• 8. The Disease Today

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  Roughly 90% of the estimated 200,000 yellow fever cases that occur worldwide each year happen in Africa. The WHO estimates 130,000 severe infections and 78,000 deaths on the continent in 2013 alone. The number of cases has been rising since the 1980s, driven by reduced population immunity, urbanization, frequent human movement, and climate change expanding the range of mosquito habitat.

  In South America, the 2016-2017 sylvatic outbreak in Minas Gerais state spread rapidly through neotropical monkey populations. By late May 2017, more than 3,000 suspected cases had been recorded, with 758 confirmed and 264 deaths confirmed as yellow fever. The outbreak moved toward the Brazilian coast in April 2017, where most residents were unvaccinated. The CDC issued a Level 2 alert during this period.

  The 2016 Angola outbreak produced something unprecedented: in March and April of that year, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first recorded appearance of yellow fever in Asia. Concern remains about the disease spreading to Southeast Asia, where A. aegypti already lives. Phylogenetic analysis has identified seven genotypes in total, five of which occur only in Africa. West Africa genotype I, found in Nigeria and surrounding areas, appears to be especially prone to triggering major outbreaks. The East African genotype went undetected for 40 years before reappearing in outbreaks in Kenya in 1992-1993 and Sudan in 2003 and 2005.