There was a time when yellow fever was one of the most feared human diseases in the whole western world. Unfortunately, it is still around and we won’t eradicate it anytime soon. Here is why.

As they study their visa requirements, travellers to some of the less developed parts of the world will learn — perhaps with some surprise — that they must be vaccinated against yellow fever. It was one of the few remaining mandatory health protection measures before COVID-19 struck. Although the term “yellow fever” may trigger thoughts about celebrity gossip at first, it is a historically significant and much older health problem. Luckily, it lasts for a much shorter time than the addiction to following celebrity gossip, which can be lifelong for many people. Yellow fever is caused by a specific virus. Microbiologists classify it among viruses with ribonucleic acid (RNA), in the genus Flavivirus. Its presence in the body can only be confirmed by detecting the RNA molecule of the virus in the blood of a person who is unwell. This is accomplished by using a molecular-biological laboratory technique called polymerase chain reaction (PCR), which is used to detect a target DNA or RNA molecule in the body.

The presence of the yellow fever virus in the body leads to a reasonably short illness. It starts with fever, chills and headache. Loss of appetite, nausea and muscle pain often occur, especially in the back. Thus, the disease does not start differently from other mild viral infections, which attack the majority of people several times a year. Why was it called “yellow fever”, then? This is because about a day or two after the affected seem to have recovered, every sixth person develops a fever yet again, but this time it is accompanied by abdominal pain. In this unfortunate minority, this virus infection causes damage to the liver. The skin of these patients soon turns yellow, due to the development of characteristic jaundice. In addition, the risks of internal bleeding and kidney problems increase.

The yellow fever virus, just like Plasmodium that causes malaria, is transmitted by female mosquitoes. The virus is not only adapted to humans, but to other primates, too — and we will understand the importance of this a bit later. In cities, the most common carrier is the mosquito called Aedes aegypti. We can control this disease by using a vaccine and implementing mosquito spraying. For those unfortunate people who develop severe form, there is hardly any effective treatment. As a result, about half of severe cases would die, adding up to 50,000 deaths a year worldwide. The vast majority of those deaths are recorded in Africa. Up to a billion people still live in areas where yellow fever remains a threat — primarily in Africa and in South America, but not in Asia, where there is no such disease at the moment.

Once the virus enters the bloodstream by a mosquito bite, it will multiply in an infected person without presenting any symptoms during the first week. Then, the symptoms begin and they last only for a few days. Therefore, all of the real danger associated with this disease lies in its transition to the second phase. It is characterised by bleeding, which can occur in the mouth, eyes, and in digestive system. This leads to vomiting of blood, hence the Spanish name for yellow fever — “vomito negro”, i.e. black vomiting. This places yellow fever in a group of diseases that are still potentially extremely dangerous to humanity. We collectively call them “viral hemorrhagic fevers” because they are accompanied by bleeding. Some of the other diseases from this group are Ebola, Lassa, Marburg and Junin.

After being introduced into the bloodstream by a mosquito bite, the virus kills by reaching the liver cells, for which it has a special affinity. Once in the liver, it causes cell breakdown. The so-called “cytokines,” which are small signalling proteins that have different stimulatory effects on other cells, enter the blood. They can lead to “cytokine storms”, which is then followed by a general shock of the entire organism, associated with multiple organ failure. Patients who survive yellow fever will, fortunately, acquire permanent immunity to it.

Yellow fever can occur epidemically. We call this phenomenon an “urban cycle”, when it spreads to cities in the tropics. Also transmitted by mosquitoes, Zika, chikungunya and Dengue fever spread in a similar way. However, with yellow fever, there is also the so-called “sylvatic cycle,” referring to its spread in forests and jungles, which remains out of sight of most people. The sylvatic cycle presents the problem that prevents us from eradicating yellow fever, as we already learned in the introductory paragraph because this virus can use other species as reservoirs and not just humans. In these forests, the disease spreads from mosquitoes to other primates, so it manages to survive even when we completely prevent its spread among humans by vaccination. Simply put, we share yellow fever with other primates to which the virus has adapted. That is how the disease continues to survive, no matter what we humans do to protect ourselves. We cannot vaccinate all the primates in the jungles, too. At some point, people enter the woods and become infected again by mosquito bites. This example shows that there are infectious diseases that we cannot eradicate. Thanks to biomedical science, though, modern people are protected because a single dose of the vaccine ensures lifelong immunity.

Looking through the evolutionary lens, the yellow fever virus has most likely originated in East and Central Africa, where it “jumped” from primates to humans and then spread to West Africa. During colonial times in Africa, historians recorded that a flu-like illness had infected many, but killed almost exclusively newcomers, i.e. the colonialists themselves. This probably implies that the local population in Africa had acquired partial immunity to it by that time. The virus and its vector, the mosquito Aedes aegypti, most likely crossed the Atlantic and spread to the Americas during the slave trade back in the 17th century. The first recorded epidemic outside Africa occurred during the mid-17th century on the island of Barbados, and then it went on to spread to the Yucatán Peninsula, where the indigenous Maya people called it “xekik” — “the vomiting of blood”. In the late 17th century, yellow fever epidemics began to hit Brazil, too. The spread of mosquitoes throughout Latin America was assisted by deforestation and the development of sugar plantations. There were fewer and fewer birds, which used to feed on mosquitoes and their larvae, thus controlling their numbers.

From Latin America, yellow fever gradually began to spread to the north. At the end of the 17th century, New York itself had an epidemic. At the very end of the 18th century, it affected Philadelphia, which was then the capital of the United States. Thousands of people died, roughly a tenth of the city’s population at the time. The national government, along with President George Washington himself, managed to escape it in time. But in the U.S., yellow fever caused the most problems throughout the 18th and 19th centuries in the Mississippi River valley, where it was most feared. It struck New Orleans repeatedly. Local residents called it “Yellow Jack.” In that part of the United States, it is thought to be responsible for the deaths of as many as 150,000 people.

It was further noted that the city of Memphis had an unusually large amount of rain in one year, which favoured the increase in mosquito numbers and led to a large epidemic of yellow fever. The steamboat “John D. Porter” boarded the people fleeing from Memphis to the north, hoping to avoid contracting the disease. However, when on board, the crew and passengers began to fall ill and die. Because of this, the passengers were not allowed to disembark at any port along the river. The ship floated down the Mississippi River for the following two months like a “ghost ship”.

Because of yellow fever, the soldiers of 18th and 19th-century European colonial powers were trying to avoid being stationed in South America at all costs. Records show that the mortality of British soldiers in Jamaica was seven times higher than in Canada. Even Napoleon had to withdraw in the face of yellow fever. Wanting to gain control of the lucrative sugar trade in Saint-Domingue, a French colony on the Caribbean island of Hispaniola, now shared by the Dominican Republic and Haiti, the great French military leader sent his troops under the command of his brother-in-law, Charles Leclerc, to Saint-Domingue. He wanted to take advantage of the rebellion of the local slaves to gain control over the island and its sugar supplies. However, according to historian J. R. McNeill, of the 45,000 casualties recorded during the fights, as many as 35,000 of them could be attributed to yellow fever and only 10,000 to all other causes. Only a third of the French soldiers who were sent there eventually managed to leave the island alive and return home to France. It is believed that Napoleon’s realisation of the great danger of yellow fever for his soldiers, which was all the clearer because his brother-in-law was also involved in the operation at Hispaniola, was one of the reasons why he gave up his conquest plans on the American continent and decided to sell Louisiana to the USA in 1803.

Throughout the 18th and 19th centuries, yellow fever was considered to be one of the most dangerous human diseases. In the 19th century, it also reached southern Europe, leading to significant problems in Gibraltar and Barcelona. An interesting person from the late 19th century, Ezekiel Stone Wiggins, also known as the “Prophet of Ottawa,” suggested that the cause of the yellow fever epidemic that then hit Jacksonville, Florida, could be explained by astronomy and the influence of the stars. His hypothesis was that many planets were aligned with the sun and the Earth at the time, leading to the ‘’cyclones and earthquakes’.’ Because of that, there was a “thickening of the atmosphere”, so there was “significantly more carbon” in the atmosphere. As a result, “a lot more microbes were created” than usual. He thought Mars also had an unusually dense atmosphere, but that its inhabitants were protected from yellow fever. This was probably thanks to “channels” on the surface of Mars, which had been discovered by telescopes in previous years, and which he suggested were made to “absorb excessive amounts of carbon and thus prevent this disease on that planet”.

The example of Wiggins, the “Prophet of Ottawa”, shows how human knowledge has been limited in all periods of history, but this did not prevent some humans from using their existing knowledge in various ways to develop wild research hypotheses. Centuries later, they may sound extremely strange, but at that time, due to their incorporation of several new pieces of human knowledge, they were taken very seriously.

It is interesting to note that, although yellow fever was raging and taking many casualties, no one thought at the time that mosquitoes could be transmitting it. People believed that it was spread through direct contact, from person to person.

It wasn’t until the mid-19th century that Josiah C. Nott, who, in carefully studying the patterns of transmission and the spread of this disease, suggested that yellow fever could be spread by insects such as moths or mosquitoes. Carlos Finlay, a Cuban physician and scientist, also independently suggested mosquitos as likely culprits in the late 19th century. Human losses due to yellow fever in the Spanish-American War of the 1890s were very large, prompting U.S. military physicians to conduct systematic experiments to try to better understand yellow fever. They were led by the famous Dr. Walter Reed, whose team successfully proved Finlay’s “mosquito hypothesis”. Although Dr. Walter Reed later received much of the credit in American history books for “understanding and addressing yellow fever”, he personally fully acknowledged Dr. Carlos Finlay’s merits as the discoverer of yellow fever’s vectors and his ideas on ways to control the disease.

By applying the methods proposed by Finlay, the U.S. Government and the military have managed to eradicate yellow fever in Cuba. They did so under the leadership of Dr. William Gorgas, who then became involved in the fight against yellow fever as part of another important event of the time — the construction of the Panama Canal. France had previously tried to build the Panama Canal. It would enable ships sailing from Europe to the west coast of the American continent, and then further to the Pacific Ocean, to avoid travelling around the whole of South America and through the dangerous Strait of Magellan. The French failed in their plan because too many workers were consistently dying of yellow fever, as well as from malaria.

Like the United States, Cuba, and Panama, Brazil also used the time period between the late 19th and early 20th centuries to conduct a very successful sanitary campaign against mosquitoes and yellow fever. It was led by the famous Dr. Oswaldo Cruz, then the first man of public health in Brazil. That campaign not only resulted in the eradication of the disease but also reshaped the physical landscape of Brazil’s cities, such as Rio de Janeiro. During the rainy periods of the year, Rio de Janeiro regularly suffered from floods, as the water would fill the narrow alleys. Coupled with poor drainage systems, this created swampy conditions in city neighbourhoods. Pools of water would linger along the city streets throughout the year, leading to an increase in the mosquito population. Under Cruz’s leadership, public health squads known as “mosquito inspectors” fought intensely against yellow fever in Rio de Janeiro, spraying and exterminating mosquitoes and rats. They also improved the drainage system and unhygienic housing, which changed the appearance of Rio de Janeiro. Its poor inhabitants were pushed out of the city districts into the suburbs of Rio, and in later years they also constructed numerous slums, so-called “favelas,” all over the city.

During the first two decades of the 20th century, the Rockefeller Foundation undertook a very expensive but also highly successful campaign to eradicate yellow fever in Mexico. This was a very courageous and far-sighted political move by the U.S. The success of this action resulted in gratitude from the Mexican Federal Government and improved general relations between the U.S. and Mexico, which had not been friendly in the past.

Thanks to the aforementioned Dr. Walter Reed, after whom the most famous American military hospital in Washington, D.C., was later named, the yellow fever virus became the first virus isolated from patients’ blood, in 1927. Yellow fever also became the first disease for which the possibility of transmission by human blood was proven.

The isolation of the virus paved the way for vaccine development. The live attenuated vaccine, known as “17D,” was developed by South African-American virologist Max Theiler at the Rockefeller Institute in New York City in 1937. Building on Ernest Goodpasture’s previous work, Theiler used chicken eggs to cultivate the virus and develop the vaccine. Within the next few years, the vaccine was deployed by the U.S. military during World War II. After the end of the war, in 1951, Theiler’s contribution was awarded with the Nobel Prize in Physiology or Medicine. Remarkably, Theiler’s 17D vaccine is still in use today, and more than 400 million doses have been distributed. Due to the effectiveness of this vaccine, very little research has been conducted in recent decades to develop newer vaccines against yellow fever. Some researchers expressed concerns that a 60-years-old technology for the production of 17D vaccine has become too slow to avert a potential major epidemic of yellow fever.

Today, at least 600 million people, and perhaps even up to a billion, continue to live in areas where they could be infected with yellow fever. At least 200,000 people fall ill with it each year, and up to 30,000 of them may die, the vast majority of them in Africa. Since the 1980s, the number of cases of yellow fever has increased again, and the mosquito Aedes aegypti has returned to the urban centres of South America. This is partly due to the limitations of available insecticides, as well as climate change in habitats, but partly also due to fatigue in implementing transmission control programmes. Although no new epidemic “urban cycle” has yet been reported, scientists believe this is something that could potentially occur again in the foreseeable future. Although there is no yellow fever in Asia, back in 2016, 11 cases were reported in China. All of them were linked to flights that had arrived from the area of Africa affected by an epidemic, resulting in yellow fever’s very first appearance in Asia. The “Yellow Fever Initiative,” launched by the World Health Organisation back in 2006, has seen more than 105 million people in 14 West African countries vaccinated, and Brazil is also seeking to achieve full vaccination coverage. Attempts are still being made to fight the mosquitoes. There is still no cure for patients with a more severe form of this disease, and the only available treatment is intensive care. Also, aspirin is not given to lower fever because of its effects on blood clotting — it can significantly increase internal bleeding.

Even today, it is not entirely clear why Asia and Australia were spared from the global spread of yellow fever. The main vector of the disease, the female mosquito Aedes aegypti, also appears in these parts of the world. It is unclear why it doesn’t transmit this disease in those locations. Some researchers think that the slave trade was the main mode of transmission to South America, and that wasn’t the case with Asia. So, the answer may lie in that historic fact, but through a mechanism that we still don’t understand. Yellow fever has also been studied in several countries as a potential biological weapon, so it should not be thought of as a health problem that has been resolved. We can only hope that this dangerous disease will not resurface again and surprise us in an unpleasant way yet again in any foreseeable future.

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Declaration: Professor Igor Rudan, FRSE, is the President of the International Society of Global Health; co-Editor-in-Chief of the “Journal of Global Health”; Joint Director of the Centre for Global Health and the WHO Collaborating Centre at the University of Edinburgh, UK.

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Image credit: Pavel Czerwinski, Unsplash.com.

Director of the Centre for Global Health and the WHO Collaborating Centre at the University of Edinburgh, UK; Editor-in-Chief, Journal of Global Health