Yellow fever vaccine (Inventions)

The invention: The first safe vaccine agaisnt the virulent yellow fever virus, which caused some of the deadliest epidemics of the nineteenth and early twentieth centuries.

The people behind the invention:

Max Theiler (1899-1972), a South African microbiologist Wilbur Augustus Sawyer (1879-1951), an American physician Hugh Smith (1902-1995), an American physician

A Yellow Flag

Yellow fever, caused by a virus and transmitted by mosquitoes, infects humans and monkeys. After the bite of the infecting mosquito, it takes several days before symptoms appear. The onset of symptoms is abrupt, with headache, nausea, and vomiting. Because the virus destroys liver cells, yellowing of the skin and eyes is common. Approximately 10 to 15 percent of patients die after exhibiting terrifying signs and symptoms. Death occurs usually from liver necrosis (decay) and liver shutdown. Those that survive recover completely and are immunized.
At the beginning of the twentieth century, there was no cure for yellow fever. The best that medical authorities could do was to quarantine the afflicted. Those quarantines usually waved the warning yellow flag, which gave the disease its colloquial name, “yellow jack.”
After the Aedes aegypti mosquito was clearly identified as the carrier of the disease in 1900, efforts were made to combat the disease by wiping out the mosquito. Most famous in these efforts were the American army surgeon Walter Reed and the Cuban physician Carlos J. Finlay. This strategy was successful in Panama and Cuba and made possible the construction of the Panama Canal. Still, the yellow fever virus persisted in the tropics, and the opening of the Panama Canal increased the danger of its spreading aboard the ships using this new route.
Moreover, the disease, which was thought to be limited to the jungles of South and Central America, had begun to spread arounds the world to wherever the mosquito Aedes aegypti could carry the virus. Mosquito larvae traveled well in casks of water aboard trading vessels and spread the disease to North America and Europe.


Max Theiler received his medical education in London. Following that, he completed a four-month course at the London School of Hygiene and Tropical Medicine, after which he was invited to come to the United States to work in the department of tropical medicine at Harvard University.
While there, Theiler started working to identify the yellow fever organism. The first problem he faced was finding a suitable laboratory animal that could be infected with yellow fever. Until that time, the only animal successfully infected with yellow fever was the rhesus monkey, which was expensive and difficult to care for under laboratory conditions. Theiler succeeded in infecting laboratory mice with the disease by injecting the virus directly into their brains.
Laboratory work for investigators and assistants coming in contact with the yellow fever virus was extremely dangerous. At least six of the scientists at the Yellow Fever Laboratory at the Rockefeller Institute died of the disease, and many other workers were infected. In 1929, Theiler was infected with yellow fever; fortunately, the attack was so mild that he recovered quickly and resumed his work.
During one set of experiments, Theiler produced successive generations of the virus. First, he took virus from a monkey that had died of yellow fever and used it to infect a mouse. Next, he extracted the virus from that mouse and injected it into a second mouse, repeating the same procedure using a third mouse. All of them died of encephalitis (inflammation of the brain). The virus from the third mouse was then used to infect a monkey. Although the monkey showed signs of yellow fever, it recovered completely. When Theiler passed the virus through more mice and then into the abdomen of another monkey, the monkey showed no symptoms of the disease. The results of these experiments were published by Theiler in the journal Science.
This article caught the attention of Wilbur Augustus Sawyer, director of the Yellow Fever Laboratory at the Rockefeller Foundation International Health Division in New York. Sawyer, who was working on a yellow fever vaccine, offered Theiler a job at the Rockefeller Foundation, which Theiler accepted. Theiler’s mouse-adapted, “attenuated” virus was given to the laboratory workers, along with human immune serum, to protect them against the yellow fever virus. This type of vaccination, however, carried the risk of transferring other diseases, such as hepatitis, in the human serum.
In 1930, Theiler worked with Eugen Haagen, a German bacteriologist, at the Rockefeller Foundation. The strategy of the Rockefeller laboratory was a cautious, slow, and steady effort to culture a strain of the virus so mild as to be harmless to a human but strong enough to confer a long-lasting immunity. (To “culture” something—tissue cells, microorganisms, or other living matter—is to grow it in a specially prepared medium under laboratory conditions.) They started with a new strain of yellow fever harvested from a twenty-eight-year-old West African named Asibi; it was later known as the “Asibi strain.” It was a highly virulent strain that in four to seven days killed almost all the monkeys that were infected with it. From time to time, Theiler or his assistant would test the culture on a monkey and note the speed with which it died.
It was not until April, 1936, that Hugh Smith, Theiler’s assistant, called to his attention an odd development as noted in the laboratory records of strain 17D. In its 176th culture, 17D had failed to kill the test mice. Some had been paralyzed, but even these eventually recovered. Two monkeys who had received a dose of 17D in their brains survived a mild attack of encephalitis, but those who had taken the infection in the abdomen showed no ill effects whatever. Oddly, subsequent subcultures of the strain killed monkeys and mice at the usual rate. The only explanation possible was that a mutation had occurred unnoticed.
The batch of strain 17D was tried over and over again on monkeys with no harmful effects. Instead, the animals were immunized effectively. Then it was tried on the laboratory staff, including Theiler and his wife, Lillian. The batch injected into humans had the same immunizing effect. Neither Theiler nor anyone else could explain how the mutation of the virus had resulted. Attempts to duplicate the experiment, using the same Asibi virus, failed. Still, this was the first safe vaccine for yellow fever. In June, 1937, Theiler reported this crucial finding in the Journal of Experimental Medicine.


Following the discovery of the vaccine, Theiler’s laboratory became a production plant for the 17D virus. Before World War II (1939-1945), more than one million vaccination doses were sent to Brazil and other South American countries. After the United States entered the war, eight million soldiers were given the vaccine before being shipped to tropical war zones. In all, approximately fifty million people were vaccinated in the war years.
Yet although the vaccine, combined with effective mosquito control, eradicated the disease from urban centers, yellow fever is still present in large regions of South and Central America and of Africa. The most severe outbreak of yellow fever ever known occurred from 1960 to 1962 in Ethiopia; out of one hundred thousand people infected, thirty thousand died.
The 17D yellow fever vaccine prepared by Theiler in 1937 continues to be the only vaccine used by the World Health Organization, more than fifty years after its discovery. There is a continuous effort by that organization to prevent infection by immunizing the people living in tropical zones.
See also Antibacterial drugs; Penicillin; Polio vaccine (Sabin); Polio vaccine (Salk); Salvarsan; Tuberculosis vaccine; Typhus vaccine.

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