Max Theiler conducted research that led to the 17D vaccine for yellow fever, one of the deadliest diseases of the nineteenth and twentieth centuries.

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 the terrifying signs and symptoms. Death occurs usually from liver necrosis (decay) and liver shutdown. Victims who survive, however, recover completely and are immunized. [kw]Theiler Develops a Treatment for Yellow Fever (June, 1937)
[kw]Treatment for Yellow Fever, Theiler Develops a (June, 1937)
[kw]Yellow Fever, Theiler Develops a Treatment for (June, 1937)
[kw]Fever, Theiler Develops a Treatment for Yellow (June, 1937)
Yellow fever;vaccine
Medicine;yellow fever
Vaccines;yellow fever
Diseases;yellow fever
[g]United States;June, 1937: Theiler Develops a Treatment for Yellow Fever[09490]
[c]Health and medicine;June, 1937: Theiler Develops a Treatment for Yellow Fever[09490]
Theiler, Max
Sawyer, Wilbur Augustus
Smith, Hugh

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 Aëdes aegypti mosquito Mosquitoes as disease vectors 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 Reed, Walter and the Cuban physician Carlos Juan Finlay Finlay, Carlos Juan . 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 around the world to wherever the mosquito Aëdes 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’s 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, Haagen, Eugen 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.

Max Theiler.

(The Nobel Foundation)

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 occurred. 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 during the war years.

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. Severe outbreaks of yellow fever occurred in the 1980’s in Ghana, Burkina Faso, and Nigeria. In 2001 the World Health Organization reported that the incidence of yellow fever rose during the 1980’s and 1990’s, infecting up to two hundred thousand people and causing thirty thousand deaths per year. This resurgence of the disease was attributed to deforestation, the proliferation of environments in which mosquitoes breed, and large unvaccinated populations in developing countries of Africa and Latin America.

More than fifty years after its development, the 17D yellow fever vaccine prepared by Theiler in 1937 continues to be the only vaccine against the disease used by the World Health Organization, which is involved in a continuous effort to prevent infection by immunizing the people living in tropical zones. Yellow fever;vaccine
Medicine;yellow fever
Vaccines;yellow fever
Diseases;yellow fever

• Bendinger, Elmer. “Max Theiler: Yellow Jack and the Jackpot.” Hospital Practice, June 15, 1988, 211-244. An excellent article on the life story of Max Theiler. Opens with Theiler’s childhood in South Africa, where he began his fascination with biology, and continues through his brilliant scientific career.
• Bres, P. L. J. “A Century of Progress in Combating Yellow Fever.” Bulletin of the World Health Organization 64 (December, 1986): 775-786. Surveys the epidemiological situation of yellow fever in the fifty years that followed the discovery of the vaccine. Discusses major scientific advancements in the study of the virus and the disease. Includes a short description of the history of yellow fever epidemics and research on yellow fever.
• Hill, Ralph Nading. The Doctors Who Conquered Yellow Fever. New York: Random House, 1957. Depicts the story of the fight against yellow fever through the life story of Walter Reed. Includes a brief description of the developments in the fight against the disease following Reed’s death up to Theiler’s development of the 17D vaccine.
• Oldstone, Michael B. A. Viruses, Plagues, and History. New York: Oxford University Press, 1998. Examines the effects of deadly viruses on human history and discusses scientists’ efforts to eradicate such viruses. Chapter 5 is devoted to the successful fight against yellow fever.
• Pierce, John R., and Jim Writer. Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets. New York: John Wiley & Sons, 2005. Focuses on the impact of yellow fever epidemics in the United States and on Walter Reed’s work to determine the disease’s mode of transmission.
• Strode, George K., ed. Yellow Fever. New York: McGraw-Hill, 1951. The most authoritative book on yellow fever at the time of its publication. Chapters were written by the foremost experts in the field, including one by Max Theiler on the virus. Covers topics such as the history of the fight against yellow fever, the search for a vaccine against the disease, and the cost of this effort.
• Williams, Greer. Virus Hunters. New York: Alfred A. Knopf, 1959. Describes the development of a vaccine against yellow fever in chapter 15, titled “Theiler: Yellow Fever’s Second Exit.” Includes annotated bibliography.

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