Biologics Regulation and ResearchThe People and Work of Buildings 29 & 29A

Yellow Fever

Yellow fever has been around since at least the 18th century and was known and dreaded throughout the 19th century, especially in port towns with the arrival of new ships. It was endemic in Cuba, and so after the Spanish-American War, a Yellow Fever Commission was established in the United States to investigate the disease. Walter Reed was the head of the commission, which established that mosquitoes transmitted the disease. The focus shifted to prevention via mosquito control.

At the same time, a “French strain” was discovered in Dakar, Senegal. Andrew Watson Sellards from Harvard and his team discovered the virus survived freezing, allowing transport of infected liver tissue. There were some crude vaccines using formalin and phenol-preserved liver tissue but with uncertain results. Max Theiler knew they needed a better host, so he then inoculated mice intracerebrally and found that the virus grew well. He created the first attenuated strain of yellow fever but with increased neurotropism.

The Rockefeller Foundation was involved in research in West Africa. Tragically, many of the lead researchers died of yellow fever from the 1925 expedition, but they were able to infect rhesus monkeys and therefore could remove the virus to the lab and study it. They discovered that serum from immune humans protected monkeys against infection, immune serum from South America protected against the African virus, and the killed virus would not confer immunity.

1874 Image of Walter Reed. National Library of Medicine

Back in New York, the Rockefeller Institute continued their highly dangerous work on yellow fever. The Rockefeller vaccine was used in the United States and England. At the same time, the Pasteur Institute in Tunis developed a one-dose vaccine (usually combined with smallpox), and it was used in France and their African colonies. The French vaccine was given by scarification (scratching into the skin). It risked febrile and central nervous system reactions but could be done on crowds of people at one time.

In 1932, new technique of cultivating the virus in embryonated eggs and freeze drying them came into use. The 17D virus strain from a chance mutation at the Rockefeller Institute was attenuated enough that it didn’t need protective immune serum. Trials continued in South America, but there were problems with encephalitis and jaundice.

Old map showing areas of yellow fever from 1933-1943, endemic areas as shown by protection tests, and distribution of vectors of yellow fever

1943 Map of Yellow Fever from the U.S. Army. National Library of Medicine

World War II created a huge demand for the yellow fever vaccine. The United States used the Rockefeller Institute vaccine for almost 7 million doses. Later some 26,000 cases of jaundice were recorded and mortality rates of 3 per 1000 (but it was later shown to be hepatitis B). An investigation ensued. The serum seemed to be the culprit. Serum was donated by those affiliated with the Johns Hopkins' School of Medicine. When the serum was ultimately tested, it was revealed that several of the donors had a history of jaundice.

The yellow fever vaccine was first licensed in 1938. At the National Institutes of Health (NIH) from 1943 until her retirement in 1971, Dr. Margaret Pittman worked to assess the efficacy of and establish national and international standards for the production of the yellow fever vaccine. The NIH was also working on a yellow fever vaccine, like the Rockefeller Institute.

After WWII, the French and 17D vaccines widely used. By 1982 the French vaccine was discontinued. Since 1982, developments have included greater stabilization of the vaccine, with a longer storage life. In 1985, the complete genome of the yellow fever virus was published, allowing new research. Today all the vaccines are derived from two sub-strains of 17D.