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The story of how a lucky mutation led to the development of the yellow fever vaccine we use today

Updated: Jan 16, 2023

Durban Harbour 1895

The seemingly unstoppable plague of yellow fever

Before development of an effective yellow fever vaccine, yellow fever terrorized tropical countries and port cities all over the world. It was known as "yellow jack" because of the yellow quarantine flags infected ships would fly. Major outbreaks relentlessly hit U.S. port cities of Philadelphia, New York, Boston, New Orleans in the 1700s and 1800s. Thousands died in some of these outbreaks and tens of thousands more fled to avoid the terrible disease. The yellow fever outbreak in Philadelphia in 1793 was particularly devastating.

Investigating the cause of yellow fever

One clue to the origins of yellow fever was the infection pattern. The virus was endemic to tropical areas, meaning it was always present, year-round, 365 days a year. Port cities in the U.S., on the other hand, were struck by yellow fever only intermittently. Sometimes they would have a big breakout and sometimes they wouldn't. It didn't take too much work to connect the breakouts to the arrival of a ship coming from a region where yellow fever was endemic. So they knew it was the ships that were spreading the virus to American ports [1].

Several causes of potential spread of the virus were investigated, including sanitation, drinking water, food, environment, etc. It was actually U.S. Army medical personnel who were able to definitively prove that mosquitoes were spreading the yellow fever virus [2]. They did this using experiments on humans in Cuba, where the disease was endemic at the time. By removing all other potential sources of disease (foul air, foul water, etc.) and using staff that was immune to the virus, having already been infected previously, they found that the virus could only be spread by mosquitoes.

Developing a yellow fever vaccine

It was helpful to observe that once a person had been infected with yellow fever they gained a lifelong immunity. The immunity gave hope that an effective vaccine for yellow fever could be found. The experiments on humans in Cuba mentioned above were actually an early effort to develop a vaccine--not just an attempt to identify the mechanism by which it is spread. The inoculations by infecting people were effective but some died [1]. There was no real benefit to infecting people with the disease just so they wouldn't be susceptible to it later.

In 1918, another early attempt at a vaccine was seen as a success, administered widely but declared a failure later. This was an effort by the Rockefeller Foundation’s International Health Commission. They claimed they were able to isolate and identify the actual virus, and created both an antiserum and a yellow fever vaccine. But the vaccine they mass produced and distributed turned out to be ineffective. Other researchers weren't able to replicate their results. The issue seemed to be sloppy statistics and the misidentification of a common bacteria as the yellow fever virus [1].

Later experiments in Africa showed (at great costs to the experimenters, many of whom died of yellow fever) that (a) serum from immune humans protected monkeys from infection, (b) immune serum from South America protected against African variants (suggesting its the same virus so only one vaccine is needed), and (c) introduction of the dead virus does not confer immunity [1].

Based on work by Louis Pasteur and others to develop "attenuated" or weakened forms of viruses to be used to inoculate people against the full-strength form of the disease, efforts were undertaken to develop a weakened yellow fever virus. Ultimately it was a chance mutation that occurred during a course of animal experiments in 1932 that had weakened the virus to the extent that it could be used as a vaccine. This weakened virus, known as variant 17D and developed by accident in the labs of the Rockefeller Foundation, is still what we use today 90 years later [1].

Living with yellow fever in modern times

We now know that yellow fever is a virus that is spread by mosquitoes. Both humans and non-human primates can be attacked by the virus. In modern times the virus is mainly confined to tropical and sub-tropical areas of Africa and South America. The yellow fever virus causes fever along with associated aches and pains. In severe cases it can cause liver damage, bleeding and jaundice (yellowing of the skin due to liver poisoning and blood vessel leakage). To this day there is not an effective treatment for yellow fever so it's best to avoid it through vaccination and mosquito preventive measures. The yellow fever vaccine is safe and incredibly effective, providing up to 99% lifelong immunity. It is administered to children in countries where it is endemic and it is also required of travelers to enter many African countries, and recommended for many parts of South America.


  1. Frierson, J. G. (2010). The yellow fever vaccine: a history. The Yale journal of biology and medicine, 83(2), 77.

  2. Reed, W., Carroll, J. A. S., & Agramonte, A. (1901). The Etiology of Yellow Fever: An Additional Note. Journal of the American Medical Association, 36(7), 431-440.


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