Yellow fever had been around since at least the 18th century, and was known and feared throughout the 19th century, especially in port towns with the arrival of new ships. It was endemic in Cuba, so after the Spanish-American War, a Yellow Fever Commission was established in the United States to investigate. 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.