Yellow fever is a viral hemorrhagic disease characterized by high fever, severe muscle pain, and the jaundice that gives the condition its name. The illness carried a high mortality rate, and throughout the 18th and 19th centuries, epidemics swept through major cities, including Philadelphia and New Orleans. The prevailing, yet incorrect, belief held that the disease spread through foul air or contaminated objects, known as fomites. This left public health officials powerless to halt its transmission.
Proposing the Transmission Mechanism
The first step toward solving the yellow fever puzzle was taken by Cuban physician and epidemiologist Carlos Juan Finlay, who worked in Havana. Finlay observed that yellow fever cases aligned with the peak season for a specific type of mosquito, challenging the accepted theory of transmission by fomites. In 1881, he presented his hypothesis to the International Sanitary Conference, suggesting that a mosquito was the carrier of the infectious agent.
Finlay identified the insect as a member of the Culex genus, later reclassified as the Aedes aegypti mosquito. His theory proposed that the female mosquito would bite an infected person, acquire the agent, and then transmit it to a healthy individual. This idea was met with skepticism from the medical community. Finlay continued his observational work for nearly two decades.
Proving the Vector
The definitive proof for Finlay’s mosquito theory came nearly two decades later from the U.S. Army Yellow Fever Commission, established in 1900 and led by Major Walter Reed. The commission, which included researchers James Carroll, Jesse Lazear, and Aristides Agramonte, traveled to Cuba to study the disease under controlled conditions. They established an isolation facility called Camp Lazear.
The team designed a series of rigorous, controlled human experiments to test the competing theories of transmission. Volunteers slept in a building containing bedding, clothing, and other materials soiled by yellow fever patients. None of the volunteers exposed only to these fomites contracted the disease, effectively ruling out the long-held belief in contact transmission. Other volunteers were housed separately and exposed only to infected Aedes aegypti mosquitoes that had previously fed on patients.
These experiments proved that the mosquito was the sole agent of transmission, confirming Finlay’s initial hypothesis. The commission also discovered that an infected mosquito could only transmit the disease after a minimum incubation period of about twelve days. This scientific confirmation provided a clear public health strategy, leading to aggressive mosquito control measures that rapidly eliminated yellow fever from Havana.
Identifying the Causative Agent
The infectious agent remained a subject of scientific debate. Many researchers, including those on the Reed Commission, initially suspected a bacterium was the cause. The commission’s work indicated otherwise, as the agent could be transferred in the blood but could not be grown on standard bacterial culture media.
Filtration experiments conducted by the Reed commission demonstrated that the infectious material could pass through porcelain filters. This led to the conclusion that the cause of yellow fever was a “filterable agent.” This established yellow fever as the first human disease shown to be caused by a virus. It was not until 1927 that researchers from the Rockefeller Foundation successfully isolated and confirmed the causative agent as the Yellow Fever virus, a member of the Flaviviridae family.
Developing the Preventative Measure
The development of a vaccine was the final discovery in the fight against yellow fever. This achievement is credited to South African virologist Max Theiler. Theiler utilized the discovery that the yellow fever virus could be transmitted to laboratory mice for study.
Theiler successfully attenuated the pathogen by repeatedly passing the virus through mice and tissue cultures. This resulted in the isolation of the 17D strain of the virus in 1937. The 17D strain retained its capacity to induce protective immunity but lost its ability to cause severe disease in humans. The vaccine was cultivated in fertilized chicken embryos, allowing for large-scale production. Theiler received the Nobel Prize in Physiology or Medicine in 1951 for this work.