by Michael B.A. Oldstone

Yellow fever was endemic in Cuba and thus endangered all countries with whom Cuba traded. In 1898, with the outbreak of the Spanish-American War, yellow fever became a primary concern of the United States Army. Therefore, the Yellow Fever Commission was sent to Cuba in 1900. Interestingly, at that time, none of the four members had observed a case of yellow fever previously. Their first aim was to confirm or refute the claim that yellow fever was caused by a bacterium, namely Bacillus icteroides, as first proposed by Guiseppe Sanarelli, an Italian pathologist who injected the bacteria into five South American subjects of whom three died from jaundice. Although the conclusion that bacteria caused yellow fever brought Sanarelli notoriety and awards, the Yellow Fever Commission proved the idea untrue. The bacillus had simply been a contaminant, a passenger in patients with yellow fever; it was not the cause. The Commission then turned their investigation to the hypothesis of Carlos Finlay [1, 2, 3] that a mosquito was the transmitter of yellow fever.

Carlos Finlay, born in Camaguey, Cuba, was the son of Scottish and French parents. He entered the Thomas Jefferson Medical College in Philadelphia in 1853, a year in which yellow fever caused considerable disease in that city. This episode, in addition to the multiple cases occurring in Cuba, focused his interest and laid the foundation for his life's work in the investigation of yellow fever. He graduated from Jefferson Medical College in 1855, and in 1857 began the practice of medicine in Havana. In 1881 Finlay formally presented his thesis, "The Mosquito Hypothetically Considered as the Agent of Yellow Fever" [1]. In this report he concluded that, since yellow fever affected vascular endothelium, a blood-sucking insect might be an intermediate host responsible for transmission. He described three events necessary for the transmission of yellow fever:

Consistent with other discoveries throughout the course of medicine and science, the concept that a mosquito causes yellow fever had earlier been suggested by many but proven by none. For example, in 1807 John Crawford of Baltimore published a paper stating that the mosquito was responsible for malaria, yellow fever, and other diseases, and in 1848 Joshua Nott from Mobile, Alabama, reiterated this concept. An interesting side-line is that Dr. Nott, in his function as an obstetrician, delivered William Gorgas, who in the 1900s would virtually eliminate the Aedes aegypti mosquito from Cuba and other areas throughout the Americas including the site where the Panama Canal was to be built. In 1853 Louis Beauperthuy, a French physician working in Venezuela, also incriminated the mosquito in spreading yellow fever and malaria. However, none of these physicians provided any experimental evidence to confirm the hypothesis. To the contrary, Finlay undertook realistic experimentation. First, he trapped wild mosquitoes and allowed them to bite yellow fever patients and then bite healthy individuals who had no previous history of yellow fever. However, the results were inconclusive. Although four of the five healthy individuals became feverish and mildly ill, classic yellow fever did not occur. Indeed, the Army Surgeon General, William Sternberg, one of the premiere microbiologists in North America and the organizer of the Yellow Fever Commission, totally rejected Finlay's experiments and the mosquito theory. Having worked directly with Finlay in Cuba during the first Yellow Fever Commission of the late 1870s, Sternberg respected the work of Finlay but believed that mosquitoes did not inject anything harmful into humans. Unfortunately, Sternberg's position of power was sufficient to dampen support for Finlay's hypothesis. Nevertheless, evidence was mounting that insects could indeed transmit disease to man [3]. In 1878, Patrick Manson found that a mosquito infected humans with the parasitic disease filariasis. Theobald Smith in 1892, along with Frederick Kilbourne, showed that ticks spread the parasitic disease of cattle called "Texas Fever." In 1894, Mason showed that the tsetse fly caused human sleeping sickness or trypanosomiasis, and in 1896, Ronald Ross of the British Army showed that mosquitoes transmitted malaria.

The Yellow Fever Commission members differed in their opinions as to whether the mosquito could cause yellow fever, with Lazear being the only one among the four who strongly believed so. No animal except man was known at that time to be susceptible to yellow fever. Therefore to test the mosquito transmission hypothesis, members of the commission decided to engage in human experimentation. None were enthusiastic about taking the risk of catching yellow fever, but Carroll, Lazear, and Agramonte directly participated. Reed did not. To control these studies, they reared the mosquitoes from eggs provided by Carlos Finlay so as to rule out the mosquitoes' previous exposure to humans or to any human disease. In the first set of experiments, Lazear and eight other volunteers were bitten by mosquitoes almost immediately after they had bitten patients with yellow fever. As described by Agramonte:

None of the nine individuals came down with yellow fever.

Next, Carroll volunteered for experimentation: "I reminded Dr. Lazear that I was ready, and he at last applied to my arm an insect that had bitten a patient with a severe attack 12 days previously. . . . I was perfectly willing to take a soldier's chance." That night Carroll wrote Reed, who had returned to Washington, "I remarked jokingly, that if there were anything in the mosquito theory I should have a good dose, and so it happened."

Two days later Carroll experienced the earliest vague symptoms of yellow fever and four days later the symptoms became severe, marked by weakness, chills, and a temperature of 102°F. No malaria parasites were found in the blood that came from Carroll, ruling out the possibility of malaria. Agramonte wrote:

Carroll's attack left him so weak that two weeks later he could not stand or change position without assistance. However, Carroll had been in contact with yellow fever patients a few days immediately preceding his illness, so it was not clear whether the mosquito bite alone had caused the yellow fever or had been an incidental factor. For that reason, the next experiment was done on a volunteer who had no previous exposure to yellow fever, Private William H. Dean. On the day that Carroll became sick, Lazear applied to Dean's arm, in addition to three other mosquitoes, the same mosquito that had bitten Carroll, to provide the greatest chance of transmitting the disease. But Dean developed only a mild case of yellow fever. So, on September 13, 1890, Lazear let himself be bitten again. Five days later he began to feel ill. As the disease progressed, Lazear developed jaundice, vomited blood, and became delirious. Just 12 days after the experiment began, Jesse Lazear died.

John Carroll wrote, "I shall never forget the expression of his eyes when I last saw him alive on the third or fourth day of his illness."

The evidence was now substantial. Yellow fever was transmitted by mosquitoes, and a lag time was required between the insect's acquisition of infected blood and biting of a susceptible individual to induce disease. This latter point accounted for the failure of Finlay's experiments and of Agramonte's first attempt to become infected. This time lag after the mosquito first feeds on the blood of a subject with the yellow fever virus is twelve to twenty days, during which the virus travels from the insect's gut to its salivary gland, a position where the virus is available to infect the next susceptible individual. This timing agrees with that observed by Henry Carter, a U.S. Public Health Service physician who in 1898 conducted epidemiologic studies of yellow fever in two Mississippi villages. He concluded that an extrinsic incubation period of approximately two weeks was required for the induction of new cases of yellow fever.

Thus, of the four Commission members who undertook the study of yellow fever in Cuba, one died and another barely survived. Their conclusion that the mosquito served as an intermediate host for the agent of yellow fever and that disease was propagated through the bite of this insect was not universally accepted, however. For example, the Washington Post on November 2, 1900, in publishing the mosquito hypothesis reported, "Of all the silly and nonsensical rigmarole of yellow fever that has yet found its way into print - and there has been enough of it to build a fleet - the silliest beyond compare is to be found in the arguments and theories generated by a mosquito hypothesis."

Shortly thereafter, on November 20, the Yellow Fever Commission members established another experimental camp in Cuba. Strict quarantine was enforced and experiments conducted only on subjects never previously exposed to yellow fever. Named Camp Lazear, the facility was created to include only residents who were judged to be susceptible to yellow fever and with no previous exposure to the disease. Of five volunteers tested, four contracted the disease, but all recovered. The one volunteer who did not get sick was bitten by a mosquito later found incapable of transmitting the infection. The irrefutable conclusion was: "The precision with which the infection of the individuals followed the bite of the mosquito left nothing to be desired."

The United States Army Yellow Fever Commission and the Spanish-American War: Science and Politics in Latin America, 1898-1904 - this exhibit in 12 pages, abundantly illustrated with period pictures, tells the history of the American presence in Cuba during and after the Spanish-American War, the formation and activities of the Yellow Fever Commission, and the ultimately successful efforts to bring yellow fever under control. An extensive bibliography is included.
The above illustration, ca. 1878, is from their collection: "Death holds a 'Yellow Jack,' a yellow flag that was raised over infected cities to warn visitors to stay away. 'Yellow Jack' became a nickname for the disease itself."

The Myth of Walter Reed - an article from the Washington Post on the unexplained failure of Walter Reed (despite a pledge made with the other members of the Yellow Fever Commission) to participate in the self-experimentation that led to the identification of Aedes aegypti as the vector for yellow fever.

A Call to Physicians: Live-Attenuated HIV Vaccine Trial - a message from Charles F. Farthing, chair the of Live-Attenuated Vaccine Subcommittee of the International Association of Physicians in AIDS Care, promoting the potential benefit of a live-attenuated HIV vaccine and the need to subject it to clinical trials with human subjects. Farthing calls on his fellow physicians to volunteer themselves as subjects. A Potential Volunteer and Advocacy Registration Form is provided.

Mosquito Genomics World Wide Web Server - provides access to mosquito genomics databases and other genomics servers. Databases include Mosquitoes (general); Aedes aegypti (the yellow fever mosquito - this section features Boris Jobling's anatomical drawings of Aedes aegypti); Aedes albopictus (the Asian tiger mosquito); Aedes triseriatus (the Eastern tree hole mosquito); Anopheles gambiae (the malaria mosquito); and Culex pipiens (the northern house mosquito). Also links to the MacArthur Foundation Research Network on the Biology of Parasite Vectors; the Vector Biology Usenet newsgroup; the Insect Molecular Biology Journal; and other genomics information.

Outbreak's Yellow Fever Pages - information and an extensive list of FAQs on yellow fever, from Outbreak, an online information service addressing emerging diseases (see HMS Beagle's review of Outbreak).

Centers for Disease Control Information on Yellow Fever - information on yellow fever and vaccination from the Centers for Disease Control. Includes guidance on infection prevention, and on who should not be vaccinated. Also see the CDC's Division of Vector-Borne Infectious Diseases, and the yellow fever section of the Health Information for International Travel Yellow Book.

Expanded Programme on Immunization: Yellow Fever - article from the World Health Organization on efforts to vaccinate at-risk populations against yellow fever. Part of WHO's Global Programme for Vaccines and Immunization.

Traps for the Collection of Aedes aegypti and Aedes albopictus - descriptions and illustrations of traps designed specifically for the collection of Aedes aegypti and Aedes albopictus. Traps may be ordered online; pricing and additional information is provided.

Politicians Who Died of Yellow Fever - a chronological list of U.S. politicians who succumbed to yellow fever; includes brief information on their political careers and places of burial. From The Political Graveyard: A Database of Historical Cemeteries, "The Web Site That Tells Where the Dead Politicians are Buried."