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The first human virus that was identified was the agent that causes yellow fever. The story of its identification in 1901 is instructive, as it highlights the contributions of creative thinking, collaboration, serendipitous timing, and even heroism in identifying new pathogens.

Although not recognized, yellow fever was widespread in tropical countries since the 15th century, and was responsible for devastating epidemics associated with extraordinary rates of mortality (for example, over a quarter of infected individuals died in the New Orleans epidemic of 1853). While the disease can be relatively mild, with transient symptoms that include fever and nausea, more-severe cases result in major organ failure. Destruction of the liver causes yellowing of the skin (jaundice), the symptom from which the disease name is derived. Despite its impact, little was known about how yellow fever was spread, although it was clear that the disease was not transferred directly from person to person. This property prompted speculation that the source of the infection was present in the atmosphere, and led to desperate efforts to “purify” the air, including burning barrels of tar and firing cannons. Some believed that the pathogen was carried on fomites, such as bedding or clothing, although this hypothesis was disproved when volunteers remained healthy after sleeping in the nightwear of yellow fever victims.

The first real advance in establishing the origin, or etiology, of yellow fever came in 1880, when the Cuban physician Carlos Juan Finlay proposed that a bloodsucking insect, most likely a mosquito, played a part in the transmission of the dis ease. A commission to study the basis of yellow fever was established in 1899 in Cuba by the U.S. Army under Colonel Walter Reed. This commission was formed in part because of the high incidence of the disease among soldiers who at that time were stationed in Cuba. Jesse Lazear, a member of Reed’s commission, confirmed Finlay’s hypothesis when he allowed himself to be bitten by a yellow fever virus-infected mosquito. “I rather think I am on the track of the real germ,” wrote Lazear to his wife, sadly just days before he died of yellow fever himself. The results of the Reed Commission’s study proved conclusively that mosquitos are the vectors for this disease. In retrospect, a mosquito-borne mode of transmission made sense, as the disease was predominantly found in warm and humid regions (e.g., Cuba, New Orleans) where mosquitos were, and remain, abundant. The members of this courageous team, perhaps the first true epidemiologists, are depicted in a dramatic 1939 painting (Fig. 1.1).

The nature of the pathogen was established in 1901, when Reed and James Carroll injected diluted, filtered serum from the blood of a yellow fever patient into three healthy individuals. Two of the volunteers developed yellow fever, leading Reed and Carroll to conclude that a “filterable agent,” which we now know as yellow fever virus, was the cause of the disease. In the same year, a professor at the University of Havana attempted to produce immunity by exposing volunteers to mosquitos that were allowed to take a blood meal from an individual who showed signs of yellow fever. Of 19 volunteers, 8 contracted the disease, and 3 died. One of the deceased was Clara Louise Maass, a U.S. Army nurse. Maass’s story is of interest, as she had volunteered to be inoculated by infected mosquitos some time before, developed only mild symptoms, and survived. Her agreement to be infected a second time was to test if her earlier exposure provided protection from a subsequent challenge. This was a prescient idea, because at that time, virtually nothing was known about immune memory, which is the underlying principle of vaccines. Maass’s death prompted a public outcry and helped to end yellow fever experiments in human volunteers.

Figure 1.1 Conquerors of yellow fever. This painting by Dean Cornwell (1939) depicts the experimental exposure of James Carroll to infected mosquitos. Walter Reed, in white, stands at the head of the table, while Jesse Lazear applies the infected mosquitos to Carroll’s arm. Also depicted in this painting is Carlos Finlay, in a dark suit. Despite the care that Cornwell took to ensure accuracy of his portrayal of the participants and their uniforms, the event documented in this painting never took place; rather, artistic license was used to place all the major players in one depiction of a watershed moment in medical history. Courtesy of the Cornwall Historical Society, accessed April 1, 2020, http://www.cornwallhistoricalsociety.org/omeka/items/show/241.

Yellow fever had been endemic in Havana for many years, but the conclusions of Reed and his colleagues about the nature of the pathogen, and the vector that transmitted it, led to rapid implementation of effective mosquito control measures that dramatically reduced the incidence of disease within a year. To this day, mosquito control remains an important method for preventing yellow fever, as well as other viral diseases transmitted by arthropod vectors (Box 1.2).

Other human viruses were identified during the early decades of the 20th century (Fig. 1.2). However, the pace of discovery was slow, in great part because of the dangers and difficulties associated with experimental manipulation of human viruses so vividly illustrated by the experience with yellow fever virus. Consequently, agents of some important human diseases were not identified for many years, and then only with some good luck.

A classic example is the identification of the virus responsible for influenza, a name derived in the mid-1700s from the Italian language because of the belief that the disease resulted from the “influence” of contaminated air and adverse astrological signs. Worldwide epidemics (pandemics) of influenza had been documented in humans for well over 100 years. Such pandemics were typically associated with mortality among the very young and the very old, but the 1918–19 pandemic following the end of World War I was especially devastating. It is estimated that one-fifth of the world’s population was infected, resulting in more than 50 million deaths, far more than were killed in the preceding war. Unlike in previous epidemics, healthy young adults were often victims (Fig. 1.3).