Although the pandemic of 1918–1919 was shattering on a global scale, “The first pandemic of influenza in the bacteriological era,” according to Richard Shope, “was that of 1889–1890” (56) (Fig. 6). During that epidemic, R. Pfeiffer isolated the bacillus Haemophilus influenzae (48). Pfeiffer held that the bacillus was present in cases associated with influenza but not in other individuals. John R. Mote reviewed the literature disputing this view but nonetheless assented that “. . . Pfeiffer’s bacillus was for years considered by many workers to be the cause of epidemic influenza” (42). As Patrick Playfair Laidlaw described in his Linacre lecture, H. influenzae “. . . had held an almost undisputed position since the end of the pandemic 1899–1890” (31).
Figure 6 L’influenza à Paris. This cover is from a Parisian weekly in 1890 during the influenza pandemic of 1889–1890. Originating in Russia and spreading westward, influenza became known as “Russian flu.” The cover depicts four scenes relating to the epidemic in Paris (clockwise from top left): a tent set up in a hospital courtyard, the interior of tent ward for the sick, the distribution of clothes to families of victims, and two men singing a new song, “L’influenza, tout l’monde l’a!” (“Influenza, Everyone Has It!”). (Courtesy of the National Library of Medicine.)
doi:10.1128/9781555818586.ch2.f6
The accepted ethical norms of disease investigation in humans seemed to be suspended when the influenza pandemic of 1918–1919 came toward the end of World War I. Historically, wartime overthrew many usual constraints on the study of illness. As the science writer Gina Kolata put it, “But in 1918, such ethical arguments were rarely considered. Instead, the justification for a risky study with human beings was that it was better to subject a few to a great danger in order to save the many” (30). Negative studies with sailors in Boston, MA, and San Francisco, CA, were recounted by Kolata: intense exposure of presumed susceptible subjects to infected persons and their mucus, blood, exhalations, and coughs failed to induce the disease. While other groups of investigators appeared to have some success, the results were not consistent enough to reach a conclusion. As expressed by Laidlaw, one of the investigators who successfully transmitted influenza to ferrets, “One can never be sure that the experimental subject is susceptible and therefore negative results can be discounted; while positive results, though perhaps more significant, are always open to the suspicion that infection was picked up in some accidental manner” (31).
Attempts to transfer the illness to animals that had proven susceptible to other human viral pathogens were inconclusive (42). Monkeys, rabbits, guinea pigs, and mice were among those tested. Mote’s compilation serves to emphasize the importance of at least three experimental variables: the material transmitted, blood versus sputum or throat washings; the site of transmission, intraperitoneal versus intranasal; and the susceptibility of the host. No clear etiological agent emerged from the 1918–1919 influenza pandemic. It was not until the study of swine influenza in two epizootics in 1928 and 1929 in Iowa by Richard Shope and Paul Lewis of the Department of Animal Pathology of the Rockefeller Institute at Princeton, NJ (36, 54, 55), that a new story began to emerge.
Swine influenza had been recognized during 1918–1919 by J. S. Koen of the U.S. Bureau of Animal Industry. According to Richard Shope’s review in 1958, Koen recognized in swine similarities in prevalence and symptoms to human influenza, but he was criticized for calling it “flu” (56). The objections were economic and arose from a fear that the swine-flu connection would turn away the public from the consumption of pork. The epizootic in pigs was massive, with millions becoming sick and thousands dying. Recognizing the annual recurrence and enormity of the epizootics with such devastating economic consequences, Shope and Lewis began in earnest their investigations in 1928.
What they uncovered, reported in 1931 in a series of three articles in the Journal of Experimental Medicine, was quite remarkable (36, 54, 55). They discovered two agents working synergistically to produce the disease, with neither producing severe disease on its own. The first organism, very much like the Pfeiffer bacillus, was named Haemophilus influenzae suis and failed to induce experimental disease by itself. The second organism, a newly recognized filterable virus, induced a milder disease in experimental pigs than seen on pig farms. The more severe disease in swine resulted when the two agents were administered simultaneously. It later emerged in the report by Wilson Smith, C. H. Andrewes, and Patrick Playfair Laidlaw that the human and swine influenza viruses were antigenically closely related (57). As Shope put it, “. . . despite the failure of human investigators of the 1918 influenza pandemic to discover the cause of the outbreak, Mother Nature, using swine as her experimental animals, had done so” (56). Shope reported that he and Laidlaw independently reached the conclusion of the “. . . likelihood that swine had indeed acquired their infection from man in 1918. . . .”
Prior to his work with Smith and Andrewes in which the virus of human influenza was isolated in ferrets, Laidlaw had collaborated with S. W. Dunkin on the experimental study of canine distemper in ferrets (13–15). The work was conducted at the National Institute for Medical Research Farm Laboratories, Mill Hill, London, United Kingdom, where thorough procedures were employed to prevent exogenous infection of experimental animals. The reasons to use the ferret were that it could “be confined in a small space with ease and comfort” and that keepers claimed that ferrets were very susceptible to dog distemper, which could wipe out an entire breeding colony. Hence, special buildings, cages, personnel practices, and experimental procedures to study ferrets were well established at Mill Hill by the 1920s. In developing the ferret model under such controlled conditions, Laidlaw and Dunkin successfully showed experimental transmission of canine distemper virus to the ferret with overt expression of clinical and pathological features of disease. They demonstrated the disease to be caused by a filterable virus, not by the bacterium Bacillus bronchisepticus (Bordetella bronchiseptica), which they characterized as a secondary invader (15). When influenza appeared again in London in 1933, “The ferret obviously was the animal to test for susceptibility to influenza. . . .” (6). Laidlaw’s team was the right group to perform the studies to isolate a filterable agent.
Isolation of human influenza virus in ferrets, reported in the 8 July 1933 issue of The Lancet by Smith, Andrewes, and Laidlaw, was a signal event in the history of
