diseases in animals in the 18th and 19th centuries involved agents of agricultural import—cattle plague (rinderpest), foot-and-mouth disease, bovine pleuropneumonia, and glanders—and established the basis for comparative medicine, the study of human diseases in animals (68). Rabies straddled human and animal medicine.
Rabies is horrific in all aspects: in the savage bites by crazed wolves or dogs to implant infection, in the anxiety and fear in anticipation of whether the disease will develop, in the torturing expression of the acute disease, and in the knowledge that once expressed, rabies is an essentially fatal disease. The fear induced by the approach of a rabid dog was used to good effect in Harper Lee’s To Kill a Mockingbird: “. . . motivated by an invisible force that was inclining him toward us. We could see him shiver like a horse shedding flies; his jaw opened and shut; he was alist, but he was being pulled gradually toward us” (35) (Fig. 1). Accounts of terrifying attacks by rabid wolves in country villages have played a role in the development of treatment. It has often been cited that one of the motivations for Pasteur’s study of rabies was a childhood memory of a rabid wolf attack on the village of Villers-Farlay and the town of Arbois (21) (Fig. 2). It was reported that Pasteur was 8 when he listened in horror to the screams of victims who had come to a blacksmith’s shop for “treatment”—cauterization. In 1886, soon after Pasteur’s publicity spread worldwide concerning postexposure prophylaxis treatment of rabies, 19 Russians came to Paris seeking treatment. In the cases of two victims of a rabid wolf’s attack, one had a lip and cheek bitten off, and the other’s face had been ripped off. Of the 19, 3 died during treatment and 16 ultimately returned to Russia (11). In 1955, the WHO, reporting on the use of hyperimmune serum and vaccine, described the effects of a rabid wolf’s attack on an Iranian village (2). Twenty-nine persons were bitten, 18 with severe head wounds, including a 6-year-old boy in whom a skull bone was crushed and the dura mater covering of the brain slashed. Remarkably, 25 of 29 wounded survived, including the young boy, who received intensive treatment with hyperimmune serum and vaccine.
Figure 1 Mad Dog. The fear of rabid dogs has been portrayed throughout history. This caricature by T. L. Busby was published in London in 1826. (Courtesy Yale University, Harvey Cushing/John Whitney Medical Library.)
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Figure 2 Louis Pasteur. Pasteur was one of the principal founders of germ theory. He disproved the theory of spontaneous generation; linked agricultural, animal, and human diseases to specific infections; and developed vaccinations, including that to prevent rabies. (Courtesy of the National Library of Medicine.)
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Rabies in humans may start after an incubation period of weeks or months with itching at the site of the bite and growing apprehension. Thereafter, aerophobia and hydrophobia may develop. The description of hydrophobia by D. A. Warrell et al. serves well: “The patient picks up a cup to drink but, even before the liquid has reached his lips, his arm begins to shake, he takes a rapid succession of inspiratory gasps, his neck muscles are seen to contract forcibly, and the spasm ends with throwing away his cup and falling back with neck extended” (64). Death ensues after periods of marked agitation and fearfulness alternating with lucidity. It is no wonder that rabies attracted attention out of proportion to its incidence.
In studies of rabies transmission to animals, several experimental aspects were considered and refined, many by Pasteur and his colleagues on the road to producing a postexposure vaccine. One was the type of inoculum, infected central nervous system (CNS) tissue. Other crucial considerations were the animal species used and the route of inoculation.
In 1821, F. Magendie reported the transmission of rabies from a sick person to a dog by injecting saliva beneath the skin (39). Magendie reported that the dog became rabid in about a month. This appears to be the first acknowledged transmission of rabies from a human to an experimental animal (69). Use of the dog as the test animal, while logical as the original species tested, is dangerous because the “furious” type of rabies is expressed. The indiscriminate and aggressive biting presented very significant risks to experimenters. In contrast, a more tractable model, expressing “dumb” or paralytic rabies, would have much to recommend it. Another distinct weakness of the model as first employed was the long and variable period of incubation before disease expression. Pasteur and his colleagues would later address that issue, modifying the nature of the inoculum and route of delivery in a different host.
Great progress in the development of an experimental rabbit model was achieved by M. Galtier, who held the chair of pathology in the veterinary school at Lyons, France (68). In 1879, he reported that rabies in the dog could be transmitted to the rabbit and could be serially transmitted from rabbit to rabbit (20). Significantly, he found that the predominant symptoms in the rabbit were paralysis and convulsions, hence of much less risk to the experimenter than the furious biting behavior of the infected dog. Galtier reported that once the disease declared itself, the rabbit was able to live for 3 or 4 days, thereby facilitating further observations and transmission studies as well as an accurate demonstration of positive transmission. Of great importance as a model, the rabbit revealed a shorter incubation period than other species: the peak onset of illness in 25 cases occurred between 13 and 23 days. Thus, the rabbit model had been well characterized in Galtier’s hands by 1879, before Pasteur and his associates launched their epic work. From an examination of Pasteur’s laboratory notebooks, Gerald L. Geison confirmed that Pasteur’s work on rabies began at the end of the following year, 10 December 1880, to be precise (21). Pasteur’s laboratory notebooks, numbering over 100, had become available to scholars at the Bibliothèque nationale (National Library of France) in the 1970s, so Galtier’s priority in establishing and refining the rabbit model could be verified (21). Patrice Debré, a biographer of Pasteur, suggested that Galtier had been considered for the Nobel Prize in 1908, but he died before the award decision, precluding the honor (11).
Galtier had also attempted, without success, transmission of rabies by CNS tissue. However, Henri Duboué, a Paris physician, found otherwise. According to Debré, Duboué wrote to Pasteur in January 1881 that the “‘morbid agent’” traveled to the medulla oblongata from the site of the bite (11). Vallery-Radot’s biography of Pasteur confirmed the theory of Duboué but indicated that it was unsupported by experimental evidence (63). It remained for Pasteur and his colleagues, notably Emile Roux, to exploit the CNS aspects of the model. The goal was to shorten the period of incubation and to achieve full
