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  Chapter 2 History of Immunology
     Pauline M. H. Mazumdar
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The earliest known smallpox inoculation took place in China, perhaps as early as the 5th century . The Chinese method was reported to the Royal Society by an English merchant, John Lister, in 1700. A Jesuit priest, Father d’Entrecolles (2), provided details of the method, which he said was to collect scabs from the pustules, and blow a powder made from them into an infant’s nose. The scabs or a thread imbibed with the pus could be stored, but the operation was usually done face-to-face with a sick patient. The same method was used in Japan beginning in 1747. In precolonial India, a tika or dot would be made on a child, usually on the sole of the foot, by traditional tikadars who were invited into a home (this professional niche was later blacklisted by colonial-era medical practitioners). The Turkish method was communicated to the Royal Society by Dr. Emmannuel Timoni in 1714. As commonly practiced in Constantinople, a small perforation was made in the skin, and a spot of pus from a benign case introduced with a needle. In 1715, the method famously came to the notice of Lady Mary Montagu, wife of the English ambassador in Constantinople, who used it on her own son, and subsequently talked it up to great effect in aristocratic circles at home in England (3). Although nationalistic, ethical, and religious objections to this non-European folk practice abounded, the Royal Society with its interest in the empirical recorded many accounts of inoculation presented at its meetings. Dr. James Jurin, its secretary, an early user of the quantitative method, collected large numbers of cases in an effort to compare the risks from inoculation and from the disease. According to his figures, smallpox was both universal and often fatal: He assumed that almost everyone over the age of 2 had had it, and for every person who died, 7 or 8 recovered; inoculation, on the other hand, had a death rate of about 1 in 50. He had not, he said, been able to learn of any person either in England or Turkey, who had been inoculated but still took the disease in the natural way (4). The mathematician Daniel Bernoulli calculated similarly that if one neglected the point of view of the individual, inoculation would be useful to the state. In 18th-century France, according to Anne-Marie Moulin, the method was discussed, for instance by the Encyclopédistes, but not practiced; it was made illegal by a decree of 1763, and only permitted after the revolution. In England, on the other hand, it seems possible that it was used often enough by the end of the 18th century to affect the incidence and severity of smallpox (5).

The use of Vaccinia (cowpox) as inoculum was suggested several times in the late 1700s; the country doctor and inoculator Edward Jenner tried it out in 1798. He had heard it said that milkmaids who had had cowpox, never caught smallpox, and it struck him that he might be able to propagate the disease as he was accustomed to do with his usual inoculum. It is not clear whether in practice the material actually used was always Vaccinia (6). Vaccine production was unregulated; the operation was painful and sometimes did not "take." Nevertheless, public health authorities enforced it, for example, in Prussia and later under the British Compulsory Vaccination Act of 1853. Compulsion led to worldwide antivaccination movements with strong political and anticolonial overtones (7). However, the demographer Alex Mercer makes a strong case for its effectiveness: He argues that inoculation and subsequently vaccination were key in the general decline in death rates that took place from the late 18th through the 19th century, as the incidence of smallpox declined. With it went a network of linked respiratory diseases, late sequelae of the damage done by smallpox even when not fatal (8).

It should not be supposed, however, that because vaccination was accepted, an immune theory of disease resistance was an obvious conclusion. The experience of colonial troops in the tropics, where most of them died within a year or two of arrival throughout the 18th and 19th centuries, prompted a racial view of resistance, coupled with the development of acclimatization or seasoning in those few who survived. The constitution of the alien race soon broke down in the unfamiliar conditions of temperature and humidity; the expatriates felt themselves weakened by perspiration, tight clothes, and local miasmas that did not seem to affect the natives. There is a large 19th-century literature advising the displaced European on how to survive a posting to India, the Caribbean, or the Philippines, and on the tragic return home of the soldier or sailor broken in health by the tropics (9). The importation of Africans to work as slaves in the conditions that were so fatal to Europeans and white Americans was one of the results of the racial view of disease resistance. A theory with such significant historical connotations cannot be ignored (10).

The word vaccine originally applied only to Vaccinia. Anne-Marie Moulin points out that it was Louis Pasteur, who by claiming Jenner as his predecessor, metaphorically included in that word all prophylactic inoculation by attenuated virus-vaccins, organisms attenuated by passage through another species or by treatment with oxygen or antiseptics (11). Vaccines were prepared in this way against anthrax (1881), which was then a common agricultural problem, and rabies (1885) a frighteningly fatal result of the bite of a rabid animal. These vaccines were dramatically effective, although it was never clear whether the victim of a dog bite had in fact been infected. They led to a flood of donations from a hero-worshipping public, with which the Institut Pasteur was established in 1888.

In 1891, Robert Koch too had a dramatic announcement, which also paved the way for the establishment of an institute under his direction. "Koch’s lymph" was a cure for tuberculosis, raising the hopes of sufferers who rushed to Berlin to be treated by the man who had discovered the tubercle bacillus. The reaction was acute and sometimes quite harmful to the patients, and the results were certainly not as good as expected. But it was not the debacle that has sometimes been thought. Koch’s Old Tuberculin continued to be made until the 1940s for use as a treatment for chronic tuberculosis of bones, lymph nodes, and skin. The material was a protein extract of tubercle bacilli, which Koch regarded as an exotoxin similar to that produced by diphtheria bacilli. It was later used under the name of the Mantoux reaction as a skin test for tuberculosis (12).

In 1896, Sir Almroth Wright of St. Mary’s Hospital in London and Richard Pfeiffer and Wilhelm Kolle in Berlin simultaneously prepared a vaccine against typhoid, an important disease in Europe and the colonies. Like the smallpox vaccine, it was very promising, but was attacked passionately by antivaccinationists. Their position was primarily political and ideological, but typhoid was a water-borne infection, and it was argued that improvements in sanitation and water supplies would eventually make vaccination unnecessary. Hostility focused on Wright’s vaccine especially; it made its recipients feel very ill, and its effectiveness was statistically doubtful. Sir William Leishman of the Royal Army Medical Corps developed a vaccine incorporating typhoid and the newly defined paratyphoids A and B in 1909. Armies in France, Germany, and the United States were beginning to use the newer type, but in Britain compulsion was politically unacceptable, and when World War I came, the Royal Army Medical Corps depended upon pro-vaccination propaganda. As acceptance of the vaccine increased among the troops, the results became more obvious: Compared to dysentery, a disease that was similarly transmitted through infected water supplies, the numbers of enteric cases reported in the field fell steeply (13). Attempts to develop a dysentery vaccine were unsuccessful.

In the 1880s, germ theory had started to sound persuasive (14). In 1883, the Russian zoologist Élie Metchnikov had suggested that white blood cells attacked invaders from outside the body, an idea based on the Darwinian concept of interspecies struggle for existence, and which he saw as a form of "physiological inflammation" (15). Pasteur liked Metchnikov’s idea, and invited him to Paris. Alfred Tauber sees Metchnikov’s phagocytosis theory as the foundation of the self-not self concept, later to be central to immunology, and thinks that Metchnikov should be regarded as having founded the discipline (16). But as Anne-Marie Moulin points out, Metchnikov’s phagocytes had neither specificity nor memory; they simply engulfed particles (17).

In the first half of the 20th century, the practical aspects of immunity, vaccination, and serum therapy defined research in the field. Serology and immunochemistry strove to provide a theoretical basis for these practices. Mechnikov’s phagocytosis theory was briefly at center stage but was soon overtaken by a rush of publications from Koch and colleagues in Berlindthe Franco-Prussian war of 1870 was still being fought by other means (18). As bacteriologists, the Berlin group favored "humoral immunity" in preference to cellular: They focused on immune sera for their specificity to identify bacteria, and ignored the cells, which seemed to carry a taint of old-fashioned vitalism.

Cell-based vaccination systems, however, were to prove popular and very lucrative for their producers, especially in France. At the Institut Pasteur, Metchnikov’s lineage of workers in the cellular style continued to flourish. Alexandre Besredka came to Paris in 1893; he was from Odessa, like Metchnikov, and found work in Metchnikov’s laboratory. In 1918, he succeeded Metchnikov at its head. His interest centered on the then newly described phenomenon of anaphylaxis (19). He was concerned with sensitization and desensitization of the skin, an interest that was to evolve into his studies of natural resistance and acquired localized immunity. He proposed a system of specific dressings or local injections of a prepared antigen, a parallel to the local injections that desensitized animals to anaphylactic shock. The "terrain," the skin cells that allowed entry to the infection, was to be made resistant (20). Besredka’s co-worker, Michel Bardach, was also from Odessa. He began work on an anti-reticuloendothelial serum along the lines suggested by a Russian researcher, Alexander Bogomoletz, who claimed that his serum was effective in a broad range of diseases involving that system. After World War II, the serum was successfully and profitably marketed through the Institut Pasteur as a nonspecific stimulator of immunity, only to be abandoned in the 1950s as ineffective, perhaps by contrast with the stunning success of penicillin.

A rather similar cell-based system had been developed in England. Sir Almroth Wright, originator of an early typhoid vaccine, linked cells with serum in an effort to boost immunity by the preparation of autovaccines from a patient’s own lesion; they were thought to raise a patient’s serum "opsonic index," and like Bardach’s serum at a later date, to stimulate phagocytosis (21). Wright’s slogan of 1909, "The physician of the future will be an immunisator," seems to have been perfectly true for the first decades of the 20th century (22). Wright’s department at St. Mary’s Hospital London made autovaccines and carried out thousands of index measurements yearly between 1908 and 1945. He built up a practice on a huge, even industrial, scale, out of which the department and the hospital itself were financed. As Wei Chen has commented, his laboratory was a vaccine factory, profitably manufacturing typhoid vaccine as well as the autovaccines that were Wright’s specialty (23). The effectiveness of autovaccine therapy, like the effectiveness of his typhoid vaccine, was attacked by the statisticians. Even so, laboratory texts until the mid-1940s generally included a chapter on the technique of preparing an autovaccine (24). Wright’s student George Ross carried both antityphoid and autovaccine manufacture with him to Canada in 1907, to an appointment at the Toronto General Hospital, where his techniques established and funded a new laboratory-based Department of Immunization and Medical Research, a precursor to the Connaught Laboratory, Toronto’s serum institute (25). The use of Wright’s autovaccines, along with Koch’s Old Tuberculin, persisted more or less up to the appearance of penicillin on the therapeutic scene in 1945, when all such minimally effective treatments were swept away by the brilliance of the first antibiotics. Wei Chen has suggested that Wright’s vaccine program provided a model and a financial goal for his junior colleague Alexander Fleming’s "construction" of penicillin. She shows that penicillin was initially seen as a means of differentially culturing Bacillus influenzae from cases of influenza, and supporting Wright’s claim that a vaccine made from that bacillus would be useful in the disease (26).

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