Early assays including complement fixation, neutralization, and hemagglutination were fundamental to early viral diagnostic labs and made clinical laboratory diagnosis more accessible. With these key discoveries, Koch’s postulates gained new meaning as applied by T. M. Rivers for viral diseases (36).
Protection: the Case of Smallpox
The role of recovery from a first episode of an infectious disease in providing protection against another attack has been known for centuries. Characteristic traces of smallpox, pockmarks on the skin, were recognized as evidence of past infection and hallmarks of immunity to reinfection. Acute smallpox infection had to be distinguished from other viral exanthema such as measles. Rhazes, a Persian physician of the 10th century in Baghdad, wrote A Treatise on the Smallpox and Measles, which is regarded as a landmark in clinical description (34). Rhazes reported the symptoms that may precede the skin eruptions: “. . . a continued fever, pain in the back, itching in the nose, and terrors in sleep.” The authority of this treatise in Europe extended into the 17th century.
Two millennia before Rhazes, Ramses V died in 1157 BCE of what was assumed to be smallpox, and his body was mummified. Donald R. Hopkins recounts a remarkable episode in which he was granted permission by Egyptian president Anwar el Sadat to examine the front upper half of the unwrapped mummy in 1979 (19). After describing the rash of elevated “pustules,” Hopkins concluded that the appearance and distribution were “similar to smallpox rashes I have seen in more recent victims.” Hopkins, a physician who participated in the WHO Smallpox Global Eradication Programme, also wrote the classic treatise on the history of smallpox, Princes and Paupers. It was first published in 1983 and republished in 2002 with a new introduction as The Greatest Killer. While the exact origins of smallpox cannot be documented with certainty, it has been assumed that it arose millennia ago when aggregations of populations in towns and small cities emerged that supported epidemic spread.
The terror and dread occasioned by smallpox were well captured by the British historian Thomas Babington Macaulay in his History of England: “. . . the smallpox was always present, filling the churchyards with corpses, tormenting with constant fears all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover” (quoted in reference 10). Macaulay’s characterization of “all whom it had not yet stricken” is an implicit statement of the immunological protection of those “whose lives it spared.”
In contrast to lands where “the smallpox was always present,” populations in which smallpox had not previously existed were devastated on its first appearance. Nowhere, perhaps, is this more stunning and graphically illustrated than with its introduction into the western hemisphere—so stunning, in fact, that the American historian William McNeill began his seminal Plagues and Peoples asking how Hernando Cortez, with fewer than 600 soldiers, was able to conquer the Aztec empire of Mexico with its millions of inhabitants and later how Pizarro was able to conquer the Inca empire in South America (25). The scourge of smallpox nearly wiped out the previously unexposed Aztec and Inca populations, allowing Cortez easy victory over his diminished opposition. McNeill implicitly notes the role of immunological protection in that the Spaniards had the advantage of previous exposure to smallpox, whereas the Amerindians had not. He writes that smallpox was “. . . . a disease that killed only Indians and left Spaniards unharmed.” McNeill comments, “the lopsided impact of infectious disease upon Amerindian populations therefore offered a key to understanding the ease of the Spanish conquest of America—not only militarily but culturally as well.” Elsewhere on the North American continent, Francis Parkman wrote of a smallpox outbreak among the Huron Indians north of Lake Ontario in 1636: “Terror was universal . . . its ravages were appalling. . . . No house was left unvisited. . . . Everywhere was heard the wail of the sick and dying children” (quoted in reference 11). European history was also significantly influenced by smallpox: McNeill documents that smallpox altered the course of British political history. Hopkins termed the killing of kings, queens, an emperor, and a tsar in or around the 18th century “. . . a regicidal rampage without parallel . . .” (19). Thus, whole populations were devastated by smallpox in the New World, and leadership as well as the common people was destroyed in the Old World.
When the opportunity presented itself to offer protection against smallpox by inoculation with smallpox material, a practice known as variolation, it was accepted in some European nations more successfully than in others. The procedure had been known elsewhere, including nasal insufflation, in which scabs from a mild case of smallpox were blown into the nostril. It had been practiced in ancient China as “planting of flowers,” and inoculation had been known in India “since before the Christian era” (19). The campaign to bring inoculation against smallpox to England was waged by Lady Mary Wortley Montagu (Fig. 1), who first encountered it while in Turkey with her husband, the British ambassador. Lady Montagu was an English aristocrat, beauty, and intellectual who jousted with no less a figure than Alexander Pope, the 18th-century poet. In 1717 she wrote to a friend that “the smallpox, so fatal, and so general amongst us, is here entirely harmless, by the invention of ingrafting which is the name they give it.” Lady Montagu described the procedure and quoted the French ambassador as saying that it is taken “by way of diversion.” She went on to say in part that “I am patriot enough to take pains to bring this useful invention into fashion in England . . . (19).” Strong willed and intelligent, Lady Montagu was highly motivated with respect to smallpox. She had lost her brother to smallpox, and her own attack of smallpox had taken her beauty, leaving her with a pockmarked face. She had her own children inoculated, and on her return to England the royal family took note. The successful inoculation of the two daughters of the Prince of Wales in 1722 “began the firm establishment of inoculation as acceptable medical practice in England” (19). However, there was early resistance to the practice in France, for example, where it was officially accepted finally in 1769.
Figure 1 Lady Mary Wortley Montagu. Lady Montagu, an aristocrat of considerable intellectual sophistication and beauty, brought the practice of variolation against smallpox to England from Turkey. It consisted of inoculating smallpox material and preceded Jenner’s discovery of vaccination, the inoculation of cowpox to prevent smallpox. Lady Montagu is shown in a Turkish embellished costume with a jeweled turban in an illustration from The Letters of Horace Walpole. (Courtesy of the James Smith Noel Collection, Louisiana State University, Shreveport, LA.)
doi:10.1128/9781555818586.ch3.f1
The risks and benefits of inoculation against smallpox and the attitude change in the population from resistance to acceptance were nicely documented by John B. Blake for colonial Boston (5). In the epidemic of 1721, theological and political considerations complicated the medical concerns. The death rate rose to 105 per 1,000, while that for the whole period from 1701 to 1774, including the epidemic, averaged 35 per 1,000. Inoculation was introduced in Boston in the 1721 outbreak
