In the case of vitamin deﬁciency diseases, preventive measures were available long before effective means of control were adopted. A similar case can be made for the prevention of smallpox, a viral disease. At least in theory, smallpox could have been eradicated by the methods avail- able at the beginning of the nineteenth century. But smallpox was not attacked on a global scale until the second half of the twentieth century, when the costs of protecting wealthy nations from the disease exceeded the costs of eliminating the disease from the world’s poorest countries.
Variola, the smallpox virus, is a member of the orthopoxvirus family, which includes cowpox, buffalopox, camelpox, swinepox, gerbil- pox, and monkeypox. The origin of smallpox is unknown, but epidemi- ologists suggest that it might have evolved from one of the poxviruses of wild or domesticated animals. Based on the characteristics of the pox- viruses and genomic sequencing, virologists have suggested that small- pox and the other poxviruses might have evolved from a common ancestral virus whose natural host was a rodent. Several forms of variola, which differ in virulence, have been characterized. The complete genome of vaccinia, the virus used in vaccines that provide protection against smallpox, was decoded in 1990. Four years later, scientists established the complete genetic code of one of the more virulent strains of variola. Despite the marked differences in virulence of the two viruses, vaccinia and variola are remarkably similar in terms of their DNA sequences. Unlike most viruses, the smallpox virus is quite stable outside its host and can retain its powers of infectivity over fairly long periods of time. Typically, the disease spreads from person to person by droplet infection; however, the virus may also be transmitted by clothing, blankets, or shrouds contaminated with pus or scabs. After a person is exposed, the virus multiplies rapidly and spreads throughout the body. Following an incubation period of about 14 days, there is a sudden onset of ﬂu-like symptoms, including fever, aches and pains, coughing, sneezing, and fatigue. At this stage an accurate diagnosis is almost impossible, because many illnesses begin with fever, aches, sneez- ing, nausea, and fatigue.
A few days later ﬂat, red vesicles appear, ﬁrst in the mouth and throat, then on the face, and ﬁnally on the arms, legs, palms, and soles. The vesicles turn into pus-ﬁlled blisters, which eventu- ally dry out as scabs form, but in some cases the whole body is covered with a bloody rash. Other patients might, according to Sir William Osler, become a ‘‘dripping unrecognizable mass of pus,’’ suffering from delirium due to high fever and giving off a putrid, stiﬂing odor. Septic poisoning, broncho-pneumonia, cardiovascular collapse, scars, blind- ness, and deafness were not uncommon complications, but the worst form of the disease, known as black or hemorrhagic smallpox, was almost always fatal. Presumably, smallpox smoldered in obscurity for centuries among the innumerable local fevers of Africa or Asia until changing patterns of human migration, warfare, and commerce carried the disease to Persia and Europe, Central Asia, and China. Characteristic scars on the mummy of Ramses V (d. 1157 B.C.E) and the existence of Indian and African deities devoted to smallpox suggest the antiquity of the dis- ease. By the seventeenth century, smallpox was greatly feared in Europe as ‘‘the most terrible of all the ministers of death.’’ In his Essay on Fevers (1750), John Huxham (1692–1768) noted the great variability in the form and severity of smallpox, even within the same village, household, and family.
In some cases the pocks were mild and distinct; in others they were highly malignant and nearly conﬂuent. Moreover, Huxham noted that some people visited the sick in order to acquire the disease at a propitious time, but remained well; then, after congratu- lating themselves on escaping infection, they contracted the disease from an unknown source months or years later. Even though smallpox is considered highly contagious, it is still all but impossible to predict how many of the people who have been exposed to a person with small- pox—in the sickroom or ‘‘downwind’’ in an airport terminal—will actu- ally become infected. While mortality rates for smallpox were usually about 15 to 25 per- cent, during some epidemics 40 percent of those who contracted the dis- ease died. Smallpox, along with diarrhea, worms, and teething, was one of the inevitable crises of childhood; about 30 percent of all English chil- dren died of smallpox before reaching their third birthday.
No medicine can cure smallpox once the infection is established, but ever since the ninth century, when Rhazes separated smallpox and measles from other eruptive fevers, physicians have added to his ingenious prescriptions. Some physicians recommended opening the vesicles with a golden nee- dle, while others prescribed a dressing of horse or sheep dung for small- pox and goat manure for measles. A few skeptics warned that the physician’s ministrations might be more dangerous than the disease. Unable to afford the services of a physician, peasants in many parts of Europe attempted to protect their children by deliberately exposing them to a person with a mild case in order to ‘‘buy the pox’’ under favor- able conditions. (Members of those antediluvian generations that grew up before routine immunization against measles, mumps, and rubella may remember similar attempts to get children to catch these inevitable childhood diseases at a favorable time.) Some folk practices, however, involved methods more daring than passive exposure. Ingrafting or variolation, for example, required taking fresh material from smallpox pustules and inserting it into a cut or scratch on the skin of a healthy per- son. In China, children were exposed to the ‘‘ﬂower-blossom disease’’ by making them inhale a powder made from the crusts of smallpox scabs. Experience taught folk practitioners in Africa, Asia, India, and Turkey that deliberately exposing patients to a signiﬁcant risk at a propitious time provided long-term beneﬁts. Learned physicians, in contrast, gener- ally dismissed these practices as barbaric and superstitious. During the eighteenth century, increasing interest in natural curiosities led to closer scrutiny of many ancient folk practices, including inoculation or vario- lation. (The term inoculation comes from the Latin inoculare, to graft; variolation comes from variola, the scholarly name for smallpox.) Credit for transforming the so-called Turkish method of variolation from a curious ‘‘heathen custom’’ into a fashionable practice among the English elite is traditionally ascribed to Lady Mary Wortley Montagu (1689–1762), but some historians argue that the tribute to Lady Mary is more romance than history. Appropriately enough, the story begins with the elopement of Mary Pierrepont and Edward Wortley Montagu. In 1718, Lady Mary accompanied her husband to the Turkish Court at Constantinople, where he served as Ambassador Extraordinary. Among all the curious customs the inquisitive Lady Mary observed in Turkey, the practice of variolation was especially intriguing.
In letters to friends in England, Lady Mary described how people wishing to ‘‘take the smallpox’’ arranged to share a house during the cool days of autumn. An inoculator brought a nutshell full of matter from the very best sort of smallpox and inserted some of it into scratches made at appropriate sites. About eight days after the operation, the patients took the fever and stayed in bed for a few days. To demonstrate her faith in the pro- cedure, Lady Mary arranged to have the operation performed on her six-year-old son. Charles Maitland, the ambassador’s physician, and Emanuel Timoni (d. 1718), the Embassy surgeon, were present when young Edward was variolated by an old woman with a rather blunt and rusty needle. Timoni had already published an account of the Turk- ish method of procuring the smallpox in the Philosophical Transactions of the Royal Society (1714). A similar report by Giacomo Pylarini (1659–1718) appeared in the same volume of the journal. These descriptions of the practice, published in Latin, were written for physicians, whereas Lady Mary wrote in English for a general audience. During the smallpox epidemic of 1721, Lady Mary was back in London. When she insisted on inoculating her four-year-old daughter, Maitland demanded that several physicians be present as witnesses. According to Lady Mary, the physicians observing the inoculation were so hostile she was afraid to leave her child alone with them. Neverthe- less, after the pox erupted, one of the physicians was so impressed he had Maitland inoculate his only surviving child (all the others had died of smallpox). Clergymen and physicians immediately launched an ava- lanche of pamphlets and sermons condemning the Turkish method. In a particularly vicious attack, the Reverend Edmund Massey denounced inoculation as a dangerous, atheistic, malicious, and sinful practice invented by the Devil. According to Reverend Massey, diseases were a form of ‘‘happy restraint’’ sent into the world by God to test our faith and punish our sins. God might sometimes give man the power to treat diseases, but the power to inﬂict them was His own. Reverend Massey feared that members of his ﬂock might be less righteous if they were more healthy and less afraid of smallpox. In response to attacks on ingrafting, Lady Mary published ‘‘A Plain Account of the Inoculating of the Small Pox’’ so that ordinary people who were being ‘‘abused and deluded by the knavery and ignorance of physicians’’ could learn about the methods practiced in Constantinople. Emphasizing the loss of fees that physicians would suffer if smallpox were eliminated, she argued that physicians considered the Turkish method a terrible plot to reduce their income. A funeral monument for Lady Mary in Lichﬁeld Cathedral, erected in 1789, praised her for introducing her country to the beneﬁcial art of smallpox inoculation. Another advocate of inoculation, the Reverend Cotton Mather (1663–1728), minister to the Second Church of Boston, also became inter- ested in inoculation on learning of its use among ‘‘primitive, heathen’’ people.
The indefatigable New England clergyman was the author of about 450 pamphlets and books, a corresponding Fellow of the Royal Society of London, and the victim of a series of personal tragedies, including the deaths of two wives, the insanity of a third wife, and the loss of 13 of his 15 children. John Cotton and Richard Mather, Cotton Mather’s grandfathers, and his father, Increase Mather (1639–1723), were prominent spiritual leaders. Increase Mather was also president of Harvard College, from which Cotton earned his baccalaureate when he was 15 and his master’s degree three years later. Insatiable curiosity, as well as an obsession with ‘‘doing good,’’ drove Mather to seek knowledge of medicine and explanations for the ‘‘operations of the invisible world’’ from unortho- dox sources, including Africans, Turks, dreams, and apparitions. In The Angel of Bethesda, a medical treatise that was not published until 1972, Mather suggested that the ‘‘animated particles’’ revealed by the microscope might be the cause of smallpox. To maintain a sense of balance, we must also recall Mather’s ambiguous role in the Salem witchcraft troubles, and his conviction that while sheep ‘‘purles’’ were medicinal, human excre- ment was an unparalleled remedy. By the time John Winthrop’s ﬂeet of 17 ships set out for New England in 1630, smallpox had already exerted a profound effect on the peoples of the New World.
The Spanish conquistadors had found smallpox a more powerful antipersonnel weapon than gunpowder. Colonists in North America discovered that the impact of smallpox on Europeans was modest in comparison to the devastation it caused among Native Americans. Seventeenth-century settlers referred to the terrible toll smallpox took among the Indians as another example of the ‘‘wonder-working providences’’ by which God made room for His people in the New World. Of course even Old World stock was not exempt from the threat of smallpox. When the disease struck Boston, a city of about 12,000 inhabitants, in 1721, prayers, fast days, quarantines, and travel bans failed to halt the epidemic. Almost half the people of Boston contracted smallpox; of those who were infected about one in seven died. During this outbreak, Mather initiated the test of inoculation he had been planning since he had learned of the practice. Reverend Mather ﬁrst heard about inoculation from a young African slave given to him by members of his congregation; Mather named the young man Onesimus.
When Mather asked Onesimus if he had ever had smallpox, the young man showed him a scar on his arm and explained that in Africa people deliberately exposed themselves to a mild form of smallpox in order to avoid the more dangerous natural form. Therefore, when Mather read Timoni’s account of inoculation in the Philosophical Transactions of the Royal Society, he immediately accepted it as conﬁrmation of what he had previously learned from Onesimus. Mather was convinced that he could rid the New World colonies of smallpox if only he could secure the cooperation of the doctors. When smallpox appeared in 1721, Mather sent out letters to Boston’s doctors asking them to hold a consultation concerning inoculation. Imbued with a ﬁrm sense of ministerial privilege, duty, and author- ity, Mather saw no impropriety in offering advice to townspeople and medical men, but many New Englanders resented his interference. The most dramatic statement of displeasure consisted of a granado (ﬁre bomb) thrown through the pastor’s window. By the Providence of God the device failed to explode, allowing Mather to read the attached note: ‘‘COTTON MATHER, You Dog, Dam you, I’ll inoculate you with this, with a Pox to you.’’ Many proper Bostonians agreed with the senti- ments expressed by the mad bomber and rejected Mather’s bizarre ideas about smallpox, whether they came from African slaves, heathen Turks, or the Royal Society. Of all the physicians Mather appealed to, only Zabdiel Boylston (1680–1766), a practitioner whose medical training consisted of a local apprenticeship, was willing to test the efﬁcacy of inoculation. On June 26, 1721, Boylston tried the experiment on his own 6-year-old son, a 2-year-old boy, and a 36-year-old slave.
The operation was successful. After performing more than two hundred inoculations, Boylston con- cluded that variolation was the most beneﬁcial and effective medical innovation ever discovered. Nevertheless, as word of these experiments spread, Boston became a true ‘‘hell on earth’’ for Mather and Boylston. Bostonians were shocked and alarmed by these unprecedented experi- ments; physicians denounced Mather and Boylston for imposing a dangerous and untried procedure on the community. Boston ofﬁcials prohibited further inoculations. Some ministers denounced inoculation as a challenge to God’s plan, an invitation to vice and immorality, and an attempt to substitute human inventions for Divine guidance. But other ministers agreed with Mather and became truly zealous advocates of inoculation. The Reverend Benjamin Colman called inoculation ‘‘an astonishing mercy.’’ In response to Massey’s attack on inoculation, the Reverend William Cooper said: ‘‘Let us use the light God has given us and thank him for it.’’ In contrast, William Douglass (1691–1752), one of Boston’s most prominent and best-educated physicians, denounced inoculators for pro- moting ‘‘abuses and scandals.’’ Douglass was the only university-trained physician in Boston, a graduate of Edinburgh’s medical school. Sound- ing more like a theologian than a physician, Douglass proclaimed it a sin to deliberately infect healthy people with a dangerous disease, which they might not have contracted otherwise. How was it possible, Douglass asked, for clergymen to reconcile inoculation with their doctrine of pre- destination? Nevertheless, by 1730 Douglass reconsidered this ‘‘strange and suspect practice’’ and became an advocate of inoculation. Reﬂecting on the turmoil caused by inoculation, Mather asked the people of New England to think about the many lives that might have been saved if physicians had not ‘‘poisoned and bewitched’’ them against the procedure. Although Mather admitted that some people died after inoculation, he reminded his critics that some people died after having a tooth pulled, while others casually risked their lives by dosing themselves with emetics and cathartics, or by smoking tobacco. As the epidemic died down, the fear and hostility aroused by the inoculation experiments also ebbed away. People began to ask whether inoculation really worked and whether it was less dangerous than smallpox contracted in the natural way. Boylston’s meticulous records, published in 1726 under the title An Historical Account of the Small-Pox Inoculated in New England, pro- vided statistical evidence of the relative safety of inoculation. During the epidemic of 1721, 844 people died of smallpox. Based on the popu- lation of Boston at the time, the mortality rate for naturally acquired smallpox during this epidemic was about 14 percent. Out of 274 inoculated individuals, only 6 died of smallpox.
The case fatality rate of 2.2 percent for the inoculated group was substantially lower than the case fatality rate in the general population of Boston. Of course, such crude calculations do not take into account many important compli- cations, such as the problem of assessing the risk of acquiring smallpox naturally, or the possibility that some of those who were inoculated might have already contracted the disease. Today a vaccine with a two percent fatality rate would be unacceptable, but when compared to naturally acquired smallpox, the beneﬁts of inoculation clearly exceeded the risk. Inoculation had important ramiﬁcations for medical practitioners and public health ofﬁcials willing to accept the responsibilities inherent in this unprecedented promise of control over epidemic disease. As Benjamin Franklin so poignantly explained, weighing the risks and ben- eﬁts of inoculation became an awesome responsibility for parents. In 1736, Franklin printed a notice in the Pennsylvania Gazette denying rumors that his four-year-old son Francis had recently died of inocu- lated smallpox. Franklin was afraid that the false reports would keep other parents from protecting their children. The child acquired natural smallpox while suffering from a ‘‘ﬂux’’ that had forced Franklin to post- pone the operation. In his Autobiography, Franklin reﬂected on the bit- ter regrets he still harbored about failing to protect Francis from smallpox. Knowing that some parents refused to inoculate their children because of fear that they would never forgive themselves if a child died after the operation, he urged them to consider that uninoculated chil- dren faced the greater risk of naturally acquired smallpox. As epidemics of smallpox continued to plague New England com- munities, the isolation and recovery period required for safe inoculation tended to limit the practice to wealthy families.
An inoculated person with a mild case of smallpox was obviously a danger to others; inoculated smallpox was contagious. Indeed, during the Revolutionary War, the British were accused of conducting ‘‘germ warfare’’ by inoculating agents and sending them about the country to spread the infection. Washington initially hoped that isolation and quarantine would prevent the dissemi- nation of smallpox among his troops, but he knew that members of the British army were routinely protected against the disease by inoculation. With smallpox a constant threat to the army, General George Washington ordered secret mass inoculations of American soldiers in order to maintain an effective military force. Through such measures, smallpox gradually ceased to be ‘‘the terror of America.’’ Perhaps the greatest medical accomplishment of the Age of Enlightenment was recognition of the possibility of preventing epidemic smallpox. In England, members of the Royal Society shared an interest in curious folk customs from around the world and their journal pro- vided a vehicle for the dissemination of much curious information. Emanuel Timoni’s ‘‘Account, or history, of the procuring of the small- pox by incision, or inoculation, as it has for some time been practised at Constantinople,’’ published in the Society’s Philosophical Transactions in 1714, provides a perfect example of an inquiry into strange and exotic folk customs. Another description of inoculation was submitted to the Royal Society by Giacomo Pylarini. According to Timoni and Pylarini, the inoculator took pus from a favorable smallpox case by opening a pustule with a needle. The needle was placed in a clean glass vessel that was carried about in the inocu- lator’s armpit or bosom to keep it warm. Several small wounds were made in a healthy subject’s skin and a little blood was allowed to ﬂow. The smallpox matter was mixed with the blood and the incision was covered with half a walnut shell. A magical or religious touch could be added by inoculating at several sites to form a cross. Seven years after the appearance of these papers, a series of experi- mental trials was conducted under royal sponsorship and with the cooperation of the Royal Society and College of Physicians, to evaluate the safety of inoculation.
Six felons, who had volunteered to participate in an experiment in exchange for pardons (if they survived), were inocu- lated by Maitland on August 9, 1721, in the presence of at least 25 wit- nesses. On September 6, the experiment was judged a success and the prisoners were released, happily free from prison and fear of smallpox. As a further test, the orphans of St. James’s parish were inoculated. These experiments were closely studied by the Prince and Princess of Wales (later King George II and Queen Caroline). Based on highly favorable reports, the Princess decided to inoculate two of her daugh- ters. Inevitably, there were some highly publicized failures, which were exploited in the war of sermons and pamphlets disputing the religious, social, and medical implications of inoculation. Advocates of inoculation believed that protecting individuals from smallpox was only the beginning. Matthieu Maty (1718–1776), who championed inoculation in England, France, and Holland, predicted that within one hundred years people might totally forget smallpox and all its dangers. By the second half of the eighteenth century, inoculation was a generally accepted medical practice. Based on information reported by inoculators for the years 1723 to 1727, James Jurin (1684– 1750), a prominent physician and advocate of inoculation, calculated a death rate from inoculated smallpox of about 1 in 48 to 60 cases, in contrast to 1 death per every 6 cases of natural smallpox. Individual inoculators reported morality rates ranging from 1 in 30 to 1 in 8,000. In general, the mortality rate for inoculated smallpox probably averaged about 1 in 200. Because inoculation was most commonly demanded during epidemic years, some of the deaths attributed to inoculation might have been the result of naturally acquired smallpox. Although inoculation probably had a limited impact on the overall incidence of smallpox, it paved the way for the rapid acceptance of Edward Jenner’s cowpox vaccine and the hope that other epidemic diseases might also be brought under control.