Immunology

Except in the rarest instances, smallpox infection ended in one of only two ways: death or long-lasting immunity. Lacking an animal reservoir and the ability to remain latent within the human body, smallpox existed only as an active infection. It was one of the classic epidemic diseases, surviving in many eras and parts of the world only as rolling waves of infection. It could achieve endemicity only in large and, often, cosmopolitan populations, where it could pass in unbroken sequence through the bodies of travelers newly arrived from areas free from the malady, and through the bodies of the immunologically innocent newborn. Where it was endemic, it was usually a childhood disease, and trial by smallpox was a prerequisite for adulthood for all but a small minority.

History Antiquity

Because it only persisted by passing from one human to another, smallpox could not have existed with its historical characteristics among the sparse populations of the Paleolithic Age. It may have first appeared sporadically among the village dwellers of the Neolithic Age, derived from pox diseases of livestock, or from similar infections circulating among wild animals with whom humans were often in contact. In our own time, Africans occasionally contract monkeypox, which has symptoms similar to smallpox, but which is, fortunately, very unlikely to spread from human to human.

Smallpox may well have circulated among the ancient Egyptians. The face, neck, and shoulders of the mummy of Pharoah Ramses V, who died in 1157 B.C., are disfigured by a rash of elevated pustules like those of smallpox, but researchers cannot be absolutely sure of the infection that caused them. Dreadful epidemics rolled back and forth through the Old World in ancient times, but rarely were the symptoms described clearly enough for researchers to make diagnoses confidently. In the second and third centuries A.D., two pandemics devastated the Roman Empire, one or both of which may have been smallpox, but we know very little about the diseases clinically. There is some indication of smallpox in China by the fourth century, and stronger evidence for its arrival in Japan in the 730s.

Ninth Through Fifteenth Century

With The Treatise on Smallpox and Measles at about the turn of the ninth century by Rhazes, a Baghdad physician, we are finally on solid ground. He clearly differentiated between the two diseases, and revealed smallpox to be a common childhood disease in southwest Asia in his time. The density of population centers extending west to the Mediterranean and Atlantic and east to China and the Pacific in that era suggests strongly that smallpox was prevalent, at least in epidemic form, throughout the area of advanced Old World civilizations before the end of the first Christian millennium. In the same general period, the malady may have invaded peripheral areas: sub-Saharan Africa, northern Europe, and the Indonesian archipelago.

Smallpox, though widespread in the first millennium and a half of the Christian era, seems not to have been among humanity's chief curses in those centuries. It ranked behind plague, tuberculosis, and probably other maladies prevalent in the Old World in the period Europeans call the Middle Ages, and did not become a major demographic check in Europe until the sixteenth and seventeenth centuries.

Sixteenth Through Seventeenth Century

The most important effect of smallpox historically was as a solvent exuded by dense populations of the Old World. For example, it was an important ally of the Russian invaders of Siberia, as it was of the Hollanders in Cape Colony, South Africa. On the other hand, smallpox was a merciless enemy of barbarians trying to penetrate concentrations of dense population. The Manchus, who rode south into China and founded the Ch'ing Dynasty in the seventeenth century, were obliged to excuse princes and dignitaries from the thinly populated steppes (who had not yet contracted smallpox) from coming to Beijing to make obeisance to the Emperor. For their safety and survival, special audiences were provided in Jehol, north of the Great Wall.

No later than 1519, smallpox crossed the Atlantic to a New World still free from the disease; decimated the Arawaks of the West Indies, a people already in steep decline; accompanied the Spaniards to Mexico; and rolled on ahead of them into the Incan Empire. Amerindians had, at very best, no more resistance to the disease than did Europeans, and they must have suffered similarly high or even higher morbidity rates. The Spanish estimates of death rates among Amerindians in this, the first of their many pandemics of smallpox, ran from about one-fourth to one-half — that is, rates comparable to those of European children afflicted with the disease. The psychological effect of such experiences on peoples who believed in a direct connection between pestilence and the supernatural was considerable. The Amerindians quaked in confusion and terror; and the Europeans preened themselves as the chosen people. John Winthrop, first governor of Massachusetts Bay Colony in North America, noted on May 22, 1634: "For the natives, they are neere all dead of the small Poxe, so as the Lord hathe cleared our title to what we possess" (Winslow 1974).

Eighteenth Century

The final major chapter in the history of the expansion of smallpox opened in 1789, when the infection appeared among the Australian aborigines in contact with the newly arrived English settlers at Sydney Harbor. It destroyed half the indigenes, by English estimate, and spread over the Blue Mountains into the interior, although no one knows how far. This epidemic was probably the single greatest demographic shock ever dealt the Aborigines.

By the eighteenth century, smallpox accounted for 10 to 15 percent of all deaths in some European countries annually, 80 percent of the victims being under 10 years of age. It is likely that similar rates were common in major cities in North Africa and civilized Eurasia. Outside these areas of dense population the disease was epidemic, killing high percentages of adults essential to the functioning of the economy and society. The peoples of the Old World, living in the presence of this threat for generation after generation, were bound to devise means of defending themselves, if such could be found.

Variolation. Our modern techniques of inoculation and vaccination began-no one knows when or where - with variolation (the artificial infection with smallpox of healthy people) in the hope that this would produce mild cases of the disease but solid immunity. In China, smallpox scabs were blown up the nostril, seemingly a very dangerous method because it might produce infection through the upper respiratory tract, as in naturally incurred smallpox, but the scabs were apparently aged first, attenuating the virus. Elsewhere in the Old World, variolation was generally accomplished by obtaining material, usually fluid, from pustules of an active case of smallpox and then scratching this into the skin. If variolation was done expertly, the infection was mild, and the death rate no more than 3 or 4 percent and, when done by the most skilled practitioners, as low as 1 percent.

Variolation was practiced for a long time, not by formally trained physicians, but by folk healers. For example, Cotton Mather, a minister in the Massachu setts Bay Colony in North America, first heard of it about 1706 from his African slave, who told him that smallpox and variolation were both common in Africa. Peasants in remote parts of Scotland, Wales, Greece, the Middle East, and elsewhere in Eurasia were "buying the smallpox," as those who spoke English put it, long before the rich and well-born learned of variolation. The most famous figure of that latter event was Lady Mary Wortley Montagu, a woman whose brother died of the disease and who, attacked by smallpox as an adult, lost her beauty and even her eyebrows. While in Constantinople as wife of the British ambassador, she learned of a method practiced there of "ingrafting" the disease, which usually led to a mild infection and yet stout immunity. Lady Montagu had her son variolated in Constantinople in 1717, and her daughter, in London in 1721.

In that same year, smallpox broke out in Boston, Massachusetts, where the people, too few to maintain the disease endemically, periodically suffered terrifying epidemic waves of it. Mather knew nothing of Lady Montagu's experiments, but he had heard of variolation from his slave and had read reports about it. He persuaded Zabdiel Boylston to experiment with the new practice in Boston. Despite fierce opposition from those who viewed the practice as dangerous (which it certainly was), Boylston scratched pus from a smallpox pustule into the skins of his son and two slaves. In all, he variolated 244 people, while in nearby Cambridge and Roxbury other physicians variolated 36 more. This was the first large-scale test of the practice, at least in the West. Also - amazingly - it may have been the first example of careful quantitative analysis of the effects of a medical procedure. Boston had a population of about 11,000, thousands of whom fled during the epidemic. Of the remainder, 5,980 caught the disease naturally, and 844 - or 14 percent - died. But only 6 - or just 2.4 percent - of the 244 variolated by Boylston died.

The practice of variolation was not adopted as rapidly as the statistics above suggest that it should have. After an initial flurry of variolating among some members of the upper classes and their domestics in the 1720s, the spread of the new procedure slowed and may even have retreated. British North Americans resorted to it only during epidemics, when contracting the disease naturally seemed just as likely as, and a good deal more dangerous than, embracing it via variolation.

Acceptance of the practice was contingent on several developments. One was a rise in the fear of smallpox, which a surge of the disease around 1750 stimulated. Others were the reduction of what were at first high fees for variolation, and the improvement in technique so as to reduce the chances of dying from this procedure to a tolerable minimum. These changes were accomplished by a handful of physicians, among them the American James Kirk-patrick, and more importantly, the Britons Robert Sutton and his sons, especially Daniel. The Suttons reduced variolation to a slight pricking of the skin, rather than, as had previously often been the case, deep incisions that thrust the virus directly and dangerously into the bloodstream and that increased chances of secondary infection. The establishment of smallpox hospitals, where variolated patients could be isolated, helped to quell fears of artificially triggered epidemics.

In the 1760s and for the rest of the century, variolation became increasingly common in the British Empire, and on the continent of Europe, as well, though more slowly. The death of Louis XV of smallpox in May and the variolation of Louis XVI in June of 1774 spurred the practice everywhere. By the end of the century, many thousands had been variolated in Europe and America. How many we will never know because physicians kept poor records, and there were many itinerent inoculators, who kept no records at all. Some experts claim that the spread of this new way of promoting immunization was one of the chief causes of the beginnings of our present population explosion in the last half of the eighteenth century, but it is impossible to tease out this factor from others, such as improved nutrition. In addition, there is the question of how many deaths were caused by epidemics unintentionally started by variolation. Yet we can be sure that in the long run variolation stimulated population growth, at least indirectly, by accustoming people in general to the benefits of producing immunity by deliberately incurring mild infections.

Vaccination. The greatest windfall of variolation (and the greatest in the history of medicine) occurred in the last decades of the eighteenth century when an experienced English variolator and scientist, Edward Jenner, noticed that the variolation failed to produce symptoms of illness in people who had previously contracted a mild pox disease from livestock, usually cattle. He vaccinated (a new word derived from the Latin for "cow") several people, including his own son, with cowpox matter, and then attempted variolation. Inoculation with smallpox matter uniformly failed to produce pustules or much else in the way of illness. He published his results in June of 1798 as An Inquiry into the Causes and Effects ofVariolae Vaccinae, a Disease, Discovered in some of the Western Counties of England, particularly Gloucestershire, and known by the Name of Cow Pox. Vaccination may have been practiced before by common folk, like variolation, but now a member of the elite had introduced an account of the technique into print for the whole world to read, and that made all the difference.

Nineteenth Century

It was as if, to quote a nineteenth-century historian, "an Angel's trumpet had sounded over the earth" (Winslow 1974). England led the way in the new practice - more than 100,000 were vaccinated there by 1801 - and the rest of the world came treading on her heels. Within 3 years of the publication of Jen-ner's Inquiry, it was translated into German, French, Spanish, Dutch, Italian, and Latin. In France 1.7 million were vaccinated between 1808 and 1811, and in Russia about 2 million in the decade ending 1814, and so on across the world.

Getting potent vaccine across the great oceans as scabs or bits of thread soaked in matter from pustules was problematical, and often the virus proved dead and useless when scratched into transatlantic arms. Sometimes the virus survived and did the job, to the benefit, for instance, of the clients of Benjamin Waterhouse of Boston, Massachusetts, in 1800. The surest way of preserving the infectiousness of cow-pox virus while traveling great distances was by the serial method: Recruit a number of unimmunized people, vaccinate one, and then, when his pustules are ripe, transfer the disease to another, and so on in sequence until the destination is reached with an active case on board.

This was the technique used by Don Francisco Xavier Balmis who, empowered and financed by the Spanish monarchy, led an expedition around the world from 1804 to 1806, from Spain to the New World and thence to the Philippines, China, and St. Helena, vaccinating thousands as he went. He used young boys, usually orphans, as reservoirs of the cowpox, the first set obtained in Spain and the others as required in America and elsewhere.

During the 1800s, humanity began to win its battle with smallpox. Vaccination continued to spread, and in some countries was even made compulsory, at least for infants. Its benign effect on death rates, unlike that of variolation, was obvious, and literally millions of children, who would have died without Jenner's discovery, lived to enrich their societies with their skills and labor, and to fuel the population explosion. In a few advanced and disciplined societies, such as England and Prussia, where doctors, officials, and the public cooperated to smother smallpox, deaths due to the disease were near zero by the end of the century. Elsewhere success was equivocal, even though the benign influence of vaccination was supplemented by the appearance of V. minor toward the end of the century, displacing the more virulent form of the disease in some regions of the world.

Twentieth Century

Jenner realized that his discovery could mean "the annihilation of smallpox - the most dreadful scourge of the human race" - but not until the middle of the twentieth century did this seem not just a theoretical but also a practical possibility. By 1950 a number of wealthy societies in the temperate zones with strong governments, large numbers of skilled medical personnel, and scientifically sophisticated populations were free or nearly free of the disease. But most of the smallpox in the world raged in the tropics, where few or none of the factors just cited existed, and where smallpox vaccine lost its potency quickly in the heat. Freeze-drying, invented in the 1940s and adapted for mass production of vaccine in the 1950s, solved that problem.

In 1966, the Nineteenth World Health Assembly issued a call for the eradication of smallpox from the Earth. Donald A. Henderson, an officer of the World Health Organization, took charge of the Smallpox Eradication Programme. During its first year, 1967, smallpox existed in every continent except North America and Europe, and the estimate was that 10 to 15 million people contracted the disease each year. By 1972 it was gone from South America, as well. By the end of 1973 it was restricted to the Indian subcontinent and the horn of Africa, Ethiopia, and Somalia. In October of 1975, Rahima Banu of Bangladesh came down with V. major, the last case of smallpox in Asia. On October 26, 1977, the rash of V. minor appeared on the skin of Ali Maow Maalin of Somalia. This was the last case of this kind of smallpox and the last case of naturally occurring smallpox in the world. In August of 1978, smallpox virus somehow escaped from a laboratory in Birmingham, England, infecting Janet Parker and, subsequently, her mother. The daughter died; the mother survived. The director of the laboratory committed suicide while in quarantine. These were the last deaths associated with the ancient and now defunct scourge of smallpox. In 1979 the Global Commission for the Certification of Smallpox Eradica tion officially announced the demise of the disease. As of 1980, stocks of vaccine sufficient for 200 million vaccinations were being maintained in the unlikely case that smallpox should somehow arise again.

Humanity won the victory against the smallpox virus by displacing it with the vaccine virus. Almost everyone for nearly a century and a half believed that virus to be the organism of cowpox, but in 1939 careful comparison of vaccinia virus (which does not exist naturally) of cowpox virus and of smallpox virus showed them to be related but clearly distinct entities. One expert claims that the Jenner strain of vaccinia virus was contaminated with a mild strain of smallpox very early, and that vaccination was a continuation of variolation not only in technique but also in the identity of the virus, as well. Decades of variolation, according to this theory, produced a very attenuated strain (or strains) of smallpox virus, and vaccinia virus is no more than one of these tamed varieties. Other experts suggest that Jenner was not dealing with cowpox, but horsepox, which cattle occasionally contracted. Unfortunately, horsepox died out early in the twentieth century, and so we have no way of testing this hypothesis. Still others suggest that vaccinia virus was the product of hybridization of two or more pox viruses in the nineteenth century. Careful analysis of the DNA of the viruses of vaccinia and possible "parents" has uncovered little indication of a close and recent relationship. The stuff of smallpox vaccination is a mystery, perhaps the greatest happy accident in the history of the relationship of humans and pathogens.

Alfred W. Crosby

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