Smallpox is now a disease of historical interest only, its eradication having been certified by the World Health Assembly on May 8, 1980.¹ An exanthematous viral disease, it was once prevalent throughout the world, existing as an endemic infection wherever concentrations of population were sufficient to sustain transmission. Outbreaks of variola major, the only known variety until the end of the 19th century, resulted in case-fatality rates of 20% or more. Most of those who survived had distinctive residual facial pockmarks, and some were blind. A second variety, variola minor, produced less severe illness and was associated with case-fatality rates of 1% or less. It was first described in South Africa by de Korte² and in the United States by Chapin³ and subsequently became the prevalent variety throughout the United States, parts of South America, and Europe as well as some areas of eastern and southern Africa.⁴

Because there was no animal reservoir of smallpox and no human carriers, the virus had to spread continually from human to human to survive. Thus, historians speculate that it must have emerged sometime after the first agricultural settlements, about 10,000 BC.⁵ The first certain evidence of smallpox in the ancient world comes from mummified remains of the 18th Egyptian dynasty (1580 to 1350 BC) and of the better known Ramses V (1157 BC).⁶ Written descriptions of the disease, however, did not appear until the 4th century AD in China⁷ and the 10th century in southwestern Asia.⁸

From northeastern Africa, smallpox was probably carried by Egyptian traders to India during the first millennium BC,⁴ where it became established as an endemic infection. Whether smallpox persisted in Africa is uncertain. Although epidemics of disease are described in the Bible and in Greek and Roman literature, descriptions of clinical signs are sparse. Only one of these epidemics can be identified with some certainty as smallpox.⁷ It occurred in Athens beginning in 430 BC and is described by Thucydides. There is, however, no original Greek or Latin word for smallpox despite its distinctive rash.⁹ From the populated endemic areas of Asia and perhaps Africa, smallpox spread with increasing frequency into less populous areas of these continents and into Europe, becoming established as an endemic infection when populations increased sufficiently in number.

The name variola was first used during the 6th century by Bishop Marius of Avenches (Switzerland), the word being derived from the Latin varius (spotted) or varus (pimple).¹⁰ Although Marius provides no clinical description of the disease concerned, there is little doubt that smallpox had already become endemic in some areas of Europe by this time.⁷ In the Anglo-Saxon world, by the 10th century, the word poc or pocca, a bag or pouch, described an exanthematous disease, possibly smallpox, and English accounts began to use the word pockes. With the appearance of syphilis in Europe in the late 15th century, writers began to use the prefix small to distinguish variola, the smallpox, from syphilis, the great pox.¹¹

In the early 16th century, smallpox began to be imported into the Western Hemisphere. Catastrophic epidemics followed, which literally decimated Amerindian tribes and resulted in the collapse of both the Aztec and Incan empires.⁵ Central and southern Africa probably became endemic for smallpox about this time or soon thereafter.

The impact of smallpox on history and human affairs was profound.⁷ Deities to smallpox became a part of the cultures of India, China, and parts of Africa. In Europe, as of the end of the 18th century, an estimated 400,000 persons died annually from smallpox, and survivors accounted for one third of all cases of blindness. During the 18th century alone, five reigning European monarchs died of smallpox, and the Austrian Hapsburg line of succession shifted four times in four generations.

A method for protection against naturally acquired smallpox infection appears to have been discovered in India sometime before AD 1000.^12,13 There it became the practice to deliberately inoculate, either into the skin or by nasal insufflation, scabs or pustular material from lesions of patients. This practice resulted in an infection that was usually less severe than an infection acquired naturally by inhalation of droplets. From India, the practice spread to China, western Asia, and Africa and finally, in the early 18th century, to Europe and North America.¹⁴ Case-fatality rates associated with variolation, as it was called, were about one tenth as great as when infection was naturally acquired, but those infected in this manner were capable of transmitting smallpox by droplet inhalation to others. After cowpox began to be used as a protective vaccine, the practice of variolation diminished. Even as recently as the 1960s and 1970s, however, variolation continued to be performed among remote populations in some parts of Ethiopia, western Africa, Afghanistan, and Pakistan.⁴

In 1796, Edward Jenner (Fig. 6-1) demonstrated that material could be taken from a human pustular lesion caused by cowpox virus (i.e., an orthopoxvirus closely related to variola virus) and inoculated into the skin of another person, producing a similar infection.¹⁵ He showed that the individual was protected from inoculation with smallpox after recovery. He called the material vaccine, from the Latin vacca, meaning cow, and the process vaccination. Pasteur,¹⁶ in recognition of Jenner's discovery, later broadened the term to denote preventive inoculation with other agents, Jenner's discovery, one of the most important in medical history, was immediately recognized for its significance. Within 5 years, his paper had been translated into six other languages,¹⁷ and the vaccine had begun to be employed widely in many countries of Europe; within a decade, it had been transported to countries throughout the world. The chronicles of the de Balmis expedition of 1803 to 1806 vividly describe the transport of the vaccine by sea to Spanish colonies in the Americas and Asia by arm-to-arm vaccination of orphaned children.^18,19

As the 19th century progressed, however, the initial wave of enthusiasm for vaccination subsided when difficulties were experienced in sustaining the virus through arm-to-arm inoculation and when it was found that, on some occasions, syphilis was transmitted in the process.^20,21 Although vaccination material, dried on threads or ivory points, could be transported over long distances, it was often found, on receipt, to be noninfectious. When fresh material was sought, problems occurred in finding cows or horses with infections caused by cowpox or a related orthopoxvirus.²² In some areas, significant opposition occurred among religious leaders and antivaccinationist societies who opposed the principle of infecting humans with an animal disease.²³ Confidence in the procedure was also diminished by the occurrence of smallpox in some who had previously been successfully vaccinated. Jenner had forcefully contended that protection was lifelong, as was the case after natural smallpox, but it soon became apparent that this was not so. Although the need for revaccination was demonstrated early in the century,²⁴ this practice was not widely accepted until many decades later.

Growth of the virus on the flank of a calf offered the prospect for provision of an adequate and safer supply of vaccine material. Although this approach was employed in Italy as early as 1805,²⁵ it appears to have been unknown elsewhere until it was more widely publicized at a medical congress in 1864.²⁶ Thereafter, the practice was gradually adopted in other countries, although arm-to-arm vaccination in England, for example, continued until it was finally banned in 1898.²⁷ With an ensured source of vaccinia, the numbers of vaccinations in Europe increased, and the incidence of smallpox in the more industrialized countries diminished more rapidly. Not until after World War I, however, did most of Europe become smallpox free, and not until after World War II was transmission stopped throughout Europe and North America.

In most other parts of the world, especially in tropical and semitropical areas and in the less developed countries, smallpox continued largely unabated until the middle of the 20th century. In these countries, continuing difficulties were experienced in sustaining the virus through arm-to-arm inoculation. After calves began to be used for vaccine production, the harvested vaccine remained viable for only 1 or 2 days at ambient temperatures, thus limiting its widespread application. The only control programs that were notably successful were those in Indonesia and in certain of the French colonies, which, in the 1920s, began using a specially prepared and more stable air-dried²⁸ or freeze-dried²⁹ vaccine.

In the late 1940s, a commercially feasible process for large-scale production of a stable freeze-dried vaccine was perfected by Collier³⁰. This process offered vastly better possibilities for smallpox control. Recognizing the value of such a vaccine, the Pan American Sanitary Organization³¹ decided, in 1950, to undertake a hemisphere-wide eradication program and by 1967 succeeded in eliminating smallpox from all countries of the Americas except Brazil. Meanwhile, in 1958, the Union of Soviet Socialist Republics proposed to the World Health Assembly that a global smallpox eradication program be undertaken,³² and this was so decided the following year.³³ Some progress was made during the period from 1959 to 1966, but the results overall were disappointing. Finally, in 1966, the World Health Assembly decided to intensify the eradication program by providing additional funds specifically for this effort.³⁴

During 1967, the year the Intensified Global Eradication Program began, an estimated 10 to 15 million smallpox cases¹ occurred in 31 countries in which the disease was endemic. The campaign was based on a twofold strategy: (1) mass vaccination campaigns in each country, using vaccine of ensured potency and stability that would reach at least 80% of the population and that would be assessed by independent teams, and (2) development of a system to detect and contain cases and outbreaks.³⁵ Numerous problems had to be surmounted, including deficient supervision and discipline in national health services, epidemic smallpox among refugees fleeing areas stricken by civil war and famine, shortages of funds and vaccine, and a host of other problems posed by difficult terrain, climate, and cultural beliefs.^36–38 Despite the problems, steady progress was made, and on October 26, 1977, the last known naturally occurring case of smallpox was recorded in Merka, Somalia.³⁹ Two further cases occurred in 1978 as a result of a laboratory infection in Birmingham, England,⁴⁰ but these cases were the last. Detailed accounts of national programs are provided in books dealing with those in India,^41,42 Bangladesh,⁴³ Ethiopia,⁴⁴ and Somalia.⁴⁵

An extensively illustrated volume entitled Smallpox and Its Eradication ⁴ provides a detailed account of the eradication campaign as well as an overall account of progress in smallpox control throughout history. It also gives a description of the virology, the clinical features, and the pathogenesis of the disease. Complementing this text is a historical record of smallpox, Princes and peasants, by Hopkins.⁷