More than 200 years ago, Edward Jenner performed an experiment that laid the foundation for the eradication of smallpox and transformed humankind's fight against disease. Smallpox afflicted humankind as no other disease had done; its persistence and diffusion were without parallel. The disease brought down at least three empires. Generations watched helplessly as their children succumbed to the disease or were disfigured or blinded by it. Attempts were made to contain smallpox by isolating its sufferers and, later, by using variolation with varying degrees of success. However, the definitive solution was not found until Jenner's work was done at the end of the 18th century. Milkmaids who had developed cowpox from contact with cow udders informed Jenner that they were protected from the human form of the disease; he listened to their folk wisdom and raised it to the status of scientific fact. Jenner did not discover vaccination, but he was the first to demonstrate that this technique offered a reliable defense against smallpox. It was also a reliable defense against other illnesses, such as poliomyelitis, measles, and neonatal tetanus, although this was not known in Jenner's lifetime.
Smallpox was always present, filling the churchyard with corpses, tormenting with constant fear 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.
Smallpox has been one of humankind's greatest scourges since time immemorial. Even illnesses as terrible as the plague, cholera, and yellow fever have not had such a universal and persistent impact. Smallpox is believed to have appeared at the time of the first agricultural settlements in northeastern Africa, around 10 000 BC. It probably spread from Africa to India by means of Egyptian merchants in the last millennium BC. The earliest evidence of skin lesions resembling those of smallpox is found on the faces of mummies from the time of the 18th and 20th Egyptian Dynasties (1570 to 1085 BC) and in the well-preserved mummy of Ramses V, who died as a young man in 1157 BC.
The first recorded smallpox epidemic occurred in 1350 BC during the Egyptian-Hittite war. The illness was passed to the Hittite population by Egyptian prisoners and affected soldiers and civilians alike. The Hittite King Suppiluliumas I and his heir, Arnuwandas, were victims; their civilization fell into sharp decline.
During the epidemic in Athens in 430 BC, Thucydides noted that those who survived the disease were later immune to it. These observations were reiterated by Rhazes (Abu Bakr Muhammad Ibn Zakariya al-Razi), to whom we owe the first medical description of smallpox, De variolis et morbillis commentarius, which was written in about AD 910. Rhazes also noted that the illness was transmitted from person to person. His explanation of why survivors of smallpox do not develop the disease a second time is the first theory of acquired immunity.
The symptoms of smallpox&emdash;or the speckled monster, as it was known in 18th-century England&emdash;appeared suddenly and included high fever, chills or rigors, cephalalgia, characteristic dorsal-lumbar pain, myalgias, and prostration. Nausea and vomiting were also common. After 2 to 4 days, the fever relented and a rash appeared on the face and inside the eyes; the rash would subsequently cover the whole body. These maculopapular skin lesions evolved into vesicles and pustules and finally dried into scabs that fell off after 3 or 4 weeks. This sequence of events was characteristic for variola major.
Other clinical forms of the disease existed. Persons with fulminating smallpox (purpura variolosa) had mucocutaneous hemorrhages that preceded the appearance of the characteristic skin lesions. In malignant smallpox, the rash had a slow evolution characterized by pseudocropping, subconjunctival hemorrhages, and death when lesions on the face and limbs were confluent. In benign smallpox, the evolution of the rash differed from that of the malignant variety; this form was also less extensive (19, 20). Modified smallpox (varioloid) occurred in persons who were partially protected by vaccination and was usually benign. Variola sine eruptione was smallpox without a rash and occurred predominantly in vaccinated persons. Variola minor (alastrim, Kaffir-pox) was a mild form of smallpox caused by a less virulent strain of the virus and was endemic in Africa and South America.
The case-fatality rate associated with smallpox varied between 20% and 60% and left most survivors with disfiguring scars. Many persons went blind as a result of corneal infection. The case-fatality rate in the infant population was even higher; among children younger than 5 years of age in the 18th century, 80% of those in London and 98% of those in Berlin who developed the disease died. The case-fatality rate also varied according to the nature of the attack-it ranged from almost 100% in fulminating smallpox to 0.5% to 2% in variola minor. The ravages of smallpox were apparent in 18th-century Europe, with case-fatality rates ranging from 20 to 400 per 100 000 per year, and it is said that smallpox was responsible for 10% of deaths in Europe during that century. The incidence rate varied greatly, but during epidemics it was as high as 37.5% in Boston in 1752, 43.1% in Hastings in 1730 and 1731, and 92.7% in Chester in 1775. In Copenhagen between 1750 and 1800, the annual incidence rate ranged from 875 to 1750 per 100 000; in London between 1685 and 1801, it ranged from 313 to 2355 per 100 000; and in Sweden between 1774 and 1798, it ranged from 341 to 1024 per 100 000. The incidence rate was so high that the disease was regarded as universal or almost universal, and many authorities believed that everyone would eventually develop it. As recently as 30 years ago, smallpox was endemic in 31 countries, between 10 and 15 million persons developed smallpox yearly, and more than 2 million persons died of smallpox each year.
Vaccination done by using pustule fluid spread rapidly. By 1800, it had reached most European countries and about 100 000 persons had been vaccinated worldwide. In July of that year, only 2 years after the publication of Jenner's "Inquiry," Benjamin Waterhouse, professor of the "Theory and Practice of Physic" at Harvard Medical School, vaccinated his 5-year-old son and six servants with vaccine from England. These were the first vaccinations done in the United States. The practice soon spread from Boston to Philadelphia, New York, and Baltimore.
President Thomas Jefferson had 18 members of his family, some of their neighbors, and the last Mohican vaccinated. In December 1801, Chief Little Turtle and several of his warriors were vaccinated while on a visit to Washington, D.C., after Jefferson explained that "the Great Spirit had made a gift to the white men in showing them how to preserve themselves from the smallpox". The President himself vaccinated many persons. Waterhouse received great support from Jefferson, who appointed him Vaccine Agent in the National Vaccine Institute, an organization set up to establish vaccination in the United States.
King Charles IV of Spain sent vaccine from Spain to his dominions in North and South America and Asia through the Expedición de la Vacuna (the Balmis-Salvany Expedition) in 1803 through 1806; this was the first official program of mass vaccination overseas. The vaccine was maintained during the voyage by sequentially vaccinating, arm-to-arm, 22 susceptible orphan children brought along specifically to constitute a living chain. Before the expedition left Spain, a report by one of the king's physicians declared smallpox to be the "first and principal cause of the depopulation of America." The governor of the Council of the Indies noted that depopulation would mean a decrease in income from taxes that the Spanish received from the colonies and in commerce and farming. The economic benefits of such a mission would, in his view, justify paying for it from the royal treasury.
The impact of Jenner's work was so great that, in 1805, Napoleon himself insisted that all his troops who had not had smallpox should be vaccinated with the "Jennerian vaccine." He ordered the vaccination of French civilians 1 year later. The first smallpox vaccination law was passed in the Grand Duchy of Hesse in 1807; vaccination was declared obligatory in Bavaria in the same year and in Denmark in 1810.
The extraordinary value of vaccination was also acknowledged in England. In 1802, the British Parliament granted Jenner the sum of P10 000, which was worth $44 150 in 1802 and more than half a million dollars in today's currency. Five years later, parliament awarded him P20 000 more. Jenner received honors from the universities of Harvard, Oxford, and Cambridge, and numerous scientific societies made him an honorary member. However, he was never knighted. In 1803, the Royal Jennerian Institute was founded to provide lymph for vaccination; Jenner was its first president. Jenner's prestige was so great that Napoleon released English prisoners after his mediation. In 1813, Napoleon was reluctant to pardon Captain Millman, a relative of Jenner's who had fallen captive. When told who had made the request for the soldier's release, Napoleon exclaimed, "Ah, c'est Jenner, je ne puis rien refuser à Jenner!" [Ah, it is Jenner, I cannot refuse Jenner anything!]. The Emperor of Austria and the King of Spain also freed English prisoners after Jenner intervened.
Jenner's work represented the first scientific attempt to control an infectious illness by the deliberate use of vaccination. Strictly speaking, he did not discover vaccination but was the first person to confer scientific status on the procedure and was the instigator of its popularization. Jenner had been trained in the scientific method by Hunter and, in his studies on vaccination, was able to confirm his hypotheses by means of experimentation and observation. Jenner's experiments on the transmission of cowpox from human to human (not from cows to humans) were extraordinarily important because they meant that prophylaxis could be given even in the absence of the natural illness. His great merit, indeed his genius, lay in the fact that he performed exceptional experimental work on the basis of popular beliefs in the England of his times. Jenner demonstrated that the folk medicine tradition could be scientifically verified. Jenner's work established the practice of vaccination, although the term would not become widely accepted until it was adopted by Pasteur 80 years later.
Jenner himself showed that he was aware of the far-reaching consequences of his work when he stated that the universal application of the vaccine would lead to the eradication of smallpox. In 1802, he wrote " it now becomes too manifest to admit of controversy, that the annihilation of the small pox, the most dreadful scourge of the human species, must be the final result of his practice". In 1806, Thomas Jefferson congratulated Jenner: "Future generations," he wrote, "will know by history only that the loathsome smallpox existed and by you has been extirpated". Both of Jefferson's predictions proved to be true; less than 200 years after the vaccination of James Phipps, the penultimate act of the smallpox drama was played out in a small Somali village called Merka. Ali Maow Maalin, a cook, developed the characteristic smallpox rash on 26 October 1977 and was the last person to acquire the illness as a result of direct contact with another human being. The final act was the official declaration that the illness had been wiped off the face of the earth. This occurred on 8 May 1980, when the 33rd Assembly of the World Health Organization (WHO) accepted the Final Report of the Global Commission for the Certification of Smallpox Eradication.
In 1978, injudicious manipulation of the smallpox virus in the Medical School of the University of Birmingham led to the death of Janet Parker, a medical photographer, and the subsequent suicide of Professor Henry S. Bedson, head of the Department of Medical Microbiology. This episode emphasized the need for close supervision of smallpox virus stocks in laboratories.
The epilogue in the history of smallpox will be the destruction of all strains of smallpox virus presently stored in the high-security facilities at the Centers for Disease Control and Prevention in Atlanta, Georgia, and at the Institute for Viral Preparations in Moscow. The virus has thus far gained two reprieves; its sentence was initially postponed to 31 December 1993 and later to 30 June 1995. In both instances, its destruction was delayed because of lack of consensus among the members of the WHO's executive board. The two main arguments against destruction of the virus are that it will eliminate the possibility of future studies on the virus and that destruction of the virus in the two known repositories may not guarantee complete eradication. The main arguments for destruction are that escape of the virus from the laboratories would be a serious risk because an increasing proportion of the global population lacks immunity to the disease and that the sequence information and the availability of cloned DNA fragments of the full genome of several strains of the virus will allow most scientific questions about the properties of the viral genes and proteins to be resolved. Finally, the decision to eradicate smallpox was a collective decision of the world community made on the basis of public health considerations; all possible measures should be taken to ensure that smallpox does not again afflict mankind.
The 97th session of the WHO's executive board that met in Geneva in January 1996 recommended to the 49th World Health Assembly that the last stocks of smallpox virus be destroyed. There have also been proposals to retain 500 000 doses of smallpox vaccine and to keep the Lister Elstree strain of vaccinia virus as seed virus stock of the smallpox vaccine. The destruction would affect all stocks of smallpox virus, including variola minor, clinical specimens, and other material containing infectious smallpox virus or viral genomic DNA. Genomic DNA of the smallpox virus should be destroyed in all laboratories holding such material. The current deadline for variola virus is 31 June 1999. This would represent the first deliberate elimination of a biological species from this planet but also the extinction of an old enemy that humankind will not miss.