In the wake of the October anthrax mailings, America has become attuned to the possibility of terrorists unleashing smallpox on the United States. Unlike anthrax, smallpox is highly contagious and difficult to contain. Although smallpox was eradicated from the United States in 1949 and officially eradicated worldwide in 1980, Americans are currently very vulnerable to the disease, which might spread rapidly throughout the United States - and to other countries - upon release.

Mandatory vaccination of school children against smallpox ended in 1972 in the United States. Because the last outbreak of smallpox in the United States was in February 1949, by 1972 the risk of vaccine complications far outweighed the risk of smallpox infection. An estimated 120 million Americans - about half the population - have never been vaccinated and have no immunity to the disease. Those who have been vaccinated have not had a booster shot in decades; their immunity has waned, although no one knows by what factor and how susceptible to smallpox they may be.

Because of its extreme virulence, smallpox has impacted not only the lives of its victims but even the outcomes of wars and conquests. Smallpox scourged the entire world before Dr. Edward Jenner invented vaccinations in the 18th century and the official eradication of the disease by the World Health Organization (WHO) occurred in 1980. If smallpox were reintroduced to the United States, many fear present-day Americans would fare no better than the Native Americans, whose numbers were devastated when Europeans introduced the disease to this continent in the 16th century. "Today, we're all Indians," says Elizabeth Fenn, historian and author of Pox Americana.

The government currently has more than 100 million doses of smallpox vaccine and has signed a contract to purchase enough to vaccinate all Americans in case of an outbreak

Though the situation is grave, Fenn's warning is probably overstated. Millions of Americans have been vaccinated; their immunity -- even if it has waned over time -- would slow the spread of the disease upon an outbreak. The government currently has more than 100 million doses of smallpox vaccine and has signed a contract to purchase enough to vaccinate all Americans in case of an outbreak. These new stocks should be ready by the end of the year, but the current supply would be enough to contain isolated outbreaks. Large-scale outbreaks of genetically altered smallpox would pose more of a problem for the government.

Since its eradication, debate has continued about whether U.S. and Russian smallpox stocks -- which were generated for bio-weapons research during the cold war -- should be destroyed, since their existence leaves open the possibility of smallpox falling into the hands of bioterrorists. North Korea, Iraq, and possibly other nations, have undeclared smallpox stockpiles. No matter what protective measures the government takes, a smallpox outbreak is possible as long as such stockpiles exist.

Smallpox Pathogenesis and Symptoms

Smallpox is contracted by inhalation of variola virus particles. Lesions in the throat and mouth release large amounts of virus into the saliva, which are spread into the air by coughing. Smallpox is spread via saliva during face-to-face contact or by inhalation of virus particles from pus and scabs encountered on bed sheets and other places.

Upon inhalation, variola implants itself in the lining of the throat and nasal cavity, and then migrates to the lymph nodes and the blood. By the eighth day after contraction, the virus has undergone intense multiplication. Variolae localize in blood vessels in the skin and inside the mouth and throat. After about 12-14 days of incubation, high fever, headache, backache, and other flu-like symptoms appear. A rash appears in the mouth and throat and on the face, arms, trunk, and legs. After one or two days, the rash turns into deeply imbedded pustules, or pox, which become scabby after about a week.

At this point, the pox do not itch, but they cause excruciating, fiery pain. Sometimes the pox are so numerous and close together that they cannot be distinguished from one another. In 1634, William Bradford, governor of the Plymouth colony in Massachusetts, wrote of the horrific effect of smallpox on the skin of infected Native Americans: "Their skin... cleaves... to the matts they lye on; when they turn them, a whole side will flea off at once... they die like rotten sheep." Viral toxins and human immune complexes circulating in the blood cause death in the second week of infection. The most virulent form of smallpox, caused by variola major, is fatal in 30-50% of unvaccinated patients. A milder form of smallpox, called alastrim, is caused by the variola minor strain and has only a 1% death rate among unvaccinated people. If the smallpox patient recovers, the scabs separate and fall off after three to four weeks, accompanied by extreme itching. The pox leave behind terrible scars, especially on the face.

According to the American Medical Association (AMA), smallpox occasionally causes encephalitis and blindness, but in its most common form it rarely affects organs other than the skin.

Smallpox in Human History

The ancestor of the variola virus jumped species from rodents to African hunters thousands of years ago. Over millennia, the rodent virus specialized to infect humans, then spread across Africa and beyond, menacing the entire globe. In the seventh and eighth centuries A.D., Arab armies carried smallpox out of Africa to Southwestern Europe; in the 11th and 13th centuries the crusades and trade along the Silk Road to China also contributed to the widespread dissemination of the disease across Eurasia and beyond.

History of smallpox c. 1000 BC Earliest smallpox inoculation, practiced in India 430 BC Plague of Athens described by Thucydides in his History of the Peloponnesian War, thought to be caused by variola 700-800 AD Arab armies carry smallpox out of Africa to Southwestern Europe 1095 Pope Urban II gives the speech which spurs the first of the Crusades 13th C. European trade with China via the Silk Road begins 1519 Hernando Cortes and his troops arrive in the Aztec capital, Tenochtitlan 1717 In England, Lady Mary Wortley Montagu spurs experimental variolation on prisoners 1719-1746 London suffers 5 major smallpox epidemics 1796 Jenner performs the first vaccination Late 18th C. Smallpox kills 400,000 Europeans a year and is endemic in Eurasia Australia, South Africa, and North and South America; variolation slowly spreads across Europe and to America 1840 English Parliament passes the Vaccination Act 1880 Pasteur advances the germ theory of disease 1928 Start of the Soviet bioweapons program 1939 Downey discovers that the virus used in vaccinations is no longer cowpox but a new virus, vaccinia 1942 US army begins germ warfare research 1939-1945 World War II, smallpox infection swells across the globe 1941-46 Percentage of countries in which smallpox is endemic rises from 69% to 87% 1949 Last outbreak of smallpox in the US 1956 US intelligence discovers the existence of the Soviet Union bioweapons program 1965 atomizers with mock smallpox germs are tested in Washington international airport 1967 WHO launches the Intensified Smallpox Eradication Program; KGB agents obtain samples of a virulent strain of variola major in India 1969 Nixon ends the US biological warfare program 1972 US begins phasing out mandatory vaccination in schools; Biological and Toxic Weapons Convention treaty 1977 Last reported case of smallpox in Somalia 1980 WHO declares global eradication of smallpox 1989 Soviet scientist Pasechnik defects to Great Britain 1999 The year previously set for destruction of US and Russian smallpox stockpiles 2001 September 11 terrorist attacks 2002 Deadline for destruction of smallpox stocks extended indefinitely; NIH bioterror defense budget increased to $1.5 billion annually

According to Greek historian Thucydides's, variola is thought to be the cause of the 430 B.C. plague that weakened Athens and contributed to its defeat by Sparta. Smallpox facilitated the European conquest of North and South America. Native populations had never been exposed to variola virus and had no immunity to it. The Spaniards' victory over the Aztecs is a well-known example. In 1519, Spanish forces led by conquistador Hernando Cortes arrived in the Aztec capital of Tenochtitlan. The Aztecs were decimated two years after Cortes' arrival -- but not by the Spaniard's horses, guns, or military skill. It was smallpox that almost completely annihilated the Aztecs, causing the population to fall from 25 million in 1519 to three million 50 years later.

Smallpox also drastically affected everyday life. In 1800, English historian Thomas Macaulay wrote that the disease "was always present, filling the churchyard with corpses, tormenting with constant fears all whom it had not yet stricken ... making the eyes and cheeks of a betrothed maiden objects of horror to the lover." Between 1719 and 1746, London suffered five major smallpox outbreaks. As the 18th century drew to a close, smallpox was killing 400,000 Europeans each year and had spread from Eurasia to Australia, South Africa, and North and South America.

Vaccination

Inoculation against smallpox was first performed in India in 1000 B.C. Pus or scabs from variola pox were rubbed into a skin lesion in a process called variolation. Although variolation sometimes led to smallpox infection, it reduced the death rate among infected people from 30% to 1%. Lady Mary Wortley Montagu, the wife of a member of the English Parliament, observed variolation in the Ottoman court during a trip to Constantinople in 1717. She persuaded the Princess of Wales and her husband to sponsor a public experiment on the efficacy of variolation on prisoners. Due to the success of the experiment, the princess had her own children variolated. From then on, variolation became more widespread; however, because of medical and religious concerns it was not completely embraced by the public. The pus used for variolation was often contaminated with the bacteria that caused tuberculosis or syphilis. To cure people by infecting them seemed unnatural and immoral. However, due to variolation's dramatic reduction in smallpox death rates, the procedure spread across Europe and to America throughout the late 18th century.

In 1770, Dr. Edward Jenner, of Glouchestershire, England noticed that milkmaids who had been infected by cowpox (a much milder virus in the same genus as smallpox) had smooth complexions free of pox scars and didn't contract smallpox. To test his theory that cowpox immunity lessened the severity of smallpox, he variolated 13 milkmaids with smallpox who had had cowpox. Generally, a few pox would develop around the site of variolation, but the milkmaids he variolated in his study did not develop the characteristic lesions. In 1796, now confident in his theory that previous cowpox infection protected people from smallpox infection, Jenner performed a daring and highly unethical experiment: He injected a boy with cowpox, and then variolated him. Like the milkmaids in his previous experiments, the boy did not develop any smallpox lesions. Jenner coined the word vaccination (from Latin vacca, cow) to describe his cowpox inoculation. Jenner performed his experiments over 100 years before Pasteur advanced his germ theory of disease in 1880. Jenner did not know about immunity or viruses -- he only knew his vaccination worked.

Jenner's vaccination method was not widely accepted for several years. In 1797, the British Royal Society rejected a paper in which Jenner described his vaccination experiments. The members felt that his ideas were "too revolutionary" and his experimental evidence "too limited." Jenner published his paper privately in 1798; within the year it was translated into Latin, German, and French, and about 1000 people were vaccinated.

Jenner's method of cowpox inoculation, called vaccination, became more and more popular in Europe and America over the next 50 years, largely because it had much milder side effects than variolation and could never result in smallpox infection. Variolation involves exposing patients to variola virus; vaccination only exposes patients to cowpox. By 1800, more than 100,000 citizens of Great Britain had been vaccinated and in 1840 the British Parliament passed the Vaccination Act, mandating free vaccination of infants and outlawing variolation. Most Western governments adopted similar laws by 1900. In 1939, Allan Downie of the University of Liverpool determined that the virus used for smallpox vaccinations was no longer genetically identical to cowpox but had diverged into a new virus. Downie called the virus vaccinia. To this day no one knows why the change occurred.

In the United States, rates of smallpox infection decreased as mandatory vaccination of schoolchildren was put in place throughout the first half of the 20th century and the invention of the ice box made vaccine storage efficient. While the United States and European countries were getting smallpox under control, the developing world still suffered from it. Infection rates were high in Africa, South America, and Asia, where vaccination was not as widespread as in the West. During World War II, smallpox infection swelled. Previously unexposed regions were overtaken by variola carried by foreigners, or by soldiers who brought the virus home from foreign lands. From 1941 to 1946, the percentage of countries in which smallpox was endemic rose from 69% to 87%. During that period, smallpox killed three to four million people annually.

Worldwide Eradication

On January 1, 1967, the WHO began the Intensified Smallpox Eradication Program, one of the greatest triumphs in the history of medicine. The WHO employed a strategy of mass vaccination coupled with subsequent surveillance and containment. After mass vaccination of a population, WHO agents monitored it for isolated cases of smallpox, containing them via quarantine and small-scale vaccination. Key to the program's success was its sensitivity to local needs. Operations were specialized to each country and agents worked carefully within the framework of local cultures. Freeze-dried vaccine (which does not require refrigeration) and a hydraulically powered jet injector capable of performing 1000 vaccines per hour made eradication possible in developing countries where electricity was scarce and generators unreliable. The last reported case of smallpox occurred in Somalia in 1977; the disease was declared eradicated and large-scale vaccination ended worldwide in 1980.