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Smallpox
Classification & external resources

A child infected with smallpox
ICD-10	B03.
ICD-9	050
DiseasesDB	12219
MedlinePlus	001356
eMedicine	emerg/885
MeSH	D012899

Smallpox (also known by the Latin names Variola or Variola vera) is a contagious disease unique to humans.^[1] Smallpox is caused by either of two virus variants named Variola major and Variola minor. The deadlier form, V. major, has a mortality rate of 30–35%, while V. minor causes a milder form of disease called alastrim and kills ~1% of its victims.^[2][1] Long-term side-effects for survivors include the characteristic skin scars. Occasional side effects include blindness due to corneal ulcerations and infertility in male survivors.

Smallpox killed an estimated 60 million Europeans, including five reigning European monarchs, in the 18th century alone. Up to 30% of those infected, including 80% of the children under 5 years of age, died from the disease, and one third of the survivors became blind.^[3][4]

Smallpox was responsible for an estimated 300–500 million deaths in the 20th century.^[5][6] As recently as 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year.^[7] After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1979.^[7] To this day, smallpox is the only human infectious disease to have been completely eradicated from nature.^[8]

Electron micrograph of smallpox.

Smallpox is caused by infection with variola virus, which belongs to the genus Orthopoxvirus, the family Poxviridae, and subfamily chordopoxvirinae. Variola virus is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm,^[9] with a single linear double stranded DNA genome consisting of 186 kilobase pairs (kbp) and containing a hairpin loop at each end.^[10] The two classic varieties of smallpox are variola major and variola minor. The closest viral relative is molluscum contagiosum, which like smallpox, infects only humans. However, unlike variola species, molluscum infection is benign.

The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. In order to replicate poxvirures produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase. Both enveloped and nonenveloped virions are infectious. The viral envelop is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin.^[10] Infection with either variola major and variola minor confers immunity against the other.^[11]

Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.^[12]

Transmission of smallpox occurs through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It is transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually within a distance of 6 feet, but can also be spread through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely, smallpox has been spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.^[13] The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.^[11]

Smallpox is not notably infectious in the prodromal period and viral shedding is usually delayed until the appearance of the rash, which is often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but is most frequent during the first week of the rash, when most of the skin lesions are intact.^[12] Infectivity wanes in 7 to 10 days when scabs form over the lesions, but the infected person is contagious until the last smallpox scab falls off.^[14]

Smallpox is highly contagious, but generally spreads more slowly and less widely than other viral diseases, probably because transmission requires close contact and occurs after the onset of the rash. In temperate areas, the number of smallpox infections were highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year.^[12] Age distribution of smallpox infections depends on acquired immunity. Vaccination immunity declines over time and is probably lost in all but the most recently vaccinated populations.^[11] Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier state.^[12]

Child showing rash due to smallpox variola major virus

There are two clinical forms of smallpox. Variola major is the severe and most common form of smallpox, with a more extensive rash and higher fever. There are four types of variola major smallpox based on the Rao classification^[15]: ordinary, modified, flat, and hemorrhagic. Historically, variola major has an overall fatality rate of about 30%; however, flat and hemorrhagic smallpox are usually fatal.^[16] In addition, a form called variola sine eruptione (smallpox without rash) is seen generally in vaccinated persons. It is a febrile illness occurring after the usual incubation period and can be confirmed only by antibody studies or, rarely, by virus isolation. Subclinical (asymptomatic) infections with variola virus have also been noted, but are not believed to be common.^[12]

Variola minor is a less common presentation of smallpox, and a much less severe disease, with historical death rates of 1% or less.^[13]

The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. Once inhaled, variola virus invades the oropharyngeal (mouth and throat) or the respiratory mucosa, migrates to regional lymph nodes, and begins to multiply. In the initial growth phase the virus seems to move from cell to cell, but around the 12th day, lysis of many infected cells occurs and the virus is found in the bloodstream in large numbers (this is called viremia), and a second wave of multiplication occurs in the spleen, bone marrow, and lymph nodes. The initial or prodromal symptoms are similar to other viral diseases such as influenza and the common cold: fever (at least 38.5 °C (101 °F)), muscle pain, malaise, headache, prostration, and as the digestive tract is commonly involved, nausea and vomiting and backache often occur. The prodrome, or preeruptive stage, usually lasts 2–4 days. By days 12–15 the first visible lesions—small reddish spots called enanthem—appear on mucous membranes of the mouth, tongue, palate, and throat, and temperature falls to near normal. These lesions rapidly enlarge and rupture, releasing large amounts of virus into the saliva.^[11]

Smallpox virus preferentially attacks skin cells, causing the characteristic pimples associated with the disease. A rash develops on the skin 24 to 48 hours after lesions on the mucous membranes appear. Typically the pimples (macules) first appear on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process takes no more than 24 to 36 hours, after which no new lesions appear.^[11] By days three or four the condition worsens, and at this point Variola major infection can take several very different courses.

Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type.^[12] In this form of the disease, by the second day of the rash, the macules become raised papules. By the third or fourth day the papules fill with an opalescent fluid to become vesicles. This fluid becomes opaque and turbid within 24–48 hours, giving them the appearance of pustules; however, the so-called pustules are filled with tissue debris, not pus.^[11]

By the sixth or seventh day, all the skin lesions have become pustules. Between 7 and 10 days the pustules mature and reach their maximum size. The pustules are sharply raised, typically round, tense, and firm to the touch. The pustules are deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaks from the pustules, and by the end of the second week the pustules deflate, and start to dry up, forming crusts (or scabs). By day 16-20 scabs have formed over all the lesions, which have started to flake off, leaving de-pigmented scars.^[17]

Ordinary smallpox generally produces a discrete rash, in which the pustules stand out on the skin separately. The distribution of the rash is densest on the face; more dense on the extremities than on the trunk; and on the extremities, more dense on the distal parts than on the proximal. The palms of the hands and soles of the feet are involved in the majority of cases.^[12] In some cases, the blisters merge together into sheets, forming a confluent rash, which begin to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remain ill even after scabs have formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.^[12]

Referring to the character of the eruption and the rapidity of its development, modified smallpox occurs mostly in previously vaccinated people. In this form the prodromal illness still occurs but may be less severe than in the ordinary type. There is usually no fever during evolution of the rash. The skin lesions tend to be fewer and evolve more quickly, are more superficial, and may not show the uniform characteristic of more typical smallpox.^[17] Modified smallpox is rarely, if ever, fatal. This form of variola major is more easily confused with chickenpox.^[12]

In Flat-type smallpox (also called malignant smallpox) the lesions remain almost flush with the skin at the time when raised vesicles form in ordinary-type smallpox. It is unknown why some persons develop this type of disease. Historically, flat-type smallpox accounted for 5%–10% of cases, and the majority (72%) were in children.^[18] Flat smallpox is accompanied by a severe prodromal phase that lasts 3–4 days, prolonged high fever, and severe symptoms of toxemia. The rash on the tongue and palate is usually extensive. The skin lesions mature very slowly and by the seventh or eighth day the lesions are flat and appear to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contain very little fluid, are soft and velvety to the touch, and may contain hemorrhages. Flat-type smallpox is nearly always fatal.^[12]

Hemorrhagic smallpox is a severe form of smallpox that is accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form developed in perhaps 2% of infections and occurred mostly in adults. In hemorrhagic smallpox the skin does not blister, but remains smooth. Instead, bleeding occurs under the skin, making the skin look charred and black (this is known as black pox).

In the early, or fulminating, form, hemorrhaging appears on the second or third day as sub-conjunctival bleeding turns the whites of the eyes deep red. Hemorrhagic smallpox also produces a dusky erythema, petechiae, and hemorrhages in the spleen, kidney, serosa, muscle, and, rarely, the epicardium, liver, testes, and bladder. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. A later form of the disease occurs in patients who survive for 8–10 days. The hemorrhages appear in the early eruptive period, and the rash is flat and does not progress beyond the vesicular stage.^[12] Patients in the early stage of disease show a decrease in platelets, prothrombin, and globulin, and an increase in circulating antithrombin. Patients in the late stage have significant thrombocytopenia; however, deficiency of coagulation factors is less severe. Some in the late stage also show increased antithrombin.^[11] This form of smallpox occurs in anywhere from 3–25% of fatal cases (depending on the virulence of the smallpox strain). Overall the mortality rate is greater than 95 percent.^[16]

The historical modes of death are similar to those in burns, with catastrophic losses of fluid, protein and electrolytes beyond the capacity of the body to replace or assimilate, and fulminating sepsis, both due to the removal of the barrier between the internal milieu and outside world. Supportive treatments have improved since the last large smallpox epidemics, but it would be grossly optimistic to imagine that, even with a small number of patients, the most intensive modern treatment would ensure survival, even where the damage is predominantly only in the skin. A reduction in the severity of the disease by raising immunity is likely to make a large difference in numbers reaching the threshold of death, and supportive treatment a small one in elevating that threshold.

Smallpox virus pocks on the chorioallantoic membrane of a developing chick.

The clinical definition of smallpox is an illness with acute onset of fever greater than 101°F (38.3°C) followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause.

If a clinical case is observed, smallpox is confirmed using laboratory tests. The diagnosis of an orthopoxvirus infection can be made rapidly by electron microscopic examination of pustular fluid or scabs. However, all orthopoxviruses exhibit identical brick-shaped virions by electron microscopy.^[11] Definitive laboratory identification of variola virus involves growing the virus on chorioallantoic membrane (part of a chicken embryo) and examining the resulting pock lesions under defined temperature conditions.^[19] Strains may be characterized by polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection.^[20]

Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox can be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods are available for detecting chickenpox in evaluation of suspected smallpox cases.

Smallpox inoculation sign, 1801

By that time, a preventive treatment for smallpox had finally arrived. It was a process called inoculation, also known as insufflation or variolation. Inoculation was not a sudden innovation, as it is known to have been practiced in India as early as 1000 BC.^[21] The Indians rubbed pus into the skin lesions. The Chinese blew powdered smallpox scabs up the noses of the healthy after discovery, by a Buddhist nun, that this inoculated non-immune people. The patients would then develop a mild case of the disease and from then on were immune to it. This technique is known as variolation and although variolation had a 0.5-2% mortality rate, this was considerably less than the 20-30% mortality rate of the disease itself. The process spread to Turkey where Lady Mary Wortley Montagu, wife of the British ambassador, learned of it from Emmanuel Timoni (ca. 1670–1718), a doctor affiliated with the British Embassy in Istanbul.^[2] She had the procedure performed on her son and daughter, aged 5 and 4 respectively. They both recovered quickly and the procedure was hailed as a success and reported to the Royal Society in England. Timoni, from the University of Padova, Italy and a member of the Royal Society of London since 1703, published “an account, or history, of the procuring the smallpox by incision” in December 1713 in the Philosophical Transactions. His work was published again in 1714 in Leipzig and was followed by those of Pylarino (1715), Leduc (1722), and Maitland (1722).

In 1721, an epidemic of smallpox hit London and left the British Royal Family in fear.^[2] Reading of Lady Wortley Montagu’s efforts, they wanted to use inoculation on themselves. Doctors told them that it was a dangerous procedure, so they decided to try it on other people first. The test subjects they used were condemned prisoners. The doctors inoculated the prisoners and all of them recovered in a couple of weeks. So assured, the British royal family inoculated themselves and reassured the English people that it was safe.

But inoculation still had its critics. Prominent among them were religious preachers who claimed that smallpox was God’s way of punishing people and that inoculation was a tool of Satan.^{[citation needed]} This resistance only encouraged Montagu and the others to work even harder. By 1723 inoculations were extremely common in England, but even scientific opposition (such as the Fellow of the Royal College of Physicians Pierce Dod) continued for some time.

In 1721, Onesimus was the slave of a Boston preacher when smallpox came to Boston via a ship arriving from Barbados.^[22] His owner, Cotton Mather asked his slave if he ever had smallpox. Onesimus said, “Yes and no,” and explained a technique from his homeland in Africa, thought to be in Sudan. He explained that pus from an infected person was deliberately rubbed into a scratch or cut of a non-infected person, and when successful, the person had immunity. This remedy from an African slave was the precursor to inoculations. Cotton Mather, the son of a former Harvard University dean, was waging a campaign of his own to promote the process, although religious resistance to inoculation was very strong. At one point, Cotton Mather was in danger from a crowd that wanted to hang him. After six patients died from the procedure, he was called a murderer. But, when the population of Boston returned after the end of a smallpox epidemic in 1722, he was an instant hero. Out of the population of Boston, 7% had died from smallpox. Out of the 300 people that chose to inoculate themselves, only 2% died. In 1750, the English magazine, Gentleman's Magazine, reprinted a 1725 pamphlet that argued in support of smallpox inoculations. By 1774, it was considered odd not to choose inoculation.

Even though inoculation was a powerful method of controlling smallpox, it was far from perfect. Inoculation caused a mild case of smallpox which resulted in death in about 2% of the cases. It was also difficult to administer. Sick patients had to be locked away to prevent them from transmitting the disease to others. Thus George Washington initially hesitated to have his Revolutionary War troops inoculated during a smallpox outbreak in February 1777, writing, “should We inoculate generally, the Enemy, knowing it, will certainly take Advantage of our Situation;” but the virulence of the outbreak soon prompted him to order inoculation for all troops and recruits who had not had the disease.^[23]

In 1796, a young boy in England was inoculated by Edward Jenner. The boy suffered from the disease for an entire month and recovered completely.

At the age of thirteen, Jenner was apprenticed to Dr. Ludlow in Sodbury. He observed that people who caught cowpox while working with cows were known not to catch smallpox. He assumed a causal connection. The idea was not taken up by Dr. Ludlow at that time. After Jenner returned from medical school in London, a smallpox epidemic struck his home town of Berkeley, England. He advised the local cow workers to be inoculated. The farmers told him that cowpox prevented smallpox. This confirmed his childhood suspicion, and he studied cowpox further, presenting a paper on it to his local medical society.

Perhaps there was already an informal public understanding of some connection between disease resistance and working with cows. The “beautiful milkmaid” seems to have been a frequent image in the art and literature of this period. But we know for a fact: In the years following 1770 there were at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791), who tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. In 1796 Sarah Nelmes, a local milkmaid, contracted cowpox and went to Jenner for treatment. Jenner took the opportunity to test his theory. He inoculated James Phipps, the eight-year-old son of his gardener, not with smallpox but with cowpox. After an extremely weak bout of cowpox, James recovered. Jenner then tried to infect James with smallpox but nothing happened—the boy was immune to smallpox.

Jenner reported his observations to the Royal Society. Further work was suggested, and Jenner published a series of 23 cases, including his son Edward, none suffered severely from smallpox. Two years later a society to oppose vaccination had been established in Boston, Massachusetts^{[citation needed]} — an indication of rapid spread and deep interest. By 1800 Jenner’s work had been published in all of the major European languages. The process was performed all over Europe and the United States. The death rate was close to zero with the process, which became known as vaccination and was continued to around 1974 in the UK. A typical death rate at that time was roughly one per million, making vaccination against smallpox with vaccinia the most dangerous immunisation widely provided in modern times.^{[citation needed]} Thanks to the development of the smallpox vaccine, the disease was officially eradicated in 1979.

The Balmis Expedition (1803) carried the vaccine to Spanish America, the Philippines and China under commission of the Spanish Crown.

Some years before Dr. Jenner, Benjamin Jesty, a farmer at Yetminster in Dorset (he later moved to and is buried at Worth Matravers) is recorded as observing the two milkmaids living with his family to have been immune to smallpox and then inoculating his family with cowpox to protect them from smallpox. This was done in 1774 and can be found with Crookshank's History and Pathology of Vaccination, London 1889, vol. 1, p.110ff. But the question of who first initiated smallpox inoculation/vaccination can not be answered properly, as there is in the sources the exact date and time only for the predecessor Plett (1791), but not for Sevel, Jensen and Rendall. Louis T. Wright,^[24] an African-American and Harvard medical school graduate (1915), introduced intradermal vaccination for smallpox for the soldiers while serving in the Army during World War I.^[25]

In late 2001, the governments of United States and United Kingdom considered stockpiling smallpox vaccines, even while assuring the public that there was no "specific or credible" threat of bioterrorism.^[26] Later, the director of State Research Center of Virology and Biotechnology VECTOR warned that terrorists could easily lure underpaid former Soviet researchers to turn over samples to be used as a weapon, saying "All you need is a sick fanatic to get to a populated place. The world health system is completely unprepared for this."^[27]

In the United Kingdom, controversy erupted over the company contracted to supply the vaccine due to the political connections of its owner, Paul Drayson, and questions over the choice of vaccine strain being different to that used in the United States.^[28] Plans for mass vaccinations in the United States stalled as the necessity and undesirable side-effects came into question.^[29]

Since Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox circa 1796, various attempts were made to eliminate smallpox. In 1842, England banned inoculation, later progressing to mandatory vaccination instead. In the United States, from 1843 to 1855 first Massachusetts, and then other states required vaccination. Although some disliked these measures^[30], coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In poorer countries, vaccines and the necessary infrastructure were less affordable and available.

Vaccination during the Smallpox Eradication and Measles Control Program in Niger, February, 1969.

In 1958 the Soviet Union called for the eradication of smallpox from the planet and promised to supply vaccine and equipment. At that point, 2 million people were dying every year. In 1967, an international team was formed under the leadership of an American, Donald Henderson. Despite the lack of official recognition, experts on smallpox say there is little doubt that the eradication effort, conducted in partnership with the former Soviet Union at the height of the cold war, succeeded in large part because of Dr. Henderson's cunning and derring-do. ^[31]

To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as ring vaccination. The key to this strategy was surveillance and containment. Surveillance can be best defined as the monitoring of cases in a community. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities.

The fact that humans are the only reservoir for smallpox infection played a significant role in WHO deciding to eradicate smallpox. There are many other pox viruses, such as monkeypox, however none appear to be of public health significance. In addition, smallpox carriers did not exist.

WHO established a network of consultants who assisted countries in setting up surveillance and containment activities.

Eradicating smallpox required huge effort and concentration of manpower. In India and Bangladesh, religion and civil strife along with natural disasters became obstacles. In fear of offending the goddess associated with the disease, many Hindus refused the vaccine. In some countries, such as the Sudan, civil war threatened to interfere with eradication attempts. Health teams placed themselves in great danger by working in war-torn areas. Surprisingly, none of the team members were hurt in the process.^{[citation needed]}

Natural events also impeded the vaccination team’s efforts. The monsoon rains burst dams and dikes. The rain and flooding forced people to flee, once again allowing smallpox to spread. This outbreak took the team a whole year to stop.

The last major European outbreak of smallpox was the 1972 outbreak of smallpox in Yugoslavia. After a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus, an epidemic infected 175 people, causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook massive revaccination of the population, enlisting the help of the WHO and Donald Henderson. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May-July of 1963 in Stockholm, Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of local population.^[32]

The last naturally occurring case of Variola Minor was diagnosed in Somalia on a cook named Ali Maow Maalin on October 26, 1977. The last naturally occurring case of the more deadly Variola Major had been detected in October 1975 in a two-year-old Bangladesh girl, Rahima Banu. In the final tally, the U.S. had applied $300 million to the eradication program^{[citation needed]}.

This 1980 photograph, taken at the Centers for Disease Control, shows three former directors of the Global Smallpox Eradication Program as they read the good news that smallpox had been eradicated on a global scale. From left to right: Dr. J. Donald Millar, (Director: 1966 to 1970), Dr. William H. Foege (Director: 1970 to 1973), and Dr. J. Michael Lane (Director: 1973 to 1981.

The global eradication of smallpox was certified, based on intense verification activities in countries, by a commission of eminent scientists on December 9, 1979 and subsequently endorsed by the World Health Assembly on May 8, 1980.^[33][34]

However, there are samples housed in laboratories in Atlanta, Georgia and Moscow.^{[citation needed]}

In 1978, there was evidently an escape of smallpox from containment in a research laboratory in Birmingham, England. A medical photographer, Janet Parker, died from the disease itself, after which the scientist responsible for the unit, Professor Henry Bedson, committed suicide. In light of this accident, all known stocks of smallpox were destroyed, except the stocks at the United States Centers for Disease Control and Prevention (CDC) and the Russian State Research Center of Virology and Biotechnology VECTOR in Koltsovo, where a regiment of troops guards it. Under such tight control, smallpox would, it was thought, never be let out again. Even though the destruction of virus stocks was ordered in 1993, 1994, 1995, and 1996^{[citation needed]}, they have not yet been destroyed, since a number of researchers still wish to retain the stocks for scientific purposes.

In March 2003 smallpox scabs were found tucked inside an envelope in a book on Civil War medicine in Santa Fe, New Mexico.^[35] The envelope was labeled as containing the scabs and listed the names of the patients they came from. Assuming the contents could be dangerous, the librarian who found them did not open the envelope. The scabs ended up with employees from the CDC who responded quickly once informed of the discovery. The discovery raised concerns that smallpox DNA could be extracted from these and other scabs and used for a biological attack. Even with Variola sequenced, assembling a virus from scratch remains challenging.

In 1986, the World Health Organization recommended destruction of the virus, and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1995.^[36]

In 2002 the policy of the WHO changed to be against its final destruction.^[37]

In World War II, scientists from the United Kingdom and the United States were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine.^[38]

The first smallpox weapons factory in the Soviet Union was established in 1947 in the city of Zagorsk, close to Moscow ^[39]. It was produced by injecting small amounts of the virus into chicken eggs. An especially virulent strain (codenamed India-1967 or India-1) was brought from India in 1967 by a special Soviet medical team that had been sent to India to help to eradicate the virus. The pathogen was manufactured and stockpiled in large quantities throughout the 1970s and 1980s.

An outbreak of weaponized smallpox occurred during its testing in the 1970s. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army, and a senior researcher within the Soviet program of biological weapons described this incident:

“On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came 15 km away from the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation—400 gr. of which was exploded on the island—”got her” and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of Ministry of Defense and requested to forbid the stop of the Alma-Ata—Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.” ^[40][41]

A production line to manufacture smallpox on an industrial scale was launched in the Vector Institute in 1990.^[39] The development of genetically altered strains of smallpox was presumably conducted in the Institute under leadership of Dr. Sergei Netyosov in the middle of the 1990s, according to Kenneth Alibek, although this has never been proven due to the classified nature of the program^[39]

More recent research on the related mousepox virus has reinforced fears that smallpox could be engineered to overcome immune responses, even in vaccinated individuals, making it even more formidable as a biological weapon.^[42]

It is important to note that, while historical epidemics and pandemics are believed by some historians to have been early outbreaks of smallpox, contemporary records are not detailed enough to make a definite diagnosis at this distance.^[30]

The Plague of Athens devastated the city of Athens in 430 BC, killing around a third of the population, according to Thucydides. Historians have long considered this an example of bubonic plague, but more recent examination of the reported symptoms led some scholars to believe the cause may have been measles, smallpox, typhus, or a viral hemorrhagic fever (like Ebola).

The Antonine Plague that swept through the Roman Empire and Italy in 165–180 is also thought to be either smallpox or measles.^{[43] [30]} A second major outbreak of disease in the Empire, known as the Plague of Cyprian (251–266), was also either smallpox or measles.

The next major epidemic believed to be smallpox occurred in India. The exact date is unknown. Around 400 AD, an Indian medical book recorded a disease marked by pustules and boils, saying "the pustules are red, yellow, and white and they are accompanied by burning pain … the skin seems studded with grains of rice." The Indian epidemic was thought to be punishment from a god, and the survivors created a goddess, Sitala, as the anthropomorphic personification of the disease.^[44][45][46] Smallpox was thus regarded as possession by Sitala. In Hinduism the goddess Sitala both causes and cures high fever, rashes, hot flashes and pustules. All of these are symptoms of smallpox.

Smallpox did not definitively enter Western Europe until about 581 when Bishop Gregory of Tours provided an eyewitness account that describes the characteristic findings of smallpox.^[30] Most of the details about the epidemic that followed are lost, probably due to the scarcity of surviving written records of early medieval society.

After first contacts with Europeans and Africans, some believe that the death of 90–95% of the native population of the New World was caused by Old World diseases.^[51] It is suspected that smallpox was the chief culprit and responsible for killing nearly all of the native inhabitants of the Americas. For more than 200 years, this disease affected all new world populations, mostly without intentional European transmission, from contact in the early 1500s to until possibly as early as the French and Indian Wars (1754-1767).^[49]

In 1519 Hernán Cortés landed on the shores of what is now Mexico and was then the Aztec empire. In 1520 another group of Spanish came from Cuba and landed in Mexico. Among them was an African slave who had smallpox. When Cortés heard about the other group, he went and defeated them. In this contact, one of Cortés's men contracted the disease. When Cortés returned to Tenochtitlan, he brought the disease with him.

Soon, the Aztecs rose up in rebellion against Cortés and his men. Outnumbered, the Spanish were forced to flee. In the fighting, the Spanish soldier carrying smallpox died. After the battle, the Aztecs contracted the virus from the invaders' bodies.^{[citation needed]} Cortes would not return to the capital until August 1521. In the meantime smallpox devastated the Aztec population. It killed most of the Aztec army and 25% of the overall population.^{[citation needed]} A Spanish priest left this description: "As the Indians did not know the remedy of the disease…they died in heaps, like bedbugs. In many places it happened that everyone in a house died and, as it was impossible to bury the great number of dead, they pulled down the houses over them so that their homes become their tombs."^{[citation needed]} On Cortés's return, he found the Aztec army’s chain of command in ruins. The soldiers who lived were still weak from the disease. Cortés then easily defeated the Aztecs and entered Tenochtitlán, where he found that smallpox had killed more Aztecs than had the cannons.^{[citation needed]} The Spaniards said that they could not walk through the streets without stepping on the bodies of smallpox victims.^{[citation needed]}

The effects of smallpox on Tahuantinsuyu (or the Inca empire) were even more devastating. Beginning in Colombia, smallpox spread rapidly before the Spanish invaders first arrived in the empire. The spread was probably aided by the efficient Inca road system. Within months, the disease had killed the Sapa Inca Huayna Capac, his successor, and most of the other leaders. Two of his surviving sons warred for power and, after a bloody and costly war, Atahualpa become the new Sapa Inca. As Atahualpa was returning to the capital Cuzco, Francisco Pizarro arrived and through a series of deceits captured the young leader and his best general. Within a few years smallpox claimed between 60% and 90% of the Inca population,^[52] with other waves of European disease weakening them further. However, some historians^{[attribution needed]} think a serious native disease called Bartonellosis may have been responsible for some outbreaks of illness. The effects of smallpox were depicted in the ceramics of the Moche people of ancient Peru.^{[53][citation needed]}

Even after the two mighty empires of the Americas were defeated by the virus and disease, smallpox continued its march of death. In 1633 in Plymouth, Massachusetts, the Native Americans were struck by the virus. As it had done elsewhere, the virus wiped out entire population groups of Native Americans. It reached Lake Ontario in 1636, and the lands of the Iroquois by 1679, killing thousands.

The worst sequence of smallpox attacks took place in Boston, Massachusetts. From 1636 to 1698, Boston endured six epidemics. In 1721, the most severe epidemic occurred. The entire population fled the city, bringing the virus to the rest of the Thirteen Colonies. In the late 1770s, during the American Revolutionary War, smallpox returned once more and killed an estimated 125,000 people.^[54] Peter Kalm in his “Travels in North America”, described how in that period, the dying Indian villages became overrun with wolves feasting on the corpses and weakened survivors.^[55]

Famous victims of this disease include Date Masamune of Japan (who lost an eye to the disease), Ramesses V,^[34] the Shunzhi Emperor and Tongzhi Emperor of China (official history), Mary II of England, Maximilian III Joseph, Elector of Bavaria and Peter II of Russia. Guru Har Krishan 8th Guru of the Sikhs in 1664, Peter III of Russia in 1744.^[56] Joseph Stalin, who was badly scarred by the disease early in life, often had photographs retouched to make his pockmarks less apparent.

Families prominent in history often had several people fall victim to the disease. For example, several relatives of Henry VIII survived the disease but were scarred by it. These include his sister Margaret, Queen of Scotland, his fourth wife, Anne of Cleves, and his daughter, Elizabeth I of England in 1562. His son and heir Edward VI died very shortly after apparently recovering from the disease. Some scholars assert that his death may have been due to complications from smallpox. A more distant relative, Mary Queen of Scots, contracted the disease as a child but had no visible scarring. Deaths from smallpox often impacted dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those earlier in the succession line and he himself died of the disease in 1774.

Smallpox 2002, a drama involving a fictional worldwide pandemic of smallpox unleashed by a lone bio-terrorist, was broadcast on the BBC on 5 February 2002. Shown just months after the September 11th terrorist attacks and the anthrax scares that followed, the film drew widespread criticism in the press, based mainly on the belief that an outbreak on that scale could not be caused by a single person's touch, and the film-makers were accused of deliberately trying to provoke fear in the minds of viewers.

The book Code Orange by Caroline B. Cooney features a teenage boy who finds two smallpox scabs in an envelope in an old medical textbook. He begins researching the disease for his school project, at the same time desperately trying to find out if, when he inhaled the smallpox scab dust, he contracted the virus. As a terrorist group finds out about his situation, things go from bad to worse.

• Virus
• Vaccinia
• Vaccination
• Mathematical modelling in epidemiology#The mathematics of mass vaccination
• Herd immunity
• CCR5-Δ32
• Pandemic
• Infectious disease
• Biological warfare
• Ebola VHFs
• Medieval demography
• Polio
• Population history of American indigenous peoples
• Columbian Exchange or The Grand Exchange

Wikimedia Commons has media related to:

Smallpox

• Smallpox Fact Sheet from the CDC
• Smallpox summary by AFIP (Armed Forces Institute of Pathology)
• Bioterrorism Category A Agents—Information Resources
• Smallpox Biosafety The Genetic Engineering of Smallpox: WHO’s Retreat from the Eradication of Smallpox Virus
• CDC.gov—‘Bioterrorism Agents > Smallpox Info for Specific Groups: What Everyone Should Know,’ CDC
• Smallpox as a potential WMD.

• Vaccine Research Center (VRC) - Information concerning vaccine research studies

• Photographs of smallpox patients
• Smallpox Images and Diagnosis Synopsis
• molluscum photos

• Cappel,Constance, "The Smallpox Genocide of the Odawa Tribe at L'Arbre Croche, 1763: The History of a Native American People," Lewiston, NY: The Edwin Mellen Press, 2007, ISBN 0773452206.
• WHO.int—‘Smallpox: Historical significance,’ World Health Organization (WHO)
• Inoculation for the Small-Pox defended—1750 article from Gentleman's Magazine
• Why Blame Smallpox? Small pox in ancient Peru
• History of Smallpox in South Asia
• Small pox history in India