Smallpox

A child showing rash due to ordinary-type smallpox (Variola major)

Ninety percent or more of smallpox cases among unvaccinated persons were of the ordinary type.[32] In this form of the disease, by the second day of the rash the macules had become raised papules. By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles. This fluid became opaque and turbid within 24–48 hours, resulting in pustules.

By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars.[36]

Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62 percent.[32]

Modified smallpox in a vaccinated 4 year old in Cardiff, Wales, 1962

Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox.[36] Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox.[32]

Malignant hemorrhagic smallpox in a baker during an 1896 epidemic in Gloucester, England. Died 8 days after admission.

In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10 percent of cases, and most (72 percent) were children.[3] Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia. The prodromal symptoms continued even after the onset of the rash.[3] The rash on the mucous membranes (enanthem) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign.[3] This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs.[37]

Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera. This form develops in approximately two percent of infections and occurs mostly in adults.[32] Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black,[32] hence this form of the disease is also referred to as variola nigra or "black pox".[38] Hemorrhagic smallpox has very rarely been caused by Variola minor.[39] While bleeding may occur in mild cases and not affect outcomes,[40] hemorrhagic smallpox is typically fatal.[41] Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms.[3]

Likely hemorrhagic smallpox during a 1925 Milwaukee, Wisconsin epidemic in a patient who later died. Patient described as an unvaccinated Christian Scientist, who "thought that he could by power of mind prevent smallpox."

The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain.[42] The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before.[41] Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes, skeletal muscles, pericardium, liver, gonads and bladder.[39] Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy.[39] This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males).[41] The case fatality rate of early hemorrhagic smallpox approaches 100%.[41]

There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease.[3] Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form.[32] Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin.[33] This form of smallpox occurs anywhere from three to 25 percent of fatal cases, depending on the virulence of the smallpox strain.[35] Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence.[3] The case fatality rate for late hemorrhagic smallpox is around 90-95%.[34] Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox.[3]

The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago.[43] The wide range of dates is due to the different records used to calibrate the molecular clock. One clade was the Variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both Alastrim minor (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago.[44]

A second estimate has placed the separation of variola from Taterapox (an Orthopoxvirus of some African rodents including gerbils) at 3,000 to 4,000 years ago.[45] This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses, the divergence date of variola from Taterapox has been estimated to be 50,000 years ago.[45] While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed.

Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains.[46] The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries.

Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm,[47] with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.[48][49] The two classic varieties of smallpox are variola major and variola minor.

Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.[32]

The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. To replicate, poxviruses 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 unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin.[48] Infection with either variola major or variola minor confers immunity against the other.[33]

The more common, infectious form of the virus comes from the Variola major strain.

Variola minor, also called alastrim, was a less common form of the virus, and much less deadly. Although Variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like Variola major, Variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with Variola minor conferred immunity against the more dangerous variola major.

Because variola minor was a less debilitating disease than smallpox, patients were more frequently ambulant and thus able to infect others more rapidly. As such, Variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with Variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous Variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980.[50] Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.

The genome of Variola major is about 186,000 base pairs in length.[51] It is made from linear double stranded DNA and contains the coding sequence for about 200 genes.[52] The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome.[53] The coding sequence of the central region of the genome is highly consistent across orthopoxviruses, and the arrangement of genes is consistent across chordopoxviruses[52][53]

The center of the variola genome contains the majority of the essential viral genes, including the genes for structural proteins, DNA replication, transcription, and mRNA synthesis.[52] The ends of the genome vary more across strains and species of orthopoxviruses.[52] These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family.[52] These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences.[53] These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA[53] Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop, a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames, and short tandemly repeating sequences of varying number and length.[53] The ITRs of poxviridae vary in length across strains and species.[53] The coding sequence for most of the viral proteins in Variola major have at least 90% similarity with the genome of Vaccinia, a related virus used for vaccination against smallpox.[53]

Gene expression of variola occurs entirely within the cytoplasm of the host cell, and follows a distinct progression during infection.[53] After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes.[53] About half of the viral genome is transcribed prior to the replication of viral DNA.[53] The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion.[53] These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes.[53] Unlike most DNA viruses, DNA replication in variola and other poxviruses takes place within the cytoplasm of the infected cell.[53] The exact timing of DNA replication after infection of a host cell varies across the poxviridae.[53] Recombination of the genome occurs within actively infected cells.[53] Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression.[53] The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles.[53] These proteins are then packaged into new infectious virions capable of infecting other cells.[53]

Two live samples of Variola major remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia.[54] Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA).[54] Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism.[53] Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases.[55]

The genome of Variola major was first sequenced in its entirety in the 1990s.[52] The complete coding sequence is publicly available online.The current reference sequence for Variola major was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign.[52] A genome browser for a complete database of annotated sequences of Variola and other poxviruses is publicly available through the Viral Bioinformatics Resource Center.[56]

The WHO currently bans genetic engineering of the smallpox virus.[57] However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of Variola major to add a marker gene.[57] This gene, called GFP, or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light.[58] The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome.[58] The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples.[58] The recommendation could only take effect if approved by the WHA.[58] When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time.[59] Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus.[60]

The public availability of variola's complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus.[61] Vaccinia, a cousin of the smallpox virus, was artificially synthesized in 2002 by NIH scientists.[62] They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles.[62]

In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox.[63] The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available.[63] The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of Variola major and causing other scientists to question their motives.[61] Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort.[63] Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus.[63]

Transmission occurred through inhalation of airborne Variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually, within a distance of 1.8 m (6 feet), but could also be spread through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.[31] The virus can cross the placenta, but the incidence of congenital smallpox was relatively low.[33] Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact.[32] Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off.[64]

Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year.[32] Age distribution of smallpox infections depended on acquired immunity. Vaccination immunity declined over time and was probably lost within thirty years.[33] Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state.[32]

Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated.[32]

Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa. Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.[33]

Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.

Statue of Sopona, the Yoruba god thought to cause the disease

The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE),[87][88] and China (1122 BCE),[89] as well as a study of the Egyptian mummy of Ramses V, who died more than 3000 years ago (1145 BCE).[88][90] It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan.[3] In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population.[17][91] At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala, was worshipped in temples throughout the country.[92]

A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox.[93][94]

The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in "Ethiopia" and Egypt – or the plague that lifted Carthage's 396 BCE siege of Syracuse – with smallpox,[3] many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime.[40]

While the Antonine Plague that swept through the Roman Empire in 165–180 CE may have been caused by smallpox,[95] Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450,[3] and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola.[3] Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries.[3] In the 9th century the Persian physician, Rhazes, provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah (The Book of Smallpox and Measles).[96] During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe,[3] where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world.[3]

Drawing accompanying text in Book XII of the 16th-century Florentine Codex (compiled 1555–1576), showing Nahuas of conquest-era central Mexico with smallpox.

There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE.[44] Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas.[3] Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations,[97] and subsequently among the native-born colonists.[98] Case fatality rates during outbreaks in Native American populations were as high as 90%.[99] Smallpox was introduced into Australia in 1789 and again in 1829,[3] though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox.[100] Although smallpox was never endemic on the continent,[3] it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870.[101]

Global number of reported smallpox cases from 1920 to 2016.

By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year.[102] Up to 10 percent of Swedish infants died of smallpox each year,[17] and the death rate of infants in Russia might have been even higher.[89] The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with v. minor induces immunity against the more deadly variola major form. Thus, as v. minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates.[3]

Decade in which smallpox ceased to be endemic by country

The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ (痘疹心法) published in 1549,[103] with earliest hints of the practice in China during the 10th century.[104] In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.[105] Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years".[72] Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu, who later introduced it in the UK.[106]

An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions, a self-taught inoculator from Shetland, Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background.[107][108] His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf.[109] He was reputed not to have lost a single patient.[109] Arthur Edmondston, in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact."[110]

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

The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great, and was educated at the expense of the nation.[111]

The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch, boyhood friend and medical colleague of Jenner.[112] As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there.[113] The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies.[114]

On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act.[115][116] In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800.[117] The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.[118]

In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.[119] Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts.[120] By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.[121] In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.[122]

In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures,[89] coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels.

Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines.[123]

Smallpox quarantine order, California, c. 1910

The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization.[124] The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador.[123] In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake a global initiative to eradicate smallpox.[125] The proposal (Resolution WHA11.54) was accepted in 1959.[125] At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson.[126] In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška.[127]

Three-year-old Rahima Banu of Bangladesh (pictured) was the last person infected with naturally occurring Variola major, in 1975.

In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year.[10] To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by.[128] This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment.

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 and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries.[123] The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff.[129]

The last major European outbreak of smallpox was in 1972 in Yugoslavia, after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over.[130] Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm, Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population.[131]

By the end of 1975, smallpox persisted only in the Horn of Africa. Conditions were very difficult in Ethiopia and Somalia, where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance and containment and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner. As the campaign neared its goal, Fenner and his team played an important role in verifying eradication.[132] The last naturally occurring case of indigenous smallpox (Variola minor) was diagnosed in Ali Maow Maalin, a hospital cook in Merca, Somalia, on 26 October 1977.[32] The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu.[38]

The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980.[10][133] The first two sentences of the resolution read:

Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America.[134]

The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence.[135]

Three former directors of the Global Smallpox Eradication Program read the news that smallpox had been globally eradicated, 1980.

The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978.[136] A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the smallpox virus grown for research purposes at the Medical School laboratory.[137][138] All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR.[139]

WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999.[140] Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes.[141] Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.[142] Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests;[143] a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks.[144] The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.[145]

On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico.[146] The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States.

On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland. The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture.[147][148] After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015.[149]

In 2017, Canadian scientists recreated an extinct horse pox virus to demonstrate that the smallpox virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge.[150] This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations.[151][152]

In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment.[153]

In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region.[154][155][156] A group of Native American warriors laid siege to British-held Fort Pitt on June 22.[157] In response, Henry Bouquet, the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst, who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [sic] the Indians by means of Blankets that may fall in their hands".[158] On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect."[159][154] The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783).[160][161]

According to a theory put forward in Journal of Australian Studies (JAS) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales.[162] This theory was also considered earlier in Bulletin of the History of Medicine[163] and by David Day.[164] However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox—a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it.[165] Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of smallpox virus possessed by First Fleet surgeons. Ian and Jennifer Glynn, in The life and death of smallpox, confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789.[101] In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable.[166] However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin.[167]

W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population.[168] However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis.[169] In a 2013 lecture at the Australian National University,[170] Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox."[171]

During World War II, scientists from the United Kingdom, United States, and Japan (Unit 731 of the Imperial Japanese Army) were involved in research into producing a biological weapon from smallpox.[172] 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.[160]

In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk, 75 km to the northeast of Moscow.[173] An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described the 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 to within 15 km of 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 the 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.[174][175]

Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.[176][177]

Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat. The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility.[178] In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified.

In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo.[178] With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare.[179] Specific allegations made against Iraq in this respect proved to be false.[180]

Concern has been expressed by some that artificial gene synthesis could be used to recreate the virus from existing digital genomes, for use in biological warfare.[181] Insertion of the synthesized smallpox DNA into existing related pox viruses could theoretically be used to recreate the virus.[181] The first step to mitigating this risk, it has been suggested, should be to destroy the remaining virus stocks to enable unequivocal criminalization of any possession of the virus.[182]

In 1767, the 11-year-old composer Wolfgang Amadeus Mozart survived a smallpox outbreak in Austria that killed Holy Roman Empress Maria Josepha, who became the second consecutive wife of Holy Roman Emperor Joseph II to die of the disease, as well as Archduchess Maria Josepha. (See Mozart and smallpox.)

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V,[183] the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac, the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan, died of smallpox in 1520, shortly after its introduction to the Americas, and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan, 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died),[184] George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died).

Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret, his wife Anne of Cleves, and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots, contracted the disease as a child but had no visible scarring.

In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. He was left scarred and disfigured. His wife, Catherine the Great, was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul, so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale. While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately 2 million inoculations were administered in the Russian Empire.[185]

In China, the Qing dynasty had extensive protocols to protect Manchus from Peking's endemic smallpox.

U.S. Presidents George Washington, Andrew Jackson, and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751.[186] Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not.[186] Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.[186]

Famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation.[187]

Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent.[188]

Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.[189]

The Hindu goddess Shitala was worshipped to prevent or cure smallpox.

In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World, for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang (Chinese: 痘疹娘娘).[190] Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花, literally "heaven flower").[191] In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night.[191] If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house.[190]

In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules.[192] Among the Yorùbá people of West Africa, and also in Dahomean religion, Trinidad, and in Brazil, The deity Sopona, also known as Obaluaye, is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona.[193] Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered.[193] However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon his victims to heal them.[194] The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents.[194][193]

India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox.[191] India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected.[195][196] Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients.[191] Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes.[197]

In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons, who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England.[3] Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring,[3] this belief persisted even until the 1930s.