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The art of  Fernan Federici  Jim Haseloffand on WellcomeImages on flickr utilizes stains and a powerful microscope to highlight the patterns in bacteria.  None of these are photoshopped. Kind of hard to look at the identified bacteria that cause illnesses like HIV, etc., but I can’t deny how beautiful they are, especially the ones in color, not photo-shopped! Infection with smallpox is focused in small blood vessel+s of the skin and in the mouth and throat before disseminating. After vaccination+ campaigns throughout the 19th and 20th centuries, the WHO certified the global eradication+ of smallpox in 1979.
The incubation period+ between contraction and the first obvious symptoms of the disease is around 12 days. Smallpox virus preferentially attacks skin cells, causing the characteristic pimples (called macule+s) associated with the disease. Ninety percent or more of smallpox cases among unvaccinated persons were of the ordinary type. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles form in the ordinary type.
Hemorrhagic+ smallpox is a severe form that is accompanied by extensive bleeding into+ the skin, mucous membranes, and gastrointestinal tract. 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. Smallpox is caused by infection with variola virus, which belongs to the genus Orthopoxvirus+, the family Poxviridae+ and subfamily chordopoxvirinae. Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometer+s by 244 to 270 nm, with a single linear double stranded DNA+ genome+ 186 kilobase pair+s (kbp) in size and containing a hairpin loop+ at each end.
Four orthopoxviruses cause infection in humans: variola, vaccinia+, cowpox+, and monkeypox+. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Transmission occurs through inhalation of airborne+ variola virus, usually droplets expressed from the oral, nasal, or pharyngeal+ mucosa+ of an infected person. 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 lesion+s in the mouth and pharynx. Smallpox is highly contagious, but generally spreads more slowly and less widely than some other viral diseases, perhaps because transmission requires close contact and occurs after the onset of the rash. The clinical definition of smallpox is an illness with acute onset of fever equal to or greater than followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause.
Microscopically+, poxviruses produce characteristic cytoplasmic+ inclusions, the most important of which are known as Guarnieri bodies+, and are the sites of viral replication+. 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. The earliest procedure used to prevent smallpox was inoculation+ (known as variolation after the introduction of smallpox vaccine+ to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe.
Lady Mary Wortley Montagu+ observed smallpox inoculation during her stay in the Ottoman Empire+, writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. The current formulation of smallpox vaccine is a live virus preparation of infectious vaccinia virus. The antibodies+ induced by vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972, and was abandoned in most European countries in the early 1970s. Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. The overall case-fatality rate for ordinary-type smallpox is about 30 percent, but varies by pock distribution: ordinary type-confluent is fatal about 50–75 percent of the time, ordinary-type semi-confluent about 25–50 percent of the time, in cases where the rash is discrete the case-fatality rate is less than 10 percent. In fatal cases of ordinary smallpox, death usually occurs between the tenth and sixteenth days of the illness. Complications of smallpox arise most commonly in the respiratory system+ and range from simple bronchitis+ to fatal pneumonia+.
The earliest credible clinical evidence of smallpox is found in the smallpox-like disease in medical writings from ancient India (as early as 1500 BC), Egyptian+ mummy+ of Ramses V+ who died more than 3000 years ago (1145 BC) and China (1122 BC). There are no credible descriptions of smallpox-like disease in the Americas+ before the westward exploration by Europeans in the 15th century AD. By the mid-18th century smallpox was a major endemic disease+ everywhere in the world except in Australia and in several small islands.
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.
The first hemisphere+-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization+. In the early 1950s an estimated 50 million cases of smallpox occurred in the world each year. 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 global eradication of smallpox was certified, based on intense verification activities in countries, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The last cases of smallpox in the world occurred in an outbreak of two cases (one of which was fatal) in Birmingham+, UK+ in 1978.
In 1986, the World Health Organization+ first recommended destruction of the virus, and later set the date of destruction to be 30 December 1993. In March 2004 smallpox scabs+ were found tucked inside an envelope in a book on Civil War+ medicine in Santa Fe, New Mexico+. In July 2014 several vials of smallpox were discovered in an FDA laboratory at the National Institutes of Health+ location in Bethesda, Maryland+. The British used smallpox as a biological warfare+ agent at the Siege of Fort Pitt+ during the French and Indian Wars+ (1754–1763) against France and its Native American+ allies. According to a theory put forward in ''Journal of Australian Studies'' (JAS) by an independent researcher, in 1789, British marines used smallpox against indigenous tribes in New South Wales+. Only five editions of each microbe are produced for sale—unfortunately, their potentially lethal counterparts aren’t nearly so rare.
Patients with ordinary-type smallpox usually had bumps filled with a thick and opaque fluid, often with a depression or dimple in the center.
In the skin it results in a characteristic maculopapular rash+ and, later, raised fluid-filled blister+s.
The earliest physical evidence of it is probably the pustular rash on the mummified body of Pharaoh Ramses V+ of Egypt.
Smallpox is one of two infectious disease+s to have been eradicated, the other being rinderpest+, which was declared eradicated in 2011.
Variola major was the severe and most common form, with a more extensive rash and higher fever. Once inhaled, variola major virus invades the oropharyngeal (mouth and throat) or the respiratory+ mucosa, migrates to regional lymph nodes+, and begins to multiply. In this form of the disease, by the second day of the rash the macules became raised ''papule+s''. In this form the prodromal illness still occurred but may be less severe than in the ordinary type. Hemorrhagic smallpox also produces a dusky erythema+, petechiae+, and hemorrhages in the spleen, kidney, serosa+, muscle, and, rarely, the epicardium+, liver+, testes+, ovaries+ and bladder+. The "dumbbell-shaped" structure inside the virion is the viral core, which contains the viral DNA; Mag. Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm+ of the cell rather than in the nucleus+.
The viral envelope is made of modified Golgi+ membranes containing viral-specific polypeptides, including hemagglutinin+. 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 (1.8 m), but can also be spread through direct contact with infected bodily fluid+s or contaminated objects (fomite+s) such as bedding or clothing. 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. The overall rate of infection is also affected by the short duration of the infectious stage. Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs.
Strains may be characterized by polymerase chain reaction+ (PCR) and restriction fragment length polymorphism+ (RFLP) analysis. However, the idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit+ medical texts described the process of inoculation. In 1721, Cotton Mather+ and colleagues provoked controversy in Boston by inoculating hundreds. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. Neutralizing antibodies are detectable 10 days after first-time vaccination, and seven days after revaccination. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction+ at the site of the vaccination (erythema multiforme+), spread of the vaccinia virus to other parts of the body, and to other individuals.
Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of disease.
However, antiviral+ treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir+ might be useful as a therapeutic agent. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs.

Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin.
Pustules can form on the eyelid, conjunctiva+, and cornea+, leading to complications such as conjunctivitis+, keratitis+, corneal ulcer+, iritis+, iridocyclitis+, and optic atrophy+. It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BC, where it remained as an endemic human disease for at least 2000 years. Smallpox is not clearly described in either the Old+ or New Testament+s of the Bible or in the literature of the Greeks or Romans. Smallpox was introduced into the Caribbean island of Hispaniola+ in 1509, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico bringing smallpox with them. In Europe smallpox was a leading cause of death in the 18th century, killing an estimated 400,000 Europeans each year. The introduction of the vaccine to the New World took place in Trinity, Newfoundland+ in 1800 by Dr.
The campaign was successful in eliminating smallpox from all American countries except Argentina, Brazil, Colombia, and Ecuador. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. A medical photographer, Janet Parker+, contracted the disease at the University of Birmingham Medical School+ and died on September 11, 1978, after which Professor Henry Bedson, the scientist responsible for smallpox research at the university committed suicide. The envelope was labeled as containing scabs from a vaccination and gave scientists at the Centers for Disease Control and Prevention+ an opportunity to study the history of smallpox vaccination in the U.S. Variola minor+ was a less common presentation, and a much less severe disease, with historical death rates of 1 percent or less. 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 blood+stream in large numbers (this is called ''viremia+''), and a second wave of multiplication occurs in the spleen, bone marrow+, and lymph nodes. Typically the 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. By the third or fourth day the papules filled with an opalescent fluid to become ''vesicles+''.
Historically, it accounted for 5–10 percent of cases, and the majority (72 percent) were children. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. The wide range of dates is due to the different records used to calibrate the molecular clock. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. In order 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+. Rarely, smallpox has been spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.
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.
In temperate+ areas, the number of smallpox infections were highest during the winter and spring.
They are found in virtually all poxvirus infections but the absence of Guarnieri bodies cannot be used to rule out smallpox.
Serologic+ tests and enzyme linked immunosorbent assay+s (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty+.Temple, Robert. In 1796, Edward Jenner+, a doctor in Berkeley, Gloucestershire+, rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox+ lesion. The needle is used to prick the skin (usually the upper arm) a number of times in a few seconds. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator+ assistance. The drug must be administered intravenously+, however, and may cause serious kidney+ toxicity. Circulating immune complex+es, overwhelming viremia+, or an uncontrolled immune response+ may be contributing factors.
Secondary bacteria+l infection of the skin is a relatively uncommon complication of smallpox. Blindness+ results in approximately 35 percent to 40 percent of eyes affected with keratitis and corneal ulcer.
Smallpox was probably introduced into China during the 1st century AD from the southwest, and in the 6th century was carried from China to Japan.
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 BC siege of Syracuse+ with smallpox, 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. Smallpox devastated the native Amerindian+ population and was an important factor in the conquest of the Aztec+s and the Inca+s by the Spaniards. Up to 10 percent of Swedish+ infants died of smallpox each year, and the death rate of infants in Russia+ may have been even higher. 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.
Authorities declared martial law+, enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO.
In light of this incident, all known stocks of smallpox were destroyed or transferred to one of two WHO reference laboratories which had BSL-4+ facilities; the Centers for Disease Control and Prevention+ (CDC) in the United States and the State Research Center of Virology and Biotechnology VECTOR+ in Koltsovo+, Russia. British officers, including the top British commanding generals, ordered, sanctioned, paid for and conducted the use of smallpox against the Native Americans. The initial or prodromal symptoms are similar to other viral diseases such as influenza+ and the common cold+: fever+ of at least , muscle pain+, malaise, headache and prostration+. This fluid became opaque+ and turbid+ within 24–48 hours, giving them the appearance of pustule+s; however, the so-called pustules were filled with tissue debris, not pus. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. The skin lesions tended to be fewer and evolve more quickly, are more superficial, and may not show the uniform characteristic of more typical smallpox.
Malignant smallpox was accompanied by a severe prodromal+ phase that lasted 3–4 days, prolonged high fever, and severe symptoms of toxemia+.
Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also known as black pox+.
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. The virus can cross the placenta+, but the incidence of congenital+ smallpox is relatively low. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic+ examination of pustular fluid or scabs. 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.
Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter.
Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis+ or severe necrosis+ in the area of vaccination (called progressive vaccinia). Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock+, such as fluid resuscitation+.
The fatality rate for flat-type is 90 percent or greater and nearly 100 percent is observed in cases of hemorrhagic smallpox. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops.
In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. While the Antonine Plague+ that swept through the Roman Empire+ in AD 165ndash: 180 may have been caused by smallpox, Saint Nicasius of Rheims+ became the patron saint of smallpox victims for having supposedly survived a bout in 450,"".
Settlement of the east coast of North America in 1633 in Plymouth, Massachusetts+ was also accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. 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.
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. The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment. 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+.
In addition, a form called ''variola sine eruptione'' (smallpox without rash) was seen generally in vaccinated persons. As the digestive tract+ is commonly involved, nausea and vomiting and backache often occur. At this point variola major infection can take several very different courses, resulting in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic.
Fluid slowly leaked from the pustules, and by the end of the second week the pustules deflated, and started to dry up, forming crusts (or scabs).
Patients with confluent smallpox often remained ill even after scabs have formed over all the lesions.

The hemorrhages appear in the early eruptive period, and the rash is flat and does not progress beyond the vesicular stage. 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. However, all orthopoxviruses exhibit identical brick-shaped virions+ by electron microscopy. A variety of laboratory methods are available for detecting chickenpox in evaluation of suspected smallpox cases. Jenner called the material used for inoculation vaccine+, from the root word+ ''vacca'', which is Latin+ for cow. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus, and begins to drain. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burn+s. Cause of death in hemorrhagic cases involved heart failure+, sometimes accompanied by pulmonary edema+. In 2 to 5 percent of young children with smallpox, virions reach the joints and bone, causing ''osteomyelitis+ variolosa''. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona+ in the Yoruba religion+. Case fatality rates during outbreaks in Native American populations were as high as 80–90%. 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. 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.
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. As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.
Jack Carmody claimed the cause of the outbreak in question was more likely due to chickenpox, which at the time was sometimes identified as a mild form of smallpox. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by virus isolation. Historically, smallpox has an overall fatality rate+ of about 30 percent; however, the malignant and hemorrhagic forms are usually fatal. By day 16–20 scabs had formed over all the lesions, which have started to flake off, leaving depigmented+ scars. Skin lesions matured slowly and by the seventh or eighth day they were flat and appeared to be buried in the skin. However, if particles with the characteristic morphology of herpesvirus+es are seen this will eliminate smallpox and other orthopoxvirus infections. The procedure was much safer than variolation, and did not involve a risk of smallpox transmission. Lesions are symmetrical, most common in the elbows, tibia+, and fibula+, and characteristically cause separation of an epiphysis+ and marked periosteal+ reactions. In India, the Hindu goddess of smallpox, Sitala Mata+, was worshiped in temples throughout the country.
In the United States and South Africa a much milder form of smallpox, ''variola minor'', was recognized just before the close of the 19th century. Congress+ passed the Vaccine Act of 1813+ to ensure that safe smallpox vaccine would be available to the American public.
Overall, however, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent+. 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 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.
I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown.
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. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages.
A second estimate has placed the separation of variola from Taterapox+ at 3000–4000 years ago.
Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier+ state. Swollen joints limit movement, and arthritis+ may lead to limb deformities, ankylosis+, malformed bones, flail joints, and stubby fingers.
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''). Although the disease was never endemic on the continent, it was the principal cause of death in Aboriginal+ populations between 1780 and 1870.
By the mid-20th century ''variola minor'' occurred along with ''variola major'', in varying proportions, in many parts of Africa. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson+. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. The last naturally occurring case of the more deadly ''Variola major'' had been detected in October 1975 in a two-year-old Bangladesh+i girl, Rahima Banu+. There are also accounts that smallpox was used as a weapon during the American Revolutionary War+ (1775–1783). These lesions rapidly enlarge and rupture, releasing large amounts of virus into the saliva+. Patients in the late stage have significant thrombocytopenia+; however, deficiency of coagulation factors is less severe.
This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by vaccinia+ virus.
During the Middle Ages+, smallpox made periodic incursions into Europe but did not become established there until the population increased and population movement became more active during the era of the Crusades+. 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. In British India+ a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.
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 Raska+. 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. Blindness+ resulting from corneal ulcer+ation and scarring, and limb deformities due to arthritis and osteomyelitis+ were less common complications, seen in about 2–5 percent of cases. However, if the mutation rate is assumed to be similar to that of the herpesvirus+es, the divergence date between variola from Taterapox has been estimated to be 50,000 years ago. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by stubborn 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.
This form of smallpox occurs in anywhere from 3 to 25 percent of fatal cases depending on the virulence of the smallpox strain.
While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete.
With its introduction into populated areas in India, China and Europe, smallpox affected mainly children, with periodic epidemics that killed as many as 30 percent of those infected.
By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans+.
The settled existence of smallpox in Europe was of particular historical importance, since successive waves of exploration and colonization by Europeans tended to spread the disease to other parts of the world. In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination+. However, because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. By the 16th century it had become an important cause of morbidity and mortality throughout much of the world. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.
Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease. In the United States, from 1843 to 1855 first Massachusetts, and then other states required smallpox vaccination. Although some disliked these measures, 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, until the mid to late 1970s as protection against reintroduction. 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.

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