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114-741: The Western Fever Hospital, Fulham , originally the Western Hospital , was set up as a public hospital for isolating smallpox by the Metropolitan Asylums Board in Fulham, London, in 1877. In 1933 the LCC took over its management. In 1949 the site became part of the National Health Service . During its century-long existence the hospital always specialised in various forms of infectious diseases, ending up as

228-410: A marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether

342-443: A clinical case was observed, smallpox was confirmed using laboratory tests. Microscopically , poxviruses produce characteristic cytoplasmic inclusion bodies , the most important of which are known as Guarnieri bodies , and are the sites of viral replication . Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but

456-415: 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

570-518: 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. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the root word vacca , which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox

684-455: A fatality rate of around 30%, while variola minor’s mortality rate was about 1%. Throughout the 18th century, variola major was responsible for around 400,000 deaths annually in Europe alone. Survivors of the disease often faced lifelong consequences, such as blindness and severe scarring, which were nearly universal among those who recovered. In the first half of the 20th century, variola major

798-404: A greatly reduced risk of death – 1–2% – compared to those contracting Variola major with 30% mortality. Infection via inhaled viral particles in droplets spread the infection more widely than the deliberate infection through a small skin wound. The smaller, localised infection is adequate to stimulate the immune system to produce specific immunity to the virus, while requiring more generations of

912-614: A host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. 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. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in

1026-416: A method for the prevention of smallpox by deliberate introduction of material from smallpox pustules from one person into the skin of another. The usual route of transmission of smallpox was through the air, invading the mucous membranes of the mouth, nose, or respiratory tract, before migrating throughout the body via the lymphatic system , resulting in an often severe disease. In contrast, infection of

1140-408: A more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical ( asymptomatic ) infections with variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash) was seen generally in vaccinated persons. This form

1254-596: A piece of dough; it ferments, and diffuses through the whole mass of blood the qualities with which it is impregnated. The pustules of the child in whom the artificial small-pox has been thus inoculated are employed to communicate the same distemper to others. There is an almost perpetual circulation of it in Circassia; and when unhappily the small-pox has quite left the country, the inhabitants of it are in as great trouble and perplexity as other nations when their harvest has fallen short... Voltaire does not speculate on where

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1368-601: A potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . 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. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on

1482-423: 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. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with

1596-421: A source of infection”; noted that “Current recommendations for control of secondary smallpox infections emphasize transmission ‘by expelled droplets to close contacts (those within 6–7 feet)’”; but warned that the “emphasis on spread via large droplets may reduce the vigilance with which more difficult airborne precautions [i.e. against finer droplets capable of traveling longer distances and penetrating deeply into

1710-399: A specific meaning for procedures done in vitro (in glass, i.e. not in a living body). These include the transfer of microorganisms into and from laboratory apparatus such as test tubes and petri dishes in research and diagnostic laboratories, and also in commercial applications such as brewing, baking, oenology (wine making), and the production of antibiotics . For example, blue cheese

1824-582: Is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox

1938-420: 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. 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

2052-490: Is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus 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

2166-541: Is believed to have had a mortality rate of less than 1%, as compared to variola major'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 virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through

2280-411: Is caused by infection with variola virus, which belongs to the family Poxviridae , subfamily Chordopoxvirinae , genus Orthopoxvirus . 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. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade

2394-488: 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

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2508-447: 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. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in

2622-561: Is estimated to have killed up to 300 million people in the 20th century and around 500 million people in the last 100 years of its existence. Earlier deaths included six European monarchs , including Louis XV of France in 1774. As recently as 1967, 15 million cases occurred a year. The final known fatal case occurred in the United Kingdom in 1978 . Inoculation for smallpox appears to have started in China around

2736-461: Is known that the Chinese banned the practice of using smallpox material from patients who actually had the full-blown disease of Variola major (considered too dangerous); instead they used proxy material of a cotton plug inserted into the nose of a person who had already been inoculated and had only a few scabs, i.e. Variola minor . This was called "to implant the sprouts", an idea of transplanting

2850-429: Is made by inoculating it with Penicillium roqueforti mold, and often certain bacteria. The term inoculate entered medical English through horticultural usage meaning to graft a bud from one plant into another. It derives from Latin in- 'in' + oculus 'eye' (and by metaphor , 'bud'). (The term innocuous is unrelated, as it derives from Latin in- 'not' + nocuus 'harmful'.) Inoculation originated as

2964-415: Is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain, known for its significantly higher mortality rate compared to its counterpart, variola minor. Variola major had

3078-493: 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. Autopsy reveals petechiae and bleeding in

3192-453: Is typically fatal. 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. 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. The skin becomes dusky and erythematous, and this

3306-698: The East India Company stationed in China and another by Clopton Havers . 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. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where

3420-571: The King 's physician. Sufficient interest arose that Maitland gained permission to test inoculation at Newgate Prison on six prisoners due to be hanged in exchange for their freedom, an experiment which was witnessed by a number of notable doctors. All survived, and in 1722 the Prince of Wales' daughters received inoculations. The practice of inoculation slowly spread amongst the royal families of Europe, usually followed by more general adoption amongst

3534-854: The Province of Massachusetts Bay explained the inoculation procedure to Cotton Mather during the 18th century; he reported to have acquired the knowledge from Africa. Most Old World diseases of known origin can be traced to Africa and Asia and were introduced to Europe over time. Smallpox originated in Africa or Asia, plague in Asia, cholera in Asia, influenza in Asia, malaria in Africa and Asia, measles from Asian rinderpest , tuberculosis in Asia, yellow fever in Africa, leprosy in Asia, typhoid in Africa, syphilis in America and Africa, herpes in Africa, zika in Africa. Thus

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3648-422: The common cold : fever of at least 38.3 °C (101 °F), muscle pain , malaise , headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate , and throat, and

3762-470: The horsepox virus using publicly available sequence data for horsepox. 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. 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. Critics found it especially concerning that

3876-468: The replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of

3990-519: The sinologist Joseph Needham states that this information comes from the Zhongdou xinfa (種痘心法) written in 1808 by Zhu Yiliang, centuries after the alleged events. The first clear and credible reference to smallpox inoculation in China comes from Wan Quan 's (1499–1582) Douzhen Xinfa (痘疹心法) of 1549, which states that some women unexpectedly menstruate during the procedure, yet his text did not give details on techniques of inoculation. Inoculation

4104-409: The yang potency will be lost in approximately twenty days. The best material is that which had not been left too long, for when the yang potency is abundant it will give a 'take' with nine persons out of ten people – and finally it becomes completely inactive, and will not work at all. In situations where new scabs are rare and the requirement great, it is possible to mix new scabs with

4218-492: The 10th century. A Song dynasty (960–1279) chancellor of China , Wang Dan (957–1017), lost his eldest son to smallpox and sought a means to spare the rest of his family from the disease, so he summoned physicians, wise men, and magicians from all across the empire to convene at the capital in Kaifeng and share ideas on how to cure patients of it until an allegedly divine man from Mount Emei carried out inoculation. However,

4332-465: The 1500s. Europe adopted this practice from Asia in the first half of the 18th century. In 1796, Edward Jenner introduced the modern smallpox vaccine. In 1967, the WHO intensified efforts to eliminate the disease. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest (a disease of even-toed ungulates ) in 2011. The term "smallpox" was first used in England in

4446-409: The 16th century to distinguish the disease from syphilis , which was then known as the "great pox". Other historical names for the disease include pox, speckled monster, and red plague. The United States and Russia retain samples of variola virus in laboratories, which has sparked debates over safety . There are two forms of the smallpox. Variola major is the severe and most common form, with

4560-624: The 18th and 19th centuries. Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. 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 an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses

4674-464: The 18th century (according to Voltaire, there was a 60% incidence of first infection, a 20% mortality rate, and a 20% incidence of severe scarring), many parents felt that the benefits of inoculation outweighed the risks and so inoculated their children. Two forms of the disease of smallpox were recognised, now known to be due to two strains of the Variola virus . Those contracting Variola minor had

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4788-478: The 18th century in India. Oliver Coult in 1731 wrote that it had been "first performed by Dununtary a physician of Champanagar". However these reports have been called into question. Vaccinations were introduced to India in 1802, when 3-year-old girl in Mumbai received a smallpox vaccine , making her the first person to take a vaccine in India. The widespread rumour since the nineteenth century that vaccination

4902-611: The British ambassador to the Ottoman Empire from 1716 to 1718. She witnessed firsthand the Ottoman use of inoculation in Istanbul , and was greatly impressed: she had lost a brother to smallpox and bore facial scars from the disease herself. When a smallpox epidemic threatened England in 1721, she called on her physician, Charles Maitland , to inoculate her daughter. She invited friends to see her daughter, including Sir Hans Sloane ,

5016-724: The Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul , which he successfully did in 1768. In 1796, Edward Jenner ,

5130-553: The Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". The Turkish practice was presented to the Royal Society in 1714 and 1716, when the physicians Emmanuel Timoni and Giacomo Pylarini independently sent letters from Istanbul. Inoculation is mentioned in the Ayurvedic text Sact'eya Grantham . The outside world was exposed to it later on, as evidenced by

5244-587: The French scholar Henri Marie Husson, who noted it in the journal Dictionaire des sciences médicales . However, the idea that inoculation originated in India has been also taken in account, as few of the ancient Sanskrit medical texts described the process of inoculation. Variolation is documented in India from the eighteenth century, thanks to the 1767 account by the Irish-born surgeon John Zephaniah Holwell . Holwell's extensive 1767 description included

5358-600: The Indian goddess of smallpox, in Bengal. Early travellers to Ethiopia report that variolation was practiced by the Amhara and Tigray peoples . The first European to report this was Nathaniel Pearce , who noted in 1831 that it was performed by a debtera who would collect "a quantity of matter" from a person with the most sores from smallpox, then "cuts a small cross with a razor in the arm" of his subject and puts "a little of

5472-491: The Latin word variola = smallpox), the predecessor to the smallpox vaccine . The smallpox vaccine, introduced by Edward Jenner in 1796, was called cowpox inoculation or vaccine inoculation (from Latin vacca = cow). Smallpox inoculation continued to be called variolation, whereas cowpox inoculation was called vaccination (from Jenner's term variolae vaccinae = smallpox of the cow). Louis Pasteur proposed in 1861 to extend

5586-401: The Turks derived their use of inoculation from neighboring Circassia . The Circassian women have, from time immemorial, communicated the small-pox to their children when not above six months old by making an incision in the arm, and by putting into this incision a pustule, taken carefully from the body of another child. This pustule produces the same effect in the arm it is laid in as yeast in

5700-833: The United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. 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). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox,

5814-565: 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. Variola minor

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5928-531: The WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. 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 virus to add

6042-507: The absence of Guarnieri bodies could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections. Definitive laboratory identification of variola virus involved growing

6156-442: The activity is not dissipated. The container must not be exposed to sunlight or warmed beside a fire. It is best to carry it for some time on the person so that the scabs dry naturally and slowly. The container should be marked clearly with the date on which the contents were taken from the patient. In winter, the material has yang potency within it, so it remains active even after being kept from thirty to forty days. But in summer

6270-460: The atmosphere; that these are the cause of all epidemical diseases, but more particularly of the small pox. Holwell ascribes this account to his Brahman informants. However, such a theory has not yet been discovered in any Sanskrit or vernacular treatise. Doctors who performed variolation were known as Tikadars . By the 18th century, variolation was widely practiced in India. Several historians have suggested that variolation may be older than

6384-448: The bloodstream in large numbers, a condition known as viremia . This resulted in the second wave of multiplication in the spleen , bone marrow , and lymph nodes. The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause. When

6498-477: The central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses. The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate

6612-503: The closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized

6726-674: The country's specialist centre for the treatment of Poliomyelitis . With the dramatic decline in cases globally, the NHS shut down the facility in 1979 and sold off the 13 acre site to commercial developers. The hospital was established as the Western Hospital in Fulham, London, in 1877. It became the Western Fever Hospital in 1885 (soon after the 1884 establishment of nearby Fulham Parish Infirmary , later renamed Fulham Hospital), and additional fever blocks were built in

6840-621: 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. 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. Concern about possible use of smallpox for biological warfare led in 2002 to Donald K. Milton's detailed review of existing research on its transmission and of then-current recommendations for controlling its spread. He agreed, citing Rao, Fenner and others, that “careful epidemiologic investigation rarely implicated fomites as

6954-403: The diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could 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

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7068-595: The disease dates to around 1500 BC in Egyptian mummies . The disease historically occurred in outbreaks . It was one of several diseases introduced by the Columbian exchange to the New World , resulting in large swathes of Native Americans dying . In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox. Smallpox

7182-479: The disease included fever and vomiting. This was followed by formation of ulcers in the mouth and a skin rash . Over a number of days, the skin rash turned into the characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or rarely via contaminated objects . Prevention

7296-498: The disease which fit their conception of beansprouts in germination . Needham quotes an account from Zhang Yan's Zhongdou Xinshu (種痘新書), or New book on smallpox inoculation , written in 1741 during the Qing dynasty (1644–1912), which shows how the Chinese process had become refined up until that point: Method of storing the material. Wrap the scabs carefully in paper and put them into a small container bottle. Cork it tightly so that

7410-507: The disorder infect the Army in the natural way and rage with its usual virulence, we have more to dread from it than from the sword of the enemy." This was the first mass inoculation of an army, and was successful, with only isolated infections occurring, and no regiments incapacitated by the disease. Inoculation grew in popularity in Europe through the 18th century. Given the high prevalence and often severe consequences of smallpox in Europe in

7524-552: The early 1890s. It joined the National Health Service under the management of the South West Metropolitan Regional Health Board in 1948. It closed in 1979 and the hospital was subsequently demolished. This United Kingdom hospital article is a stub . You can help Misplaced Pages by expanding it . This article about a London building or structure is a stub . You can help Misplaced Pages by expanding it . Smallpox Smallpox

7638-439: The following, that points to the connection between disease and "multitudes of imperceptible animalculae floating in the atmosphere": They lay it down as a principle, that the immediate cause of the smallpox exists in the mortal part of every human and animal form; that the mediate (or second) acting cause, which stirs up the first, and throws it into a state of fermentation, is multitudes of imperceptible animalculae floating in

7752-408: The genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to

7866-429: The group was able to recreate viable virus in a short time frame with relatively little cost or effort. 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. Smallpox

7980-498: The hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA. Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop ,

8094-436: 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% of cases, and most (72%) were children. 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

8208-614: The lives of thousands." Likewise, in the United States, the Continental Congress issued a proclamation in 1776 prohibiting Surgeons of the Army from performing inoculations. However, in 1777, George Washington , witnessing the virulent spread of smallpox, and fearing the likelihood of mass transmission of the disease throughout the Continental Army , weighed the risks and overruled this prohibition, conducting smallpox inoculation of all troops. He wrote, "Should

8322-406: The lower respiratory tract] are maintained”. Once inhaled, the variola virus invaded the mucous membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in

8436-408: The malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by

8550-464: The matter" into the cut which was afterwards bound up with a bandage. Subsequent visitors who described this practice included the British traveller William Cornwallis Harris and Dr. Petit of the French scientific mission of 1839–1841. Inoculation against smallpox seems to have been known to West Africans, more specifically the Ga-Adangbe people of Accra . An enslaved African named Onesimus in

8664-584: The more aged ones, but in this case more of the powder should be blown into the nostril when the inoculation is done. Two reports on the Chinese practice 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 . But no action was taken. According to Voltaire (1742),

8778-587: The necessity of immunity through inoculation did not arise until those diseases were introduced in Europe. In January 1714 the Philosophical Transactions of the Royal Society published an account of a letter John Woodward had received from Emmanuel Timonius in Istanbul . Smallpox inoculation was advocated as a proven method of curbing the severity of the disease. The practice was introduced to England by Lady Mary Wortley Montagu . Lady Montagu's husband, Edward Wortley Montagu , served as

8892-404: The onset of the rash. 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

9006-429: 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. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox

9120-523: 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%. 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,

9234-534: The people. The practice is documented in America as early as 1721, when Zabdiel Boylston , at the urging of Cotton Mather , successfully inoculated two slaves and his own son. Mather, a prominent Boston minister, had heard a description of the African practice of inoculation from Onesimus , an enslaved man in his household, in 1706 and later from Timoni's report to the Royal Society. However, Mather had been previously unable to convince local physicians to attempt

9348-420: The person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of smallpox. 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

9462-497: The practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. 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 . If successful, inoculation produced lasting immunity to smallpox. Because

9576-478: The procedure. Following this initial success, Boylston began performing inoculations throughout Boston, despite much controversy and at least one attempt upon his life. The effectiveness of the procedure was proven when, of the nearly three hundred people Boylston inoculated during the outbreak, only six died, whereas the mortality rate among those who contracted the disease naturally was one in six. Boylston traveled to London in 1724. There he published his results and

9690-491: 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. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox)

9804-454: The same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases. The earliest procedure used to prevent smallpox was inoculation with variola minor virus (a method later known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before

9918-479: 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

10032-491: The separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. 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 virus from Taterapox has been estimated to be 50,000 years ago. While this

10146-403: The skin usually led to a milder, localized infection – but, crucially, still induced immunity to the virus. This first method for smallpox prevention, smallpox inoculation, is now also known as variolation . Inoculation has ancient origins, and the technique was known in India, Africa, and China. The earliest hints of the practice of inoculation for smallpox in China come during

10260-438: The small inoculum, and the single point of initial infection, the resulting case of smallpox was generally milder than the naturally occurring form, produced far less facial scarring, and had a far lower mortality rate . As with survivors of the natural disease, the inoculated individual was subsequently immune to re-infection. In 1798, British physician Edward Jenner published the results of his experiments and thus introduced

10374-520: The spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. 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). The case fatality rate of early hemorrhagic smallpox approaches 100%. There

10488-425: The temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva. Variola virus tended to attack skin cells, causing the characteristic pimples, or macules , associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to

10602-412: The terms vaccine and vaccination to include the new protective procedures being developed. Immunization refers to the use of vaccines as well as the use of antitoxin , which contains pre-formed antibodies such as to diphtheria or tetanus exotoxins . In nontechnical usage inoculation is now more or less synonymous with protective injections and other methods of immunization. Inoculation also has

10716-411: 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. Ordinary smallpox generally produced

10830-475: The vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. 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 . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on

10944-439: The virulence of the smallpox strain. 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. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. Smallpox

11058-442: The virus on chorioallantoic membrane (part of a chicken embryo ) and examining the resulting pock lesions under defined temperature conditions. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in

11172-533: The virus to reach levels of infection likely to kill the patient. The rising immunity terminates the infection. This ensures the less fatal form of the disease is the one caught, and gives the immune system the best start possible in combating it. Inoculation in the East was historically performed by blowing smallpox crusts into the nostril. In Britain, Europe and the American Colonies the preferred method

11286-554: The whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and

11400-421: Was achieved mainly through the smallpox vaccine . Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after the disease was eradicated. The risk of death was about 30%, with higher rates among babies. Often, those who survived had extensive scarring of their skin, and some were left blind. The earliest evidence of

11514-431: Was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of

11628-477: Was an infectious disease caused by variola virus (often called smallpox virus), which belongs to the genus Orthopoxvirus . The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated to date. The initial symptoms of

11742-486: Was documented in India before the discoveries of Edward Jenner can all be traced to propaganda tracts written in Sanskrit and the Indian vernaculars by colonial officers, in the hope of convincing pious Indians to accept the newly discovered Jennerian procedure and abandon older variolation practices. A landmark anthropological study by Ralph Nicholas described the mid-twentieth century rituals of appeasement to Śītalā ,

11856-525: Was elected to the Royal Society in 1726. In France , considerable opposition arose to the introduction of inoculation, and it was banned by the Parlement . Voltaire , in his Lettres Philosophiques , wrote a criticism of his countrymen for being opposed to inoculation and having so little regard for the welfare of their children, concluding that "had inoculation been practised in France it would have saved

11970-507: Was first vividly described by Yu Chang in his book Yuyi cao (寓意草), or Notes on My Judgment , published in 1643. Inoculation was reportedly not widely practiced in China until the reign of the Longqing Emperor (r. 1567–1572) during the Ming dynasty (1368–1644), as written by Yu Tianchi in his Shadou Jijie (痧痘集解) of 1727, which he alleges was based on Wang Zhangren's Douzhen Jinjing Lu (痘疹金鏡錄) of 1579. From these accounts, it

12084-428: 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

12198-442: Was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from

12312-404: Was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture . In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal. The initial symptoms were similar to other viral diseases that are still extant, such as influenza and

12426-421: 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. 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. Hemorrhagic smallpox

12540-444: Was rubbing material from a smallpox pustule from a selected mild case ( Variola minor ) into a scratch between the thumb and forefinger. This would generally be performed when an individual was in normal good health, and thus at peak resistance. The recipient would develop smallpox; however, due to being introduced through the skin rather than the lungs, and possibly because of the inoculated individual's preexisting state of good health,

12654-424: Was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known. Inoculation Until the early 1800s inoculation referred only to variolation (from

12768-440: Was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. 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

12882-404: Was the primary cause of smallpox outbreaks across Asia and most of Africa. Meanwhile, variola minor was more commonly found in regions of Europe, North America, South America, and certain parts of Africa. Variola minor virus, 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

12996-516: 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 (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. A second estimate has placed

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