Smallpox
Classification and external resources
Girl infected with smallpox. Bangladesh, 1973. In ordinary type smallpox the bumps are filled with a thick, opaque fluid and often have a depression or dimple in the center. This is a major distinguishing characteristic of smallpox.
ICD-10	B03
ICD-9	050
DiseasesDB	12219
MedlinePlus	001356
eMedicine	emerg/885
MeSH	D012899

Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor.^[1] The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple". The term "smallpox" was first used in Europe in the 15th century to distinguish variola from the "great pox" (syphilis).^[2] The last naturally occurring case of smallpox (Variola minor) was diagnosed on 26 October 1977.

Smallpox localizes in small blood vessels of the skin and in the mouth and throat. In the skin it results in a characteristic maculopapular rash and, later, raised fluid-filled blisters. V. major produces a more serious disease and has an overall mortality rate of 30–35%. V. minor causes a milder form of disease (also known as alastrim, cottonpox, milkpox, whitepox, and Cuban itch) which kills about 1% of its victims.^[3][4] Long-term complications of V. major infection include characteristic scars, commonly on the face, which occur in 65–85% of survivors.^[5] Blindness resulting from corneal ulceration and scarring, and limb deformities due to arthritis and osteomyelitis are less common complications, seen in about 2–5% of cases.

Smallpox is believed to have emerged in human populations about 10,000 BC.^[2] The earliest physical evidence of it is probably the pustular rash on the mummified body of Pharaoh Ramses V of Egypt.^[6] The disease killed an estimated 400,000 Europeans annually during the closing years of the 18th century (including five reigning monarchs),^[7] and was responsible for a third of all blindness.^[3][8] Of all those infected, 20–60%—and over 80% of infected children—died from the disease.^[9] Smallpox was responsible for an estimated 300–500 million deaths during the 20th century.^[10][11][12] As recently as 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year.^[13]

After vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1979.^[13] Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was declared eradicated in 2011.^[14][15][16]

Classification[link]

There are two clinical forms of smallpox. Variola major is the severe and moet common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, and a much less severe disease, with historical death rates of 1% or less.^[17] Subclinical (asymptomatic) infections with variola virus have been noted but are not common.^[18] In addition, a form called variola sine eruptione (smallpox without rash) is seen generally in vaccinated persons. This form is marked by a fever that occurs after the usual incubation period and can be confirmed only by antibody studies or, rarely, by virus isolation.^[18]

Signs and symptoms[link]

Child showing rash due to ordinary-type smallpox (variola major)

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

Smallpox virus preferentially attacks skin cells, causing the characteristic pimples (called macules) associated with the disease. A rash develops on the skin 24 to 48 hours after lesions on the mucous membranes appear. 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. The process takes no more than 24 to 36 hours, after which no new lesions appear.^[4] At this point variola major infection can take several very different courses, resulting in four types of smallpox disease based on the Rao classification:^[19] ordinary, modified, malignant (or flat), and hemorrhagic. Historically, smallpox has an overall fatality rate of about 30%; however, the malignant and hemorrhagic forms are usually fatal.^[20]

Ordinary[link]

Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type.^[18] In this form of the disease, by the second day of the rash the macules become raised papules. By the third or fourth day the papules fill with an opalescent fluid to become vesicles. This fluid becomes opaque and turbid within 24–48 hours, giving them the appearance of pustules; however, the so-called pustules are filled with tissue debris, not pus.^[4]

By the sixth or seventh day, all the skin lesions have become pustules. Between seven and ten days the pustules mature and reach their maximum size. The pustules are sharply raised, typically round, tense, and firm to the touch. The pustules are deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaks from the pustules, and by the end of the second week the pustules deflate, and start to dry up, forming crusts (or scabs). By day 16–20 scabs have formed over all the lesions, which have started to flake off, leaving depigmented scars.^[21]

Ordinary smallpox generally produces a discrete rash, in which the pustules stand out on the skin separately. The distribution of the rash is densest on the face; denser on the extremities than on the trunk; and on the extremities, denser on the distal parts than on the proximal. The palms of the hands and soles of the feet are involved in the majority of cases. Sometimes, the blisters merge together into sheets, forming a confluent rash, which begin to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remain ill even after scabs have formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.^[18]

This man is suffering from severe hemorrhagic-type smallpox.

Modified[link]

Referring to the character of the eruption and the rapidity of its development, modified smallpox occurs mostly in previously vaccinated people. In this form the prodromal illness still occurs but may be less severe than in the ordinary type. There is usually no fever during evolution of the rash. The skin lesions tend to be fewer and evolve more quickly, are more superficial, and may not show the uniform characteristic of more typical smallpox.^[21] Modified smallpox is rarely, if ever, fatal. This form of variola major is more easily confused with chickenpox.^[18]

Malignant[link]

In malignant-type smallpox (also called flat smallpox) the lesions remain almost flush with the skin at the time when raised vesicles form in the ordinary type. It is unknown why some people develop this type. Historically, it accounted for 5%–10% of cases, and the majority (72%) were children.^[22] Malignant smallpox is accompanied by a severe prodromal phase that lasts 3–4 days, prolonged high fever, and severe symptoms of toxemia. The rash on the tongue and palate is extensive. Skin lesions mature slowly and by the seventh or eighth day they are flat and appear to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contain little fluid, are soft and velvety to the touch, and may contain hemorrhages. Malignant smallpox is nearly always fatal.^[18]

Hemorrhagic[link]

Hemorrhagic smallpox is a severe form that is accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form develops in approximately 2% of infections and occurred mostly in adults.^[18] In hemorrhagic smallpox the skin does not blister, but remains smooth. Instead, bleeding occurs under the skin, making it look charred and black,^[18] hence this form of the disease is also known as black pox.^[23]

In the early, or fulminating form, hemorrhaging appears on the second or third day as sub-conjunctival bleeding turns the whites of the eyes deep red. Hemorrhagic smallpox also produces a dusky erythema, petechiae, and hemorrhages in the spleen, kidney, serosa, muscle, and, rarely, the epicardium, liver, testes, ovaries and bladder. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. A later form of the disease occurs in patients who survive for 8–10 days. The hemorrhages appear in the early eruptive period, and the rash is flat and does not progress beyond the vesicular stage.^[18] Patients in the early stage of disease show a decrease in coagulation factors (e.g. platelets, prothrombin, and globulin) and an increase in circulating antithrombin. Patients in the late stage have significant thrombocytopenia; however, deficiency of coagulation factors is less severe. Some in the late stage also show increased antithrombin.^[4] This form of smallpox occurs in anywhere from 3 to 25% of fatal cases depending on the virulence of the smallpox strain.^[20] Hemorrhagic smallpox is usually fatal.^[18]

Cause[link]

Variola virus (Smallpox)
This transmission electron micrograph depicts a number of smallpox virions. The “dumbbell-shaped” structure inside the virion is the viral core, which contains the viral DNA; Mag. = ~370,000x
Virus classification
Group:	Group I (dsDNA)
Order:	Unassigned
Family:	Poxviridae
Subfamily:	Chordopoxvirinae
Genus:	Orthopoxvirus
Type species
Vaccinia virus
Species
Variola virus

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 nanometers by 244 to 270 nm,^[24] with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.^[25][26] The two classic varieties of smallpox are variola major and variola minor.

Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.^[18]

The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. In order to replicate, 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.^[25] Infection with either variola major or variola minor confers immunity against the other.^[4]

Transmission[link]

Transmission occurs through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It is transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually within a distance of 6 feet (1.8 m), but can also be spread through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely, smallpox has been spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.^[17] The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.^[4] Smallpox is not notably infectious in the prodromal period and viral shedding is usually delayed until the appearance of the rash, which is often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but is most frequent during the first week of the rash, when most of the skin lesions are intact.^[18] 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.^[27]

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 overall rate of infection is also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections were highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year.^[18] Age distribution of smallpox infections depends on acquired immunity. Vaccination immunity declines over time and is probably lost in all but the most recently vaccinated populations.^[4] Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier state.^[18]

Diagnosis[link]

The clinical definition of smallpox is an illness with acute onset of fever greater than 101 °F (38.3 °C) followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause.^[18] If a clinical case is observed, smallpox is confirmed using laboratory tests.

Microscopically, poxviruses produce characteristic cytoplasmic inclusions, 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 the absence of Guarnieri bodies cannot be used to rule out smallpox.^[28] The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. However, all orthopoxviruses exhibit identical brick-shaped virions by electron microscopy.^[4]

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.^[29] Strains may be characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection.^[30]

Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox can be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods are available for detecting chickenpox in evaluation of suspected smallpox cases.^[18]

• 

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

• 

  In contrast to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs.

Prevention[link]

Vial containing variolation material (India)

The earliest procedure used to prevent smallpox was inoculation (also known as variolation). Inoculation was possibly practiced in India as early as 1000 BC,^[31] and involved either nasal insufflation of powdered smallpox scabs, or scratching material from a smallpox lesion into the skin. However, the idea that inoculation originated in India has been challenged as few of the ancient Sanskrit medical texts described the process of inoculation.^[32] 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.^[33] If successful, inoculation produced lasting immunity to smallpox. However, because 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% mortality rate, considerably less than the 20–30% mortality rate of the disease itself.^[18]

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.^[34] In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. 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. 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 was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by vaccinia virus. Vaccinia is in the same family as cowpox and variola but is genetically distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not known.^[18]

Components of a modern smallpox vaccination kit including the diluent, a vial of Dryvax vaccinia vaccine, and a bifurcated needle.

The current formulation of smallpox vaccine is a live virus preparation of infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) a number of times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a “Jennerian vesicle”) which fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar.^[35]

The antibodies induced by vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination, and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated.^[36] Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3%; it was 7% among those vaccinated 11 to 20 years prior, and 11% among those vaccinated 20 or more years prior to infection. By contrast, 52% of unvaccinated persons died.^[37]

There are side effects and risks associated with the smallpox vaccine. 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. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198%) 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).^[36]

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.^[13][38] Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination.^[39]) By 1986, routine vaccination had ceased in all countries.^[13] It is now primarily recommended for laboratory workers at risk for occupational exposure.^[18]

Treatment[link]

Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of disease.^[36] Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.^[40]

No drug is currently approved for the treatment of smallpox. 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 drug must be administered intravenously, however, and may cause serious kidney toxicity.^[41]

Prognosis[link]

The overall case-fatality rate for ordinary-type smallpox is about 30%, but varies by pock distribution: ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40%–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat-type is 90% or greater and nearly 100% is observed in cases of hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less.^[21] There is no evidence of chronic or recurrent infection with variola virus.^[21]

In fatal cases of ordinary smallpox, death usually occurs between the tenth and sixteenth days of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors.^[18] In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. Cause of death in hemorrhagic cases involved heart failure, sometimes accompanied by pulmonary edema. In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death.^[22] In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes beyond the capacity of the body to replace or acquire, and fulminating sepsis.^[40]

Complications[link]

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.^[18]

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 optic atrophy. Blindness results in approximately 35% to 40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2% to 5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa. Lesions are symmetrical, most common in the elbows, tibia, and fibula, and characteristically cause separation of an epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.^[4]

History[link]

Viral evolution[link]

Drawing accompanying text in Book XII of the 16th-century Florentine Codex (compiled 1540–1585), showing Nahuas of conquest-era central Mexico suffering from smallpox.

The date of the appearance of smallpox is not settled. It most likely evolved from a rodent virus between 68,000 and 16,000 years ago.^[42][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.

A second estimate has placed the separation of variola from Taterapox at 3000–4000 years ago.^[44] This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. However if the mutation rate is assumed to be similar to that of the herpesviruses the divergence date between variola from Taterapox has been estimated to be 50,000 years ago.^[44] 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.

It seems to have emerged in its endemic form in India 2500–3000 years ago.^[45] The variola virus was transferred from West Africa to South America in the 19th century.

Human history[link]

The earliest credible clinical evidence of smallpox is found in the Egyptian mummy of Ramses V who died over 3000 years ago (1145 BCE).^[6] Historical records from Asia describe evidence of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE)^[46] and China (1122 BCE).^[47] 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 was probably introduced in China during the 1st century AD from the southwest, and in the 6th century was carried from China to Japan.^[22] In Japan, the epidemic of 735–737 is believed to have killed up to one-third of the population.^[7][48] At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion. In India, the Hindu goddess of smallpox, Sitala Mata, was worshiped in temples throughout the country.^[49]

The arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not described in either the Old or New Testaments of the Bible, or in literature of the Greeks and Romans. Scholars agree it is very unlikely such a serious disease as variola major would have escaped a description by Hippocrates if it existed in the Mediterranean region.^[50] While the Antonine Plague that swept through the Roman Empire in 165–180 AD may have been caused by smallpox,^[51] other historians speculate that Arab armies first carried smallpox out of Africa to Southwestern Europe during the 7th and 8th centuries AD.^[22] In the 9th century the Persian physician, Rhazes, provided one of the most definitive observations 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).^[52] 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 time of the Crusades. By the 16th century smallpox was well established over most of Europe.^[22] With its introduction in populated areas in India, China and Europe, smallpox affected mainly children, with periodic epidemics that killed up to 30% of those infected. The appearance of smallpox in Europe is of particular importance, as successive waves of European exploration and colonization served to spread the disease to other parts of the world. By the 16th century it had become an important cause of morbidity and mortality in the known world.^[22]

Smallpox sufferer in the United States, 1912

There are no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century AD.^[43] In 1507 smallpox was introduced into the Caribbean island of Hispaniola and to the mainland in 1520, when Spanish settlers from Hispaniola arriving in Mexico brought smallpox with them. Smallpox devastated the native Amerindian population and was an important factor in the conquest of the Aztecs and the Incas by the Spaniards.^[22] 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,^[53] and subsequently among the native-born colonists.^[54] Some estimates indicate case fatality rates of 80–90% in Native American populations during smallpox epidemics.^[55] Smallpox was introduced into Australia in 1789 and again in 1829.^[22] Although the disease was never endemic on the continent,^[22] it was the principal cause of death in Aboriginal populations between 1780 and 1870.^[56]

By the mid-18th century smallpox was a major endemic disease everywhere in the world except in Australia and in several small islands. In Europe smallpox was a leading cause of death in the 18th century, killing an estimated 400,000 Europeans each year.^[57] Through the century smallpox resulted in the deaths of perhaps 10% of all the infants of Sweden every year,^[7] and the death rate of infants in Russia may have been even higher.^[47] 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. 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. 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 USA, into Canada, the South American countries and Great Britain it became the dominant form of smallpox, further reducing mortality rates.^[22]

Eradication[link]

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

Since Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, various attempts were made to eliminate smallpox on a regional scale. As early as 1803, the Spanish Crown organized a mission (the Balmis expedition) to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there.^[58] The US Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a very solid state vaccination program existed in the Dutch East Indies.^[59] In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.^[60] 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.^[61] By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.^[62] 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.^[63] In the United States, from 1843 to 1855 first Massachusetts, and then other states required smallpox vaccination. Although some disliked these measures,^[47] coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. By 1897, smallpox had largely been eliminated from the United States.^[64] 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.^[65]

The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization.^[66] The campaign was successful in eliminating smallpox from all American countries except Argentina, Brazil, Colombia, and Ecuador.^[65] 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. The proposal (Resolution WHA11.54) was accepted in 1959.^[67] At this point, 2 million people were dying from smallpox every year. Overall, however, 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.^[68] 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.^[69][70]

Two-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.^[13] To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was 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% of all vaccine was produced in developing countries.^[65]

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.^[71] 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.^[72]

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.^[73] 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.^[18] The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a two-year-old Bangladeshi girl, Rahima Banu.^[23]

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.^[13][74] The first two sentences of the resolution read:

Post-eradication[link]

Three former directors of the Global Smallpox Eradication Program read the news that smallpox had been globally eradicated, 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. A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on September 11, 1978,^[75] after which the scientist responsible for smallpox research at the university, Professor Henry Bedson, committed suicide.^[2] 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.^[76]

In 1986, the World Health Organization first recommended destruction of the virus, and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999.^[77] Due to resistance from the US and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes.^[78] Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.^[79] Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests,^[80] however, a 2010 review by a team of public health experts appointed by the World Health Organization concluded that no essential public health purpose is served by the US and Russia continuing to retain virus stocks.^[81] The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.^[82]

In March 2004 smallpox scabs were found tucked inside an envelope in a book on Civil War medicine in Santa Fe, New Mexico.^[83] 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 US.

Society and culture[link]

Biological warfare[link]

The British at least considered using smallpox as a biological warfare agent at the Siege of Fort Pitt during the French and Indian Wars (1754–63) against France and its Native American allies.^[84][85] Although it is not clear whether the actual use of smallpox had official sanction, on June 24, 1763, William Trent, a local trader, wrote, "Out of our regard for them [sc. representatives of the besieging Delawares], we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect."^[86][87] Historians do not agree on whether this effort to broadcast the disease was successful. It has also been alleged that smallpox was used as a weapon during the American Revolutionary War (1775–83).^[88][89]

During World War II, scientists from the United Kingdom, United States and Japan were involved in research into producing a biological weapon from smallpox.^[90] 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.^[91]

In 1947 the Soviet Union established a smallpox weapons factory in the city of Zagorsk, 75 km to the northeast of Moscow.^[92] An outbreak of weaponized smallpox possibly occurred during testing at the factory in the 1970s. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described 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 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.^[93][94]

Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.^[95][96]

Responding to international pressures, in 1991 the Soviet government allowed a joint US-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.^[97] 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.^[97] With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, US 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.^[98] Specific allegations made against Iraq in this respect, however, proved to be false.^[99]

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.^[100] Insertion of the synthesized smallpox DNA into existing related pox viruses could theoretically be used to recreate the virus.^[100] The first step to mitigating this risk, it has been suggested, should be to destroy the remaining virus stocks so as to enable unequivocal criminalization of any possession of the virus.^[101]

Notable cases[link]

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V of Egypt,^[102] the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor (refer to the official history) of China, 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. More recent public figures include Guru Har Krishan, 8th Guru of the Sikhs, in 1664, Peter II of Russia in 1730 (died),^[103]George Washington (survived), king Louis XV in 1774 (died) and Maximilian III Joseph, Elector of Bavaria in 1777.

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

In Europe, deaths from smallpox often changed dynastic succession. The only surviving son of Henry VIII, Edward VI, died from complications shortly after apparently recovering from the disease, thereby nullifying Henry's efforts to ensure a male successor to the throne. (His immediate successors were all females.) Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those earlier in the succession line. He himself died of the disease in 1774. William III lost his mother to the disease when he was only ten years old in 1660, and named his uncle Charles as legal guardian: her death from smallpox would indirectly spark a chain of events that would eventually lead to the permanent ousting of the Stuart line from the British throne. William III's wife, Mary II of England, died from smallpox as well.

In China, the Qing Dynasty had extensive protocols to protect Manchus from the Peking's endemic smallpox. Most notably, the Kangxi Emperor was promoted to the throne because he had survived the disease, ahead of older brothers who had not yet had it.

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.^[104] Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not.^[104] Lincoln contracted the disease during his Presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.^[104]

Famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation.^[105]

U.S.S.R. 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.^[106]

Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.^[107]

Gods and goddesses[link]

As a reaction to the devastation of smallpox, smallpox gods and goddesses were invented as a mechanism to cope with the disease. Two examples of this occurred in China and India. In China, the smallpox goddess was referred to as T’ou-Shen Niang-Niang.^[108] The Chinese actively worked to please the goddess and thus keep the disease at bay. For example, the Chinese referred to the smallpox pustules as “beautiful flowers”; this was an attempt to not offend the goddess and keep her happy.^[109] The Chinese also took great measure to protect children from the dangers of smallpox by tricking their smallpox goddess. It was believed that the goddess enjoyed passing the disease to attractive children. This transmission was most likely to occur on the last night of the year, so children wore ugly masks to bed to trick the goddess into passing over them.^[109]. If infection of smallpox did occur, shrines were set up in the homes of the victims. These shrines were worshipped and made offerings too while the victim was sick. If the victim recovered, the shrines were taken away from the home in a special handmade paper chair or boat and burned. If the patient did not recover, the shrine was destroyed and curses were used to remove the goddess from the house.^[108] India’s first records of smallpox can be found in a medical book that dates back to A.D. 400. This book describes a disease that sounds exceptionally like smallpox.^[109] India, like China, created a goddess in response to its exposure to smallpox. Shitala Mata 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 afflicted.^[110] 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 victims.^[109] Shrines were created where many India 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 Mata, placed plates of cooling foods and pots of water on the roofs of their homes.^[111]

See also[link]

Medicine portal

• 1837–1838 smallpox epidemic (in the US)
• Biological warfare
• CCR5-Δ32
• Columbian Exchange
• Herd immunity
• List of cutaneous conditions
• List of epidemics
• Mathematics of mass vaccination
• Pandemic
• Population history of indigenous peoples of the Americas
• Smallpox 2002—film
• Smallpox demon
• What the Ancients Did for Us—a BBC documentary highlighting ancient inoculation procedures in India

References[link]

Further reading[link]

External links[link]

Wikimedia Commons has media related to: Smallpox

• Smallpox Biosafety: A Website About Destruction of Smallpox Virus Stocks
• Detailed CIDRAP Smallpox overview
• Agent Fact Sheet: Smallpox, Center for Biosecurity
• Photographs of eye damage due to smallpox
• Smallpox Images and Diagnosis Synopsis
• Variola Virus Genomes database search results from the Poxvirus Bioinformatics Resource Center
• Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae

Edward Jenner FRS
Edward Jenner by James Northcote
Born	17 May 1749 Berkeley, Gloucestershire
Died	26 January 1823(1823-01-26) (aged 73) Berkeley, Gloucestershire
Residence	Berkeley, Gloucestershire
Nationality	English
Fields	Microbiology
Alma mater	St George's, University of London
Doctoral advisor	John Hunter
Known for	Smallpox vaccine

Edward Anthony Jenner (17 May 1749 – 26 January 1823) was an English physician and scientist from Berkeley, Gloucestershire, who was the pioneer of smallpox vaccine.^[1] He is often called "the father of immunology", and his work is said to have "saved more lives than the work of any other man".^[2][3][4]

Early life[link]

Edward Jenner was born on 17 May 1749^[5] (6 May Old Style) in Berkeley, as the eighth of nine children. His father was the vicar of Berkeley, so Jenner received a strong basic education.^[6] Jenner trained from the age of 13 for eight years in Chipping Sodbury, South Gloucestershire, as an apprentice to Daniel Ludlow, a surgeon . In 1770 Jenner became apprenticed in surgery and anatomy under surgeon John Hunter and others at St George's Hospital.

William Osler records that Hunter gave Jenner William Harvey's advice, very famous in medical circles (and characteristic of the Age of Enlightenment), "Don't think; try."^[7] Hunter remained in correspondence with Jenner over natural history and proposed him for the Royal Society. Returning to his native countryside by 1773, Jenner became a successful family doctor and surgeon, practicing on dedicated premises at Berkeley.

Jenner and others formed the Fleece Medical Society or Gloucestershire Medical Society, so called because it met in the parlor of the Fleece Inn, Rodborough, in Rodborough, Gloucestershire, meeting to dine together and read papers on medical subjects. Jenner contributed papers on angina pectoris, ophthalmia, and cardiac valvular disease and commented on cowpox. He also belonged to a similar society that met in Alveston, near Bristol.^[8]

Natural history, science and marriage[link]

Jenner was elected Fellow of the Royal Society in 1788, following his publication of a careful study of the previously-misunderstood life of the nested cuckoo that combined observation, experiment, and dissection.

Common Cuckoo

His description of the newly-hatched cuckoo, pushing its host's eggs and fledgling chicks out of the nest (contrary to existing belief that the adult cuckoo did it) was only confirmed in the 20th century, [1] when photography became available. Having observed this behaviour, Jenner demonstrated an anatomical adaptation for it—the baby cuckoo has a depression in its back, not present after twelve days of life, that enables it to cup eggs and other chicks. The adult does not remain long enough in the area to perform this task. Jenner's findings were published in Philosophical Transactions of the Royal Society in 1788.^[9][10]

"The singularity of its shape is well adapted to these purposes; for, different from other newly-hatched birds, its back from the scapula downwards is very broad, with a considerable depression in the middle. This depression seems formed by nature for the design of giving a more secure lodgement to the egg of the Hedge-sparrow, or its young one, when the young Cuckoo is employed in removing either of them from the nest. When it is about twelve days old, this cavity is quite filled up, and then the back assumes the shape of nestling birds in general. " (Letter to Hunter at the Royal Society, as above.)

Jenner's nephew assisted in the study.

Jenner married Catherine Kingscote (died 1815 from tuberculosis) in March 1788 after meeting her while he and other Fellows were experimenting with balloons. Jenner's trial balloon descended into Kingscote Park, Gloucestershire, owned by Anthony Kingscote, one of whose daughters was Catherine.

Jenner earned his MD from the University of St Andrews in 1792.

Jenner is also credited with advancing understanding of angina pectoris.^[11] In his correspondence with Heberden, he wrote, "How much the heart must suffer from the coronary arteries not being able to perform their functions."

Smallpox[link]

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (May 2011)

Inoculation was already a standard practice but involved serious risks. In 1721 Lady Mary Wortley Montagu had imported variolation to Britain after having observed it in Istanbul, where her husband was the British ambassador. Voltaire, writing of this, estimates that at this time 60% of the population caught smallpox and 20% of the population died of it.^[12] Voltaire also states that the Circassians used the innoculation from times immemorial, and the custom may have been borrowed by the Turks from the Circassians.^[13]

In 1765, Dr Fewster published a paper in the London Medical Society entitled "Cow pox and its ability to prevent smallpox", but he did not pursue the subject further.^[14]

In the years following 1770, at least five investigators in England and Germany (Sevel, Jensen, Jesty 1774, Rendell, Plett 1791) successfully tested a cowpox vaccine in humans against smallpox.^[15] For example, Dorset farmer Benjamin Jesty^[16] successfully vaccinated and presumably induced immunity with cowpox in his wife and two children during a smallpox epidemic in 1774, but it was not until Jenner's work some twenty years later that the procedure became widely understood. Indeed, Jenner may have been aware of Jesty's procedures and success.^[17]

Noting the common observation that milkmaids were generally immune to smallpox, Jenner postulated that the pus in the blisters that milkmaids received from cowpox (a disease similar to smallpox, but much less virulent) protected them from smallpox. He may already have heard of Benjamin Jesty's success.

On 14 May 1796, Jenner tested his hypothesis by inoculating James Phipps, a boy eight years old (the son of Jenner's gardener), with pus scraped from the cowpox blisters on the hands of Sarah Nelmes, a milkmaid who had caught cowpox from a cow called Blossom,^[18] whose hide now hangs on the wall of the St George's medical school library (now in Tooting). Phipps was the 17th case described in Jenner's first paper on vaccination.

Jenner inoculated Phipps in both arms that day, subsequently producing in Phipps a fever and some uneasiness but no full-blown infection. Later, he injected Phipps with variolous material, the routine method of immunization at that time. No disease followed. The boy was later challenged with variolous material and again showed no sign of infection.

Ronald Hopkins has written, "Jenner's unique contribution was not that he inoculated a few persons with cowpox, but that he then proved [by subsequent challenges] that they were immune to smallpox. Moreover, he demonstrated that the protective cowpox pus could be effectively inoculated from person to person, not just directly from cattle.^[19] In addition Jenner successfully tested his hypothesis on 23 additional subjects.

Jenner continued his research and reported it to the Royal Society, which did not publish the initial paper. After revisions and further investigations, he published his findings on the 23 cases. Some of his conclusions were correct, some erroneous; modern microbiological and microscopic methods would make his studies easier to reproduce. The medical establishment, cautious then as now, deliberated at length over his findings before accepting them. Eventually, vaccination was accepted, and in 1840 the British government banned variolation – the use of smallpox – and provided vaccination – using cowpox – free of charge. (See Vaccination acts). The success of his discovery soon spread around Europe and for example was used en masse in the Spanish Balmis Expedition,^[20] a three year long mission to the Americas, Philippines, Macao, China, and Saint Helena Island led by Dr. Francisco Javier de Balmis with the aim of giving thousands the smallpox vaccine. The expedition was successful, and Jenner wrote, "I don’t imagine the annals of history furnish an example of philanthropy so noble, so extensive as this."

1802 caricature of Jenner vaccinating patients who feared it would make them sprout cowlike appendages.

Jenner's continuing work on vaccination prevented his continuing his ordinary medical practice. He was supported by his colleagues and the King in petitioning Parliament and was granted £10,000 for his work on vaccination. In 1806 he was granted another £20,000 for his continuing work in microbiology.

In 1803 in London he became involved with the Jennerian Institution, a society concerned with promoting vaccination to eradicate smallpox. In 1808, with government aid, this society became the National Vaccine Establishment. Jenner became a member of the Medical and Chirurgical Society on its founding in 1805 and presented a number of papers there. The society is now the Royal Society of Medicine. In 1806, Jenner was elected a foreign member of the Royal Swedish Academy of Sciences.

Returning to London in 1811, Jenner observed a significant number of cases of smallpox after vaccination. He found that in these cases the severity of the illness was notably diminished by previous vaccination. In 1821 he was appointed Physician Extraordinary to King George IV, a great national honour, and was also made Mayor of Berkeley and Justice of the Peace. He continued to investigate natural history and in 1823, the last year of his life, he presented his Observations on the Migration of Birds to the Royal Society.

Jenner was found in a state of apoplexy on 25 January 1823, with his right side paralysed. He never fully recovered and eventually died of an apparent stroke, his second, on 26 January 1823, aged 73. He was survived by one son and one daughter, his elder son having died of tuberculosis at the age of 21.

His original report is in the Royal College of Surgeons (London)

The Rev Dr John Clinch - The first community vaccinator[link]

In a letter to Jenner in Gloucestershire dated December 1, 1796, Dr. John Clinch,^[21] a medical missionary at Trinity, then the second largest settlement in Newfoundland, asked for further information about using cowpox pustule matter as a vaccination against smallpox. Jenner had vaccinated his first subject only six months earlier. By June 1800, when Jenner published his famous pamphlet, "An Inquiry into the Causes and Effects of the Variolæ Vaccinæ,"^[22] describing his vaccination experiments on 23 subjects, Clinch probably had been vaccinating people in Newfoundland for a year or more.

Jenner and Clinch, both born in 1749, had been classmates at Reverend Dr. Washbourn’s school in Cirencester, Gloucestershire, before they went to London together to be pupils of John Hunter.^[23] Jenner returned to his home area, but Clinch practised three years in Dorset near Poole, the main shipping port for Newfoundland. In 1775 Clinch moved to Newfoundland to practice in Bonavista. After eight years, he moved to Trinity, where he also preached Anglican sermons on Sundays. Jenner’s nephew, George Jenner, seeking a similar church–medicine career, very likely began his medical apprenticeship under Clinch at Trinity in 1789.

On July 15, 1800, a second shipment of vaccine from Edward Jenner reached Clinch; one of these, most likely the first, came via George Jenner, by then the Anglican minister at Harbour Grace on the intervening peninsula between Trinity and St. John’s. By the first week of October 1800, Clinch had vaccinated additional people in the adjacent settlements of St. John’s and Portugal Cove and by the end of 1801 had vaccinated 700 people.

William R. LeFanu’s definitive bibliography of Jenner credits Clinch with being the first vaccinator in North America, before Benjamin Waterhouse, who vaccinated his own sons in July 1800 and then popularized vaccination in Boston. Sadly, exact dates for Clinch’s first vaccinations are unavailable. Clinch is honoured by a memorial plaque in Trinity.^[24] (This section reproduced from John W.R. McIntyre, MB BS; C. Stuart Houston, MD 'Smallpox and its Control in Canada'. CMAJ 14th Dec 1999)

Legacy[link]

In 1979, the World Health Organization declared smallpox an eradicated disease.^[25] This was the result of coordinated public health efforts by many people, but vaccination was an essential component. And although the disease was declared eradicated, some pus samples still remain in laboratories in Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in the United States and State Research Center of Virology and Biotechnology VECTOR in Koltsovo, Novosibirsk Oblast, Russia.

Jenner's vaccine also laid the foundation for contemporary discoveries in immunology, and the field he began may someday lead to cures for arthritis, AIDS, and many other diseases.^[26]

An illustrated history of smallpox eradication, Smallpox Zero,^[27] was published with the support of Sanofi Pasteur and distributed on May 17, 2010, in Geneva during an event sponsored by the World Health Organization.^[28][29] Smallpox Zero includes President Thomas Jefferson's letter of congratulations to Edward Jenner.

Monuments[link]

Dr Jenner's House

, The Chantry, Church Lane, Berkeley, Gloucestershire, England]]

Bronze in Kensington Gardens, London

• Edward Jenner is buried in the Jenner family vault at the Church of St. Mary's, Berkeley.^[30]
• Jenner's house in the village of Berkeley, Gloucestershire, is now a small museum, housing among other things the horns of the cow, Blossom
• A statue of Jenner by Robert William Sievier was erected in the nave of Gloucester Cathedral.
• Another statue was erected in Trafalgar Square and later moved to Kensington Gardens.^[31]
• Near the Gloucestershire village of Uley, Downham Hill is locally known as "Smallpox Hill" for its possible role in Jenner's studies of the disease.
• London's St. George's Hospital Medical School has a Jenner Pavilion, where his bust may be found^[32]
• A group of villages in Somerset County, Pennsylvania, United States, was named in Jenner's honor by early 19th century English settlers, including Jenners, Jenner Township, Jenner Crossroads, and Jennerstown, Pennsylvania
• Jennersville, Pennsylvania, is located in Chester County.
• A section at Gloucestershire Royal Hospital is known as the Edward Jenner Ward; it is where blood is drawn
• A ward at Northwick Park Hospital is called Jenner Ward
• Jenner Gardens at Cheltenham, Gloucestershire, opposite one of the scientist's former offices, is a small garden and cemetery

Publications[link]

• 1798 An Inquiry Into the Causes and Effects of the Variolæ Vaccinæ ^[22]
• 1799 Further Observations on the Variolæ Vaccinæ, or Cow-Pox. ^[33]
• 1800 A Continuation of Facts and Observations relative to the Variolæ Vaccinæ 40pgs ^[34]
• 1801 The Origin of the Vaccine Inoculation 12pgs

In popular culture[link]

• The Walking Dead television series's character Edwin Jenner, a doctor affiliated with Atlanta's Centers for Disease Control, is a homage to Edward Jenner.

See also[link]

• General practitioner
• Inoculation
• History of science

References[link]

Further reading[link]

• Papers at the Royal College of Physicians
• Baron, John M.D. F.R.S., "The Life of Edward Jenner MD LLD FRS", Henry Colburn, London, 1827.
• Baron, John, "The Life of Edward Jenner with illustrations of his doctrines and selections from his correspondence". Two volumes. London 1838.
• Edward Jenner, the man and his work. BMJ 1949 E Ashworth Underwood
• Fisher, Richard B., "Edward Jenner 1749-1823," Andre Deutsch, London, 1991.
• Cartwright K (October 2005). "From Jenner to modern smallpox vaccines". Occupational Medicine 55 (7): 563–563. DOI:10.1093/occmed/kqi163. PMID 16251374. 
• Riedel S (January 2005). "Edward Jenner and the history of smallpox and vaccination". Proceedings 18 (1): 21–5. PMC 1200696. PMID 16200144. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1200696. 
• Tan SY (November 2004). "Edward Jenner (1749-1823): conqueror of smallpox". Singapore Medical Journal 45 (11): 507–8. PMID 15510320. http://www.sma.org.sg/smj/4511/4511ms1.pdf. 
• van Oss CJ (November 2000). "Inoculation against smallpox as the precursor to vaccination". Immunological Investigations 29 (4): 443–6. PMID 11130785. 
• Gross CP, Sepkowitz KA (1998). "The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered". International Journal of Infectious Diseases 3 (1): 54–60. DOI:10.1016/S1201-9712(98)90096-0. PMID 9831677. 
• Willis NJ (August 1997). "Edward Jenner and the eradication of smallpox". Scottish Medical Journal 42 (4): 118–21. PMID 9507590. 
• Theves G (1997). "Smallpox: an historical review [Smallpox: an historical review]" (in German). Bulletin De La Société Des Sciences Médicales Du Grand-Duché De Luxembourg 134 (1): 31–51. PMID 9303824. 
• Kempa ME (December 1996). "Edward Jenner (1749-1823)--benefactor to mankind (100th anniversary of the first vaccination against smallpox) [Edward Jenner (1749-1823)--benefactor to mankind (100th anniversary of the first vaccination against smallpox)]" (in Polish). Polski Merkuriusz Lekarski 1 (6): 433–4. PMID 9273243. 
• Baxby D (November 1996). "The Jenner bicentenary: the introduction and early distribution of smallpox vaccine". FEMS Immunology and Medical Microbiology 16 (1): 1–10. DOI:10.1111/j.1574-695X.1996.tb00105.x. PMID 8954347. 
• Larner AJ (September 1996). "Smallpox". The New England Journal of Medicine 335 (12): 901; author reply 902. PMID 8778627. 
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• Kumate-Rodríguez J (1996). "Bicentennial of smallpox vaccine: experiences and lessons [Bicentennial of smallpox vaccine: experiences and lessons]" (in Spanish). Salud Pública De México 38 (5): 379–85. PMID 9092091. 
• Budai J (August 1996). "200th anniversary of the Jenner smallpox vaccine [200th anniversary of the Jenner smallpox vaccine]" (in Hungarian). Orvosi Hetilap 137 (34): 1875–7. PMID 8927342. 
• Rathbone J (June 1996). "Lady Mary Wortley Montague's contribution to the eradication of smallpox". Lancet 347 (9014): 1566. DOI:10.1016/S0140-6736(96)90724-2. PMID 8684145. 
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• Poliakov VE (December 1985). "Edward Jenner and vaccination against smallpox [Edward Jenner and vaccination against smallpox]" (in Russian). Meditsinskaia Sestra 44 (12): 49–51. PMID 3912642. 
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• Udovitskaia EF (November 1966). "Edward Jenner and the history of his scientific achievement. (On the 170th anniversary of the discovery of smallpox vaccination) [Edward Jenner and the history of his scientific achievement. (On the 170th anniversary of the discovery of smallpox vaccination)]" (in Russian). Vrachebnoe Delo 11: 111–5. PMID 4885910. 
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• Ordnance Survey showing reference to Smallpox Hil: http://explore.ordnancesurvey.co.uk/os_routes/show/1539
• 1970 Davies JW. A historical note on the Reverend John Clinch, first Canadian vaccinator. CMAJ 1970;102:957–61.
• 1970 Roberts KB. Smallpox: an historic disease. Memorial University of Newfoundland Occas Papers Med Hist 1978;1:31–9.
• 1951 LeFanu WR. A bio-bibliography of Edward Jenner, 1749–1823. London (UK): Harvey and Blythe; 1951. p. 103–8.

External links[link]

Wikisource has original works written by or about: Edward Jenner

Wikimedia Commons has media related to: Edward Jenner

• Jenner's papers on vaccination
• A digitized copy of An inquiry into the causes and effects of the variola vaccine (1798), from the Posner Memorial Collection at Carnegie Mellon
• The Edward Jenner Museum & Old Cyder House Conference Centre
• The Evolution of Modern Medicine. Osler, W (FTP)
• Flickr images tagged Edward Jenner
• Flickr images tagged Temple of Vaccinia
• Review of The Edward Jenner Museum on SoGlos.com

Donald Ainslie Henderson, known as D.A. Henderson, (born September 7, 1928) is an American physician and epidemiologist, who headed the international effort during the 1960s to eradicate smallpox. As of 2010^[update], he is a Distinguished Scholar at the University of Pittsburgh Medical Center's Center for Biosecurity and a professor of public health and medicine at the University of Pittsburgh. He is also a Johns Hopkins University Distinguished Service Professor and Dean Emeritus of the School of Public Health, with a joint appointment in the Department of Epidemiology.

Biography[link]

Early life[link]

Henderson was born in Lakewood, Ohio in the United States. He graduated from Oberlin College in 1950 and received his M.D. from the University of Rochester School of Medicine in 1954. He served both an internship (1954–1955) and a residency (1957–1959) in medicine at the Mary Imogene Bassett Hospital in Cooperstown, New York. He earned an M.P.H. degree in 1960 from the Johns Hopkins School of Hygiene and Public Health (now the Johns Hopkins Bloomberg School of Public Health).

Between his internship and residency (1955–1957) and again from 1960–1966, he worked in the Epidemic Intelligence Service of the Communicable Disease Center (CDC; now the National Centers for Disease Control and Prevention), where he created a Smallpox Surveillance Unit to deal with imports of the disease into the USA.

Eradication of smallpox[link]

Henderson (first man on left) as part of the CDC's smallpox eradication team in 1966.

In 1966 Henderson moved to Geneva to head the World Health Organization's Global Smallpox Eradication Campaign. Smallpox was at the time endemic in Brazil, Africa and South Asia.

In 1972 Henderson helped suppress an outbreak of smallpox in Yugoslavia, the last epidemic of smallpox in Europe. In 1974 he was stationed in India during one of the largest epidemics in the 20th century and was instrumental in initiating the global program of immunization. This program has vaccinated 80 percent of the world's children against six major diseases and is striving to eradicate poliomyelitis.