Smallpox is an acute and highly contagious disease caused by a virus of the Orthopox, genus called variola. The variola virus causes two forms of the disease: variola major (also called classic smallpox), the more severe form of the disease, which killed about a third of people who were infected by it; and variola minor (also called alastrim), which was milder and had a mortality rate of about 1%. The English word variola is derived from the Latin word for spotted or changing in color. Variola major acquired the name “smallpox” in fifteenth-century England to distinguish it from the “great pox,” the then-common name for syphilis. Alastrim was also called white pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.

Smallpox is unique among infectious diseases in that it was the first to prompt the development of an effective vaccine and the first to be eradicated. The World Health Organization (WHO) certified that smallpox had been eradicated in December 1979. The last-known naturally occurring case of smallpox in the United States was diagnosed in 1949, and the last case of variola minor was diagnosed in Somalia in 1977. The only known isolates of the variola virus are held in frozen form in tightly guarded laboratories in the Centers for Disease Control and Prevention (CDC) in the United States and the VECTOR Institute in the Russian Federation.


The origin of the modern smallpox virus is a subject of considerable debate among historians of medicine and paleomicrobiologists. There is general agreement that the virus originated as a zoonosis in a small African rodent species at some point between 68,000 and 16,000 years ago, long before humans began to practice agriculture and live in settled villages. The smallpox virus jumped the species barrier at some point and humans became the primary reservoir. It is less certain, however, when the smallpox virus evolved into the epidemic form that killed millions of people over the course of centuries. Some archaeologists think that the skin lesions on the mummy of Pharaoh Rameses V of Egypt (d. 1145 B.C.) were caused by the smallpox virus in its modern form, while others think that the modern virus evolved much more recently, most likely in seventeenth-century Europe.

There is evidence that Egyptian traders carried some form of smallpox to India around 1500 B.C., where it became endemic. The disease then spread to China by 100 A.D. and later to Japan, where it caused an epidemic that killed a third of the Japanese population in 735–737. Smallpox most likely entered Europe with the Arab armies in the ninth century, but the disease did not become well established among Europeans until the sixteenth century. This timing was significant because it coincided with the so-called age of discovery, the European exploration of the Americas and Oceania. As a result of European exploration and colonization, smallpox became endemic throughout the world (with the exception of Australia) by the mid-eighteenth century. It is thought to have killed about 400,000 Europeans per year by the 1770s, including King Louis XV of France (1710–1774) and four other reigning monarchs.


Smallpox can be divided into two major subtypes: variola major, the more severe and more widespread form of the disease; and variola minor or alastrim. Neither form exists in a carrier state, which means that anyone infected by the virus will become symptomatic. In general, smallpox begins about 12 days after exposure. Those who are infected experience a prodrome: a flulike illness with fever around 38.3°C (101°F), back pain, headaches, and general malaise. The patient typically feels sick enough to stay in bed. Within two to three days after symptom onset, a rash appears on the mucous membranes of the patient's mouth and throat. This is the stage at which the disease is most contagious.

The mouth rash is followed by a maculopapular rash—a combination of reddish spots and raised fluidfilled blisters or pocks on the patient's face that spreads to the arms and legs. The blisters (papules) become pustules or pus-filled lesions that break open and become bloody or oozing open sores. When these sores crust over, they form scabs that fall off several weeks later, leaving scars called pock marks. The resulting facial disfigurement was a classic indication that a person was a smallpox survivor. In addition to the pock marks, smallpox also causes such complications as blindness, arthritis, limb and joint deformities, heart disorders, and secondary bacterial infections like pneumonia or encephalitis.

Variola minor or alastrim had similar symptoms but was much less virulent. Prior to eradication, alastrim was found primarily in South Africa, South America, Australia, and parts of Europe.

Variola major was classified into four types in a system devised by an Indian researcher named Ayyagari Ramachandra Rao in the late 1960s. The four types of variola major in the Rao system are:

Morbidity and mortality rates

Historically, the mortality rate of classic variola major ranged between 20 and 60% in adults and 80% in children, with mortality approaching 95% in the malignant and hemorrhagic subtypes. Modified variola major and variola minor had much lower mortality rates, about 1%.

The morbidity of classic smallpox, however, was considerable. Most survivors had lifelong pockmarks on their faces and necks. Queen Elizabeth I (1533–1603) contracted smallpox in 1562 and wore heavy makeup to the end of her life to cover the pockmarks. About 2% of survivors lost their eyesight. Others suffered hair loss or various forms of limb and joint deformities.

Public health role and response

Variolation was followed by vaccination, the procedure developed by Edward Jenner (1749–1823), an English physician who noticed that milkmaids who had developed cowpox, a milder disease caused by another orthopoxvirus related to the variola virus, were immune to smallpox. He wondered whether inoculating people with the cowpox virus would be safer than variolation but still protective against smallpox. After inoculating a nine-year-old boy with matter from a cowpox sore on a milkmaid's hand, Jenner discovered that the boy was indeed immune to the variola virus. Jenner named the procedure vaccination, a term derived from the Latin word for cow. By the end of the nineteenth century, vaccination was widely accepted in the developed countries as the most effective protective measure against smallpox.

International efforts

At some point in the nineteenth century, Jenner's cowpox virus was gradually replaced by vaccinia virus, a closely related virus that was developed through the serial passage and cultivation of the virus in the laboratories that were used to make vaccines. Some historians of medicine think that the vaccinia virus, the cowpox virus, and the variola virus all descended from a common ancestor, while others think that the vaccinia virus was originally isolated from horses. The smallpox vaccine that ultimately led to the eradication of the disease in the twentieth century was developed using the vaccinia virus.

In the late 1940s, the mass production of freezedried vaccine made it possible to vaccinate large numbers of people in developing countries. As the death toll from smallpox began to decline worldwide, complete eradication of the disease became the goal. International efforts to end smallpox began in earnest in 1967, when an American epidemiologist named Donald Henderson (1928–2016) from the Johns Hopkins School of Public Health led a WHO unit that carried out a massive childhood vaccination campaign and search for smallpox outbreaks. Smallpox had already been eradicated in North America in 1952 and in Europe in 1953. The last case in South America was identified in Brazil in 1971; in Asia in Indonesia in 1972; and in Africa in Somalia in 1977. The WHO team then visited all the countries where smallpox had been endemic, and the agency then declared the disease eradicated in 1979.

The problem that remains is the storage of frozen stocks of smallpox virus in the United States and the Russian Federation. Both countries maintain that they continue to hold their virus repositories for only two reasons: research against bioterrorism; and insurance against a possible future discovery of a natural reservoir of smallpox.

Risk factors

As of 2017, the only people at present risk of smallpox are researchers in facilities where the virus is stored. In the event of a bioterrorism attack requiring mass vaccination of the general public against smallpox, however, most people would require vaccination, because compulsory vaccination against smallpox in the United States ended in 1972 and those vaccinated at or before that time are no longer immune.

Causes and symptoms


The cause of smallpox is the variola virus, an orthopox two-stranded DNA virus that replicates within the cytoplasm of an infected cell rather than in the nucleus. The variola virus is brick-shaped and large for a virus, about 300 nanometers in diameter. It exists only in humans and is spread by inhalation or by direct contact with the skin lesions of an infected patient; it takes only a few virions to infect a new host. In past outbreaks, the average patient infected between 4 and 10 family members and contacts. Less commonly, the virus can be spread by such fomites (inanimate objects) as clothing, towels, or bedsheets used by an infected patient.

Once inhaled, the variola virus invades the mucous tissues lining the mouth and throat, then migrates to nearby lymph nodes and begins to multiply. Around the twelfth day after exposure, many of the infected cells begin to die in large numbers, allowing the virus to enter the bloodstream. This condition is called viremia. The virus is then carried to the spleen, bone marrow, and other organs, and undergoes a second phase of multiplication.


The initial symptoms of smallpox—the prodrome—emerge when the virus invades the bloodstream. They resemble the symptoms of influenza: the patient has a fever of about 101°F (38°C), feels sick enough to stay in bed, and has a headache, muscle aches, nausea, and vomiting. About 2 to 3 days after the onset of the prodrome, the virus begins to attack the skin. Lesions appear in the patient's mouth and throat, followed by the classic maculopapular rash 1 or 2 days later.

In the ordinary form of smallpox, the lesions develop from macules to papules to pustules to sores covered with scabs that then fall off, leaving permanent scars. In some patients, however, the infection takes the modified, malignant, or hemorrhagic forms described above. Death occurs during the second week of illness, usually as a result of a cytokine storm or massive inflammatory response to the infection, leading to shock and multiple organ failure. Patients with the malignant or hemorrhagic forms of smallpox usually die within 5 to 6 days after symptom onset.


There is some concern about the difficulty of diagnosing smallpox in the posteradication era, as doctors in current practice know about the visible symptoms of the disease only through photographs from the 1960s or earlier, and the modified subtype of variola major resembles chickenpox closely enough to confuse many practitioners. At present, only patients with a documented history of exposure to the virus in a laboratory or exposure during a suspected episode of bioterrorism would be tested for the smallpox virus, and the physician would need to be vaccinated and wearing suitable protective equipment (gloves and a mask).


Smallpox may be suspected if the patient has the typical prodrome (fever plus at least one of the following: headache, backache, severe abdominal pain, chills, and vomiting) plus the skin lesions of classic smallpox. In addition, the lesions will be at the same stage of development at all locations on the patient's body, which differentiates smallpox lesions from those of chickenpox.


The physician will take a sample of matter from a skin pustule or scab and a swab of the patient's throat. These materials will be sent to a biosafety level 4 (BSL-4) laboratory for examination under an electron microscope for the characteristic virions of smallpox or for culturing on live cells. The CDC has specific instructions for specimen collection and shipment. Positive results from electron microscopy or cell culture must be confirmed by polymerase chain reaction (PCR) assay, and the CDC notified as soon as possible.

An alternate name for variola minor, the less severe form of smallpox. Alastrim was also called white pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.
Terrorism involving the intentional dissemination of bacteria, viruses, toxins, or other biological agents.
Cytokine storm—
A potentially fatal reaction of the immune system in which there is a feedback loop between cytokines (small proteins important in cell signaling) and white blood cells.
Referring to a type of skin rash characterized by a combination of small flat spots (macules) and raised round lesions (papules).
The subspecialty of microbiology devoted to the study of ancient diseases. It includes exploring the evolution of present-day disease organisms as well as identifying the organisms responsible for past epidemics.
A set of early signs or symptoms of a disease that indicate the onset of the disease before more diagnostically specific signs and symptoms appear.
In epidemiology, the term used for the long-term host of an infectious disease agent. Humans are the contemporary reservoir of the smallpox virus.
Select agent—
The legal term in the United States for biological organisms or toxins that are deemed to present a severe threat to public health and safety. Both smallpox virus (variola major) and alastrim (variola minor) are classified as Tier 1 select agents.
A variant of the cowpox virus that became established in vaccines derived from cowpox-inoculated humans.
The formal name of the double-stranded DNA virus that causes smallpox.
The presence of viruses in the bloodstream.
The form of a virus that exists as an independent particle prior to infection of a living cell. Virions consist of an outer protein shell called a capsid and an inner core of nucleic acid.
Zoonosis (plural, zoonoses)—
Any disease that can be transmitted from other animals to humans, or from humans to other animals. It is thought that smallpox began as a zoonosis.


There is no specific therapy for smallpox as of 2017; treatment is basically supportive. In a small outbreak, the patient would be hospitalized and placed in strict isolation in a negative-pressure room equipped with high-efficiency particulate (HEPA) filters for about 3–4 weeks or until the last scabs have fallen off, to prevent transmitting the disease to others. The patient's fluid and electrolyte balances would be monitored to prevent dehydration, and pain relievers given to lower fever and reduce discomfort.

The CDC has recommended designating specific hospitals as smallpox-only facilities in the event of an outbreak, although in large outbreaks, patients would be required to be isolated in their homes. Patients' contacts would be placed under surveillance and monitored daily for fever or other signs of illness.


There are no drugs licensed by the Food and Drug administration (FDA) as of 2017 specifically for the treatment of smallpox. There are, however, two investigational antiviral drugs, brincidofovir (CMX001) and tecovirimat (ST-246), which have been used to treat complications of vaccination and might be useful in treating smallpox in the event of an outbreak. According to the CDC, these two drugs have been stockpiled in the event of an outbreak even though they have not been tested in humans diagnosed with smallpox. Cidofovir is another antiviral drug that has been suggested as potential therapy for smallpox. Smallpox patients with secondary bacterial infections can be given antibiotics.


The prognosis of smallpox in the event of a future outbreak is difficult to estimate; the mortality statistics for the four subtypes of variola major and for variola minor were compiled prior to the eradication of naturally occurring smallpox. Most physicians assume that people with weakened immune systems, those with such chronic diseases as diabetes, and those suffering from malnutrition would be particularly susceptible to smallpox in the event of an outbreak. It is thought, however, that vaccination with the present form of smallpox vaccine might lower the mortality rate. The CDC states that vaccination prior to exposure to the smallpox virus would be 95% effective against contracting the disease; that vaccination within 3 days of exposure might prevent illness altogether or lead to a milder course of illness; and that vaccination within 4–7 days of exposure would still offer some protection.


Given the possibility of either the discovery of a previously unknown natural reservoir of smallpox or a bioterrorist attack using the smallpox virus as a weapon, the only preventive strategies as of 2017 are vaccination and secure storage of the remaining stocks of smallpox virus. The smallpox virus is classified as a category A (highest level) agent of bioterrorism by the CDC because it can be easily disseminated from one person to another, has a high mortality rate, would be highly likely to trigger mass panic and social disruption, and requires special public health preparedness measures.

The current FDA-approved smallpox vaccine, known as ACAM2000, is a live vaccine made from the vaccinia virus. It is presently not administered to the general public but only to laboratory workers who may be exposed to the smallpox virus and to military personnel deployed outside the continental United States. Because ACAM2000 is a live vaccine, it is not approved for use in pregnant women or immunocompromised persons, or in persons with a history of such skin disorders as eczema. About 1 person in every 10,000 will have a severe reaction to the vaccine, which is why it is not required for most people. In the event of an outbreak, public health officials will notify the public as to who should receive the vaccine.

The vaccine also requires a special administration technique and aftercare. Instead of being given as an injection, the smallpox vaccine is administered by dipping a bifurcated (two-pronged) needle in the vaccine and jabbing the instrument about 15 times into the skin of the upper arm forcefully enough to draw a small amount of blood. The area is then covered with a bandage to prevent the live virus in the vaccine from spreading to other areas of the body or to close contacts. The vaccinated person is likely to run a low fever and have sore muscles or headaches the week after vaccination. If the vaccination is successful, a lesion will form at the site and develop into a pustule followed by a scab. The site requires care for about three weeks following vaccination. The smallpox vaccine requires booster shots every three years.

In terms of bioterrorism, there are several known instances of using smallpox as a biological weapon, the best-known being the British use of smallpox-contaminated blankets against the French and their Native American allies during the French and Indian War (1754–1763). In 1947, the Soviet Union set up a weaponized smallpox facility in Zagorsk, a town near Moscow, which led to an outbreak in 1971 on an island in the Aral Sea. A scientist who defected to the United States in 1992 has suggested that some of the weaponized smallpox or persons with the expertise to manufacture it may have made themselves available to other governments after the collapse of the Soviet Union. Another concern is that even if all existing samples of the virus were destroyed, artificial gene synthesis could be used to recreate the smallpox virus from existing digital genomes and insert the synthesized smallpox DNA into existing poxviruses like monkeypox virus.

The smallpox virus stored at the CDC is kept in a secure biosafety level 4 (BSL-4) facility, defined by the Department of Health and Human Services as “appropriate for work with agents that could easily be aerosol-transmitted within the laboratory and cause severe to fatal disease in humans for which there are no available vaccines or treatments.” To protect the public in the event of a smallpox outbreak, the CDC maintains the Strategic National Stockpile, which contains enough doses of vaccine to vaccinate every person in the United States. It also contains a stockpile of brincidofovir and tecovirimat, the two investigational drugs that could be used to treat patients diagnosed with smallpox.

See also Epidemiolog ; Globalization and emerging diseases ; Pandemics ; Vaccination ; Zoonoses .



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Advisory Committee on Immunization Practices (ACIP) Secretariat, 1600 Clifton Rd. NE, Mailstop A27, Atlanta, GA, 30329-4027, (404) 639-8836, .

American Society of Tropical Medicine and Hygiene (ASTMH), One Parkview Plaza, Ste. 800, Oakbrook Terrace, IL, 60181, (847) 686-2238, Fax: (847) 686-2251,, .

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U.S. Food and Drug Administration (FDA), 10903 New Hampshire Ave., Silver Spring, MD, 20993, (888) 463-6332,, .

World Health Organization (WHO), Avenue Appia 20, Geneva, Switzerland, CH - 1211 Geneva 27, , .

Rebecca J. Frey, PhD

  This information is not a tool for self-diagnosis or a substitute for professional care.