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Smallpox is a disfiguring and potentially deadly infectious disease caused by the Variola major virus. Before smallpox was eradicated, there were two forms of the disease worldwide: Variola major, the deadly disease, and Variola minor, a much milder form. According to some health experts, over the centuries smallpox was responsible for more deaths than all other infectious diseases combined.

The last naturally occurring case of smallpox was reported in 1977. In 1980, the World Health Organization declared that smallpox had been eradicated. Currently, there is no evidence of naturally occurring smallpox transmission anywhere in the world. Although a worldwide immunization program eradicated smallpox disease decades ago, small quantities of smallpox virus officially still exist in two research laboratories in Atlanta, Georgia, and in Russia.


Scientists have not studied variola virus well because of the hazards associated with potential exposure. In addition, by international agreement, smallpox may only be studied at the Centers for Disease Control and Prevention (CDC) high-containment facility or the high-containment facility in Russia. Experiments must be approved in advance by an international committee.

Vaccinia virus used to make a smallpox vaccine and closely related to variola, has been studied thoroughly. There is one major difference between the two viruses: vaccinia can infect several types of living beings, while variola infects only humans naturally and cynomolgus monkeys under highly artificial laboratory conditions.


Smallpox is highly contagious. In most cases, people get smallpox by inhaling droplets of saliva, which are full of virus, during face-to-face contact with an infected person. When someone becomes infected, they do not immediately feel sick or shed virus to their household contacts. Exposure to the virus is followed by an incubation period during which people do not have any symptoms and may feel fine. This incubation period averages about 12 to 14 days but can range from 7 to 17 days. During this time, people are not contagious. After the virus has multiplied and spread throughout the body, a rash and fever develop. This is the "illness" portion of the disease, and it is when someone is most infectious.

Some risk of transmission lasts until all scabs have fallen off. Contaminated clothing or bed linens also can spread the virus. Those caring for people with smallpox need to use special safety measures to ensure that all bedding and clothing from the infected person are cleaned appropriately with bleach and hot water. Caretakers can use disinfectants such as bleach and ammonia to clean contaminated surfaces.


The first symptoms of smallpox may be difficult to distinguish from other flu-like illnesses and include

  • High fever
  • Fatigue
  • Malaise
  • Headache
  • Backache
  • Rash

A characteristic rash, most prominent on the face, arms, and legs, follows 2 to 3 days after the first symptoms. The rash starts with flat red lesions (sores) that develop at the same rate. After a few days, the lesions become filled with pus. They begin to crust early in the second week. Scabs develop and then separate and fall off after about three weeks.


There is no proven treatment for smallpox. People with the disease can benefit from intravenous fluids and medicine to control fever or pain as well as antibiotics for any secondary bacterial infections that may occur. If an infected person gets the smallpox vaccine within 4 days after exposure to the virus, it may lessen the severity of illness or even prevent it. The majority of people with smallpox recover, but death may occur in up to 30 percent of cases. Those who do recover are often left with disfiguring scars.


To prevent the spread of smallpox, healthcare providers must

  • Isolate infected people
  • Vaccinate close contacts of infected people


The currently licensed smallpox vaccine, which consists of a laboratory strain of vaccinia virus, is highly effective in preventing infection. Medical experts believe the vaccine may lessen the severity of, or even prevent, illness in unvaccinated people if given within 4 days of exposure to the virus.

The smallpox vaccine helps the body develop immunity to smallpox. The vaccine is made from a "pox"-type virus related to smallpox. The smallpox vaccine contains live vaccinia virus-unlike many other vaccines that use killed virus. The vaccine does not contain the smallpox virus and cannot transmit smallpox. Learn more about the smallpox vaccine from CDC.

Few data exist showing just how long vaccinia vaccines protect people against smallpox infection. Therefore, those vaccinated against the smallpox virus before 1972 may be susceptible to the disease. Military and other high-risk groups (for example, scientists who work with vaccinia and other orthopoxviruses related to Variola major) have been getting the vaccine since the United States stopped routine smallpox vaccinations in 1972.

Getting the vaccine

Healthcare providers do not use a hypodermic needle, usually used for vaccinations, to give the smallpox vaccine. Instead, they use a tiny, two-pronged needle that is dipped into the vaccine solution. When removed from the solution, the needle keeps a droplet of the vaccine. The needle is used to prick the skin, usually in the upper arm, a number of times within a few seconds. The pricking is not deep, but it will cause a sore spot and one or two droplets of blood.

If the vaccination is 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, fills with pus, and begins to drain.
  • During the second week, the blister begins to dry up and a scab forms.
  • In the third week, the scab falls off, leaving a small scar.

People who get the vaccine for the first time have a stronger reaction than those who are revaccinated.

Reactions and complications

Most people experience normal, typically mild reactions to the vaccine, which go away without treatment. The vaccine often causes a low fever, swollen glands in the armpits, as well as skin redness at the vaccination site.

The vaccine, however, can cause several complications, some life-threatening, particularly in people with immune deficiencies and skin disorders. Based on reactions to smallpox vaccines in the past, the CDC estimates that between 14 and 52 out of every 1 million people vaccinated for the first time will have potentially life-threatening complications that require medical attention, including

  • Eczema vaccinatum (EV)-spread of vaccinia skin lesions to areas of the body once or presently afflicted by eczema
  • Progressive vaccinia-uncontrolled spread of the vaccinia virus to adjacent and underlying tissues resulting in tissue death
  • Postvaccinal encephalitis-spread of the vaccinia virus to the central nervous system that is probably made worse by an over-response to the vaccine by the immune system
  • Myo/pericarditis-an inflammation of the heart that is probably also caused by an over-response to the vaccine by the immune system

CDC estimates 1 or 2 in 1 million people who receive the vaccine may die as a result of vaccination. Because of serious and potentially deadly reactions, health care providers must carefully screen potential vaccine recipients to ensure that those at increased risk do not receive the vaccine.

Healthcare providers treat certain serious complications with anti-vaccinia immune globulin-pooled antibodies taken from people recently immunized with the smallpox vaccine.

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NIAID supports basic, preclinical, and clinical research needed to advance product development for biodefense and emerging infectious diseases. Product development goals in this arena have shifted from a “one bug-one drug” approach to a more flexible strategy that is applicable to a broad spectrum of infectious diseases. Specifically, this broad-spectrum approach is being used to develop products effective against a variety of pathogens and toxins; find technologies that can be widely applied to improve multiple classes of products; and establish platforms that can reduce the time and cost of creating new products. This is evident in both the treatment and vaccine research NIAID has supported for smallpox, outlined below.

Vaccine Supply and Strength

The last naturally occurring case of smallpox was reported in 1977. In 1980, the World Health Organization declared that smallpox had been eradicated. The Dryvax vaccine was used in smallpox eradication, and the United States has enough of its successor, Acam2000, available to vaccinate the population in the case of a terrorist attack. Prior to availability of Acam2000, a NIAID-supported clinical trial that found that Dryvax could successfully be diluted up to five times and retain its effectiveness. These findings helped expand the number of individuals Dryvax could protect until sufficient doses of Acam2000 were made for the entire U.S. population.

People with weakened immune systems or skin conditions, such as atopic dermatitis, are at increased risk for serious side effects from Dryvax and Acam2000. NIAID is pursuing the development of new, safer smallpox vaccines that could be used to protect these groups. One of the most promising is being developed by the biotechnology company Bavarian Nordic and uses a vaccine platform technology known as Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN). NIAID supported early advanced development work for this important vaccine, with initial efforts largely focused on the liquid formulation. NIAID support spanned preclinical evaluation through Phase II clinical trials. The trials assessed the vaccine in healthy participants, HIV-positive volunteers, and people with atopic dermatitis or a history of atopic dermatitis. These studies evaluated factors such as safety, immunogenicity, duration of protection, and route of vaccination. The vaccine was transitioned to the Biomedical Advanced Research and Development Authority (BARDA) for advanced development. In 2013, Canada and the European Union approved the vaccine (under the trade names IMVAMUNE and IMVANEX) for use in the general population, including people with weakened immune systems or atopic dermatitis. As of August 2014, 24 million doses were delivered to the U.S. Strategic National Stockpile (SNS) for use among these groups.

NIAID also supported a project to develop a freeze-dried, or lyophilized, version of the vaccine. Compared to the current liquid formulation, the lyophilized version is more stable with a longer shelf life. NIAID has transitioned this project to the U.S. Department of Health and Human Services Biomedical Advanced Research and Development Authority (BARDA) for further development.

NIAID is supporting studies to identify adjuvants that can be used to decrease the number of vaccinations needed to provide protection and explore MVA as a platform technology to provide protection against more than one disease.


Although smallpox vaccines have been developed and procured for the SNS, they cannot completely prevent disease or attenuate the illness if given too late following exposure. Smallpox antivirals are needed for treatment or post-exposure prophylaxis. Early results from laboratory studies suggest that the drug cidofovir may be an effective treatment against the smallpox virus. (In 1996, the Food and Drug Administration [FDA] approved the use of cidofovir to treat cytomegalovirus infections.) NIAID-supported scientists are doing studies with animals to better understand the drug's ability to treat smallpox.

Based on encouraging study results, NIAID applied to FDA to use cidofovir as an experimental treatment for smallpox in the event of a bioterrorist-initiated re-emergence. Although it is effective against smallpox, cidofovir must be given intravenously and its use often results in life-threatening kidney toxicity. To circumvent the drug delivery and toxicity problems, NIAID has supported the development of brincidofovir, a derivative of cidofovir that can be given orally instead of by intravenous injection and that may have fewer side-effects. NIAID has supported brincidofovir from discovery through three Phase 1 clinical studies. In addition to its activity against smallpox, brincidofovir has activity against several other viruses that can infect humans, including herpes, adeno and polyoma viruses.

NIAID has also provided support from discovery through Phase II clinical development for a second therapeutic for smallpox, tecovirimat. Tecovirimat has a different mechanism of action from that of cidofovir or brincidofovir, and is specifically active against smallpox and closely related members of the poxvirus family.

NIAID has successfully transitioned both brincidofovir and tecovirimat to BARDA for further clinical development.

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Last Updated October 22, 2014