• Disease Overview
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report



Last updated: April 07, 2009
Years published: 2001, 2004, 2009

Disease Overview

Smallpox is an infectious disease caused by the variola virus. It is characterized by fever, a general feeling of ill health (malaise), headaches and back pain. These initial symptoms are followed by a rash and small, raised bumps or lesions (pocks) within two or three days. Smallpox was a highly contagious disease, but was declared eradicated in 1980. However, recently smallpox has become of interest because of the possibility of its use as a weapon of warfare or of terrorism. There were two strains of smallpox, variola major and variola minor.

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  • Variola Major (Smallpox)
  • Variola Minor (Alastrim)
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Signs & Symptoms

Symptoms of smallpox appear after an incubation period of approximately 12 days (7-17 days). Initial symptoms are a high fever, a general feeling of ill health (malaise), headaches, and back pain often resulting in affected individuals becoming bedridden. In some cases, severe abdominal pain and delirium may also be present.

Approximately two to three days after the onset of the disease, a characteristic rash forms on the mucous membranes (mucosa) of the mouth and throat (pharynx) as well as on the face and arms. The rash often spreads to affect the legs and trunk. Within one or two days, small, red bumps or lesions form (papules). These lesions become pus-filled (pustules) sometimes breaking open and resulting in bloody, oozing sores. Eventually, the pustules begin to crust and then scab. In three to four weeks, the scabs fall off, usually leaving scars or pox marks.

There were two strains of smallpox. Variola major was more severe and had a fatality rate of approximately 30 percent; variola minor was less severe and had a fatality rate of less than 1 percent.

Life-threatening complications that may be associated with smallpox include blood loss, the presence of toxins in the blood (toxcemia), cardiovascular problems, and/or secondary bacterial infections.

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Smallpox is caused by infection with the variola virus. The disease is spread through person to person contact, most often from inhalation of droplet nuclei expelled through the back of the throat (oropharynx) of an infected person. Droplet nuclei are small particles containing virus-infected respiratory secretions that are pushed out into the air by coughing or sneezing. These airborne particles may then be inhaled by another person. Individuals with smallpox are most infectious during the first week of illness.

Smallpox may also be spread through direct contact with an infected person or through contact with contaminated material such as clothing, blankets or bed linen.

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Affected populations

Smallpox existed for thousands of years until the World Health Organization declared it extinct in May of 1980. The last known case of smallpox occurred in Somalia in 1977.

The only known stores of the smallpox virus are in two locations: the Centers for Disease Control and Prevention (CDC) in Atlanta and Russian government laboratories near Moscow. However, government officials fear that secret stores may be maintained elsewhere and may be released deliberately as an act of warfare (bioterrorism).

Individuals with weakened immune systems such as those with leukemia, lymphoma or AIDS would be more susceptible to smallpox infection if the disease was reintroduced into society.

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Standard Therapies

In the United States before 1972, children received routine smallpox vaccinations. However, the duration of immunity granted by the vaccination may be only 10 to 15 years, so those who received the vaccine in childhood may no longer be immune to the disease.

According to the Centers for Disease Control and Prevention (CDC), the smallpox vaccine can lessen the severity or prevent illness in individuals who are exposed to the smallpox virus if administered within four days after exposure.

The smallpox vaccine contains another virus, vaccina, made from the cowpox virus. The United States currently has an emergency supply of the vaccine in storage at the CDC. During 2000 and 2001, the CDC contracted with pharmaceutical companies to manufacture more of the smallpox vaccine for use if smallpox is employed as a terrorism weapon.

In rare cases, the administration of smallpox vaccine results in a severe reaction. Such reaction may be treated by a specialty antibody prepared from human plasma that has been approved by the FDA (February 2005). This vaccine, vaccinia immune globulin intravenous (human) is also known by the trade name VIGIV and is manufactured and marketed by:

DynPort Vaccine Company LLC.

64 Thomas Johnson Drive

Frederick, Marylan. 21702.

There is no specific treatment for individuals infected by smallpox. Treatment is supportive and directed at specific symptoms present in each individual. Supportive therapy may include antibiotics for secondary bacterial infections and/or medications for pain or fever.

In 2002, the U.S. Food and Drug Administration (FDA) granted orphan status to the drug poly-ICLC (Hiltonol), to be used as an adjuvant to smallpox vaccination. Hiltonol is manufactured by Oncovir, Inc., a Washington, DC, pharmaceutical corporation. Additional information on this experimental product may be found at www.oncovir.com.

Vaxgen, Inc., in partnership with the Chemo-Sero Research Institute in Japan, is developing a smallpox vaccine, LC16m8, that has been licensed for use in Japan for several years. Their goal is to develop a vaccine that is safer than Dryvax, but equally effective.

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Clinical Trials and Studies

Research is underway to develop new antiviral drugs for the treatment of infectious diseases such as smallpox.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:


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Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996: 1765-68.

Fields BN, et al. Fields Virology, 2nd ed. New York, NY: Raven Press; 1990:2113-33.

Mandell GL, et al. eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Inc; 1995:1328-29.


Henderson DA, et al. Smallpox as a biological weapon. Medical and public health management. JAMA. 1999;281:2127-37.

Georges AJ, et al. Biohazards due to Orthopoxvirus: should we re-vaccinate against smallpox? Med Top (Mars). 1999;59:483-87.

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Programs & Resources

RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations

National Organization for Rare Disorders