Smallpox (Variola Virus)



  • Smallpox is a life-threatening, acute, eruptive, contagious disease caused by variola virus.
  • The disease is characterized by a febrile prodrome followed by the development of rash.
  • Rash evolves in a characteristic fashion: macules → papules → vesicles → pustules; scabs form and fall off, leaving scars called pockmarks.
  • There are two clinical forms of smallpox:
    • Variola minor is a less common and less severe form of disease.
    • Variola major is the more common and serious form of disease, of which there are five types.
      • Ordinary smallpox
      • Modified smallpox
      • Flat smallpox
      • Hemorrhagic smallpox
      • Variola sine eruptione


  • The last documented case of endemic smallpox was in Somalia in 1977.
  • The last case in the United States was in the late 1940s.
  • Smallpox was declared eradicated by the World Health Organization in 1979.
  • Historically, in unvaccinated individuals, ordinary smallpox accounted for 90% of cases, hemorrhagic smallpox for 7% of cases, and flat and modified smallpox for the remainder.
  • Modified smallpox was rare in unvaccinated individuals but accounted for 25% of cases of disease in vaccinated individuals.


  • Prior to 1972, all U.S. children were vaccinated.
  • Vaccines were produced from the vaccinia virus, a closely related orthopoxvirus to variola.
  • Historically, the vaccine was prepared from virus grown on the skin of animals, and in some cases, the vaccine was contaminated with animal proteins, bacteria, and other viruses.
  • Newer smallpox vaccines are developed from vaccinia clones grown in tissue culture and therefore are free of contamination from bacteria and other viruses.
  • Due to concern for use of smallpox as an agent of bioterrorism, the U.S. Strategic National Stockpile still stores smallpox vaccine.
  • The only currently U.S. Food and Drug Administration (FDA)-licensed smallpox vaccine, ACAM2000 (which replaced Dryvax®), is used for active immunization of persons determined to be at highest risk for infection.
  • The Advisory Committee on Immunization Practices (ACIP) recommends smallpox vaccination for the following:
    • Public health response teams responsible for investigating suspected smallpox cases
    • Hospital-based health care teams responsible for assessing and caring for suspected smallpox cases
    • Laboratory personnel who work with the virus that causes smallpox or other viruses similar to it
  • Vaccine efficacy
    • 95% efficacious in preventing disease if given prior to exposure
    • May prevent smallpox or decrease severity if given 1 to 3 days after exposure
    • May decrease severity of disease if given 4 to 7 days after exposure
  • Vaccination is estimated to provide protective immunity for 3 to 10 years but may decrease the severity of disease for 10 to 20 years.
  • Vaccine administration
    • A skin abrasion is created using a bifurcated needle dipped in vaccine.
    • The vaccinia vaccine is a live vaccine; thus the vaccine site should be loosely covered to prevent the spread of virus to others.
    • After 3 to 4 days, a red pruritic papule appears at the vaccination site, which evolves into a vesicle followed by a pustule; after a few weeks, a scab forms, which then falls off leaving a scar.
  • Contraindications to vaccine:
    • Atopic dermatitis or exfoliative skin disorder
    • Immunosuppression
    • Pregnancy or breastfeeding
    • Close contact of someone who is pregnant, immunosuppressed, or has skin disease
    • Allergy to vaccine component
    • Moderate or severe acute illness
    • Inflammatory eye disease
    • Heart disease (myocardial infarction, stroke, cardiomyopathy, heart failure, or angina) or ≥3 risk factors for heart disease
    • Age <1 year
    • These contraindications may be reevaluated if smallpox is reintroduced into the population.
  • Common adverse reactions to vaccination:
    • Fever, swelling, lymphadenitis, and headache are seen in 2–16% of adults receiving the vaccine for the first time.
    • A mild rash occurs in ~8% of cases.
  • Less common vaccine reactions:
    • Vaccinia keratitis and/or vision loss
    • Accidental inoculation with blister formation
    • Moderate to severe generalized rash
    • Eczema vaccinatum
    • Encephalitis
    • Congenital or generalized vaccinia
    • Myopericarditis
    • Progressive vaccinia/vaccinia gangrenosum
    • Bacterial superinfection


  • The virus infects the upper respiratory tract and replicates; rarely, primary infections can occur via skin, conjunctival, or placental routes.
  • The virus enters the bloodstream (primary viremia) and is taken up by macrophages.
    • Patient is asymptomatic during this time.
  • Next, the virus enters the reticuloendothelial system where it continues to replicate.
  • Secondary viremia occurs as the virus reenters the bloodstream and infects organs.
    • Can cause epidermal necrosis and swelling
    • Infections of the bone marrow, kidneys, liver, lymph nodes, spleen, and other organs result in coagulopathy and multiorgan system failure.
  • Exact mechanisms of viral toxicity are not understood but may involve both viral cytopathic effects and inflammatory pathology.


  • Variola virus is a member of the poxvirus family and Orthopox genus.
  • Variola is a double-stranded DNA virus most commonly transmitted during face-to-face contact via respiratory aerosols or direct contact with infected skin lesions.
  • Transmission of the virus via air in enclosed settings or via infected fomites is uncommon.
  • Humans are the only vectors.

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