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Evaluation management and treatment of adverse events of smallpox vaccine
Evaluation, Management, and Treatment of Adverse Events of Smallpox Vaccine

Department of Health and Human Services

Centers for Disease Control and Prevention

December 2002

Evaluation management and treatment of adverse events of smallpox vaccine1
Evaluation, Management, and Treatment of Adverse Events of Smallpox Vaccine

  • Learning Objectives:

    • Describe the common and serious adverse events expected after smallpox vaccination

    • Describe the treatment options available to clinicians when treating a patient with an adverse event to smallpox

Dryvax smallpox vaccine
Dryvax Smallpox Vaccine Smallpox Vaccine

  • Prepared from calf lymph containing live vaccinia virus

  • Contains polymyxin B, streptomycin, tetracycline and neomycin

  • Diluent is 50 percent glycerin and phenol as a preservative

New smallpox vaccines
New Smallpox Vaccines Smallpox Vaccine

  • Live vaccinia virus produced using cell culture technology

  • Distributed as a freeze dried powder

  • Do not contain antibiotics

  • Diluent contains glycerin and phenol

Clinical response to vaccination
Clinical Response to Vaccination* Smallpox Vaccine




Maximum erythema


Scab separation

Time after Vacc

2-5 days

7-10 days

8-10 days

14 days

21 days

*typical response in a nonimmune person

Smallpox vaccine local reactions among susceptible adults
Smallpox Vaccine Local Reactions Among Susceptible Adults person

Local sign

  • Pustule

  • Erythema

  • Induration

Mean Diameter

12 mm

16-24 mm

11-16 mm

Smallpox vaccine local reactions among susceptible adults1
Smallpox Vaccine Local Reactions Among Susceptible Adults person

  • Pain, swelling, erythema at vaccination site

  • Regional lymphadenopathy

    • Begins 3-10 days after vaccination

    • Can persist for 2-4 weeks after vaccination site heals

Smallpox vaccine reactions among susceptible adults
Smallpox Vaccine Reactions Among Susceptible Adults person

  • Elevated temperature

    • 17% >100o F

    • 1.4% >102o F

  • Systemic symptoms (malaise, myalgias)

  • 36% sufficiently ill to miss work, school, or recreational activities or had trouble sleeping

Normal variants of vaccine reaction
Normal Variants of Vaccine Reaction person

  • Local edema at vaccination site

  • Lymphangitis

  • Regional lymphadenopathy (nonfluctuant)

  • Satellite lesions

Local reactions following smallpox vaccine
Local Reactions Following Smallpox Vaccine person

  • Allergic reactions to bandage and tape adhesives

  • Large primary vaccination reactions (“robust primary takes” – RPT)

  • Secondary bacterial infection

Local reactions to adhesive
Local Reactions to Adhesive person

  • Erythema corresponds to placement of adhesive tape

  • No systemic symptoms

  • Treat with antihistamines, NSAIDs, frequent bandage/tape change

  • Steroid treatment not recommended

Robust primary takes rpt
Robust Primary Takes (RPT) person

  • Expected variant of normal reaction

  • >3 inches of erythema with induration, pain, warmth

  • Occur in 5%-15% of recipients

  • Peak at day 8-10 post-vaccination

  • May resemble bacterial infection

Robust primary takes rpt1
Robust Primary Takes (RPT) person

  • Observe carefully

  • Supportive therapy

    • Rest affected limb

    • Analgesia (non-aspirin)

    • NSAIDs

  • Usually improve in 24-48 h

Secondary bacterial infection
Secondary Bacterial Infection person

  • More common among children than adults

  • Usually Staphylococcus aureus or Group A beta hemolytic Streptococci

  • Anaerobic and mixed infections may occur

  • Evaluate with gram stain and culture

  • Antibiotic therapy based on culture

Major complications of smallpox vaccination
Major Complications of Smallpox Vaccination person

  • Definitive studies of complications of smallpox vaccination by Lane et al, published in 1969-1970

  • Led to the recommendation to cease routine smallpox vaccination in the United States

Smallpox vaccine adverse reactions
Smallpox Vaccine Adverse Reactions person

  • Inadvertent inoculation

  • Eczema vaccinatum

  • Generalized vaccinia

  • Progressive vaccinia (vaccinia necrosum)

  • Post-vaccinial encephalitis

  • Other dermatologic conditions

Smallpox vaccine adverse reaction rates
Smallpox Vaccine Adverse Reaction Rates* person

*Rates per million primary vaccinations

Smallpox vaccine adverse reactions1
Smallpox Vaccine Adverse Reactions person

  • Adverse reaction rates may be higher today than in 1960s

  • More persons at risk because of higher prevalence of immunosuppression and eczema/atopic dermatitis

  • Adverse reaction rates lower among previously vaccinated persons

Rashes following smallpox vaccine
Rashes Following Smallpox Vaccine person

  • Flat, erythematous, macular, or urticarial lesions

  • Usually do not become vesicular

  • Do not appear to involve viral multiplication or systemic dissemination

  • Occur approximately 10 days after vaccination

  • Resolve spontaneously within 2 to 4 days

Erythema multiforme
Erythema Multiforme person

  • May present as macules, papules, urticaria, or bulls-eye lesions

  • Usually appear within 10 days after vaccination

  • Do not progress

  • Do not contain vaccinia virus

  • Occasional Stevens-Johnson syndrome

  • VIG not indicated

Inadvertent inoculation
Inadvertent Inoculation person

  • Transfer of vaccinia virus from vaccination site to another site on the body, or to a close contact

  • Most frequent complication of smallpox vaccination

  • Occurred 25-529 cases per million primary vaccinations

  • Most common sites are face, eyelid, nose, mouth, genitalia, rectum

  • Lesions contain vaccinia virus

Inadvertent inoculation1
Inadvertent Inoculation person

  • Uncomplicated lesions require no therapy, self-limited, resolve in ~3 weeks

  • VIG may speed recovery if extensive or painful genital involvement

  • Hand washing after contact with vaccination site or contaminated material most effective prevention

Ocular vaccinia
Ocular Vaccinia person

  • May present as blepharitis, conjunctivitis, keratitis, iritis, or combination

  • Should be managed in consultation with an ophthalmologist

  • Treatment may include topical ophthalmic antiviral agents and VIG

Generalized vaccinia
Generalized Vaccinia person

  • Vesicles or pustules appearing on normal skin distant from the vaccination site

  • Often accompanied by fever, headache, and myalgias

  • Occurred 23-242 cases per million primary vaccinations

  • Usually occur 6-9 days after vaccination

Generalized vaccinia1
Generalized Vaccinia person

  • Differential diagnosis

    • Erythema multiforme

    • Eczema vaccinatum

    • Inadvertent inoculation at multiple sites

    • Early progressive vaccinia

    • Disseminated herpes

    • Severe varicella

Generalized vaccinia2
Generalized Vaccinia person

  • Generally self-limited

  • Most cases do not require therapy

  • VIG may be considered for recurrent disease or severe disease

  • Lesions contain vaccinia

Eczema vaccinatum
Eczema Vaccinatum person

  • Generalized spread of vaccinia on the skin of a person with eczema or true atopic dermatitis, or a history of eczema or atopic dermatitis

  • Severity independent of the activity of the underlying eczema

  • Severe cases among contacts of recently vaccinated person

  • Occurred 10 to 39 cases per million primary vaccinations

Eczema vaccinatum1
Eczema Vaccinatum person

  • Skin lesions may be papular, vesicular, or pustular

  • May occur anywhere on the body

  • Predilection for areas of previous atopic dermatitis

  • Patients often severely ill

Eczema vaccinatum2
Eczema Vaccinatum person

  • Management

    • Hemodynamic support

    • Meticulous skin care

    • Early treatment with VIG

    • Treatment of secondary bacterial or fungal infections as needed

  • Lesions contain vaccinia virus

Progressive vaccinia
Progressive Vaccinia person

  • Occurs almost exclusively among persons with cellular immunodeficiency

  • Can occur in persons with humoral immunodeficiency

  • Can occur following revaccination of people who have become immunosuppressed since their primary vaccination

  • Occurred 0.9-1.5 cases per million primary vaccinations

Progressive vaccinia1
Progressive Vaccinia person

  • Primary vaccination lesion does not heal

  • Progresses to ulcerative lesion, often with central necrosis

  • Little or no inflammation at the site and generally little pain

  • Virus continues to spread locally and through viremia

  • Protective T-cell count unknown

Progressive vaccinia2
Progressive Vaccinia person

  • Requires aggressive therapy with VIG

  • Antiviral therapy?

  • Surgical debridement?

  • Lesions contain vaccinia virus

Post vaccinial encephalitis
Post-vaccinial Encephalitis person

  • Usually affects primary vaccinees <12 months of age and adolescents and adults receiving a primary vaccination

  • Presents with any of a variety of CNS signs (e.g., ataxia, confusion, paralysis, seizures, or coma)

  • 15%-25% die, 25% develop neurological sequelae

  • Occurred 3-12 cases per million primary vaccinations

Post vaccinial encephalitis1
Post-vaccinial Encephalitis person

  • Diagnosis of exclusion

  • Other infectious or toxic causes of encephalitis should be ruled out

  • Pathophysiology not well understood

  • CSF may have increased opening pressure, lymphocytosis, elevated protein

Post vaccinial encephalitis2
Post-vaccinial Encephalitis person

  • Treatment is supportive

  • VIG not effective

  • Anticonvulsive therapy and intensive care may be required

Fetal vaccinia
Fetal Vaccinia person

  • Rare complication (<50 cases reported)

  • Usually following primary vaccination of the mother in the second or third trimester

  • Fetal infection following vaccination in the first trimester would presumably result in spontaneous abortion

  • No known pattern of congenital malformations

Fetal vaccinia1
Fetal Vaccinia person

  • Death usually occurs before birth or in preinatal period

  • VIG may be considered if infant born alive with lesions

  • No known reliable intrauterine diagnostic test

Laboratory diagnostics
Laboratory Diagnostics person

  • Adverse reactions most often diagnosed by clinical evaluation and history

  • Diagnostic testing usually done to rule out other conditions (e.g., varicella, herpes simplex)

  • Serologic testing for vaccinia not helpful

Vaccinia immune globulin
Vaccinia Immune Globulin person

  • Immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine

  • Effective for treatment of eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and ocular vaccinia

  • Not effective in post-vaccinial encephalitis

Vaccinia immune globulin1
Vaccinia Immune Globulin person

  • CDC is only source

  • IND Protocol

  • Limited stockpile currently available

  • Intravenous product being produced

Vaccinia immune globulin adverse reactions
Vaccinia Immune Globulin Adverse Reactions person

  • Pain, tenderness, swelling, erythema at injection site

  • Allergic and anaphylactoid reactions have been reported

  • Systemic non-anaphylactic reactions

  • Aseptic meningitis syndrome

Vaccinia immune globulin contraindications and precautions
Vaccinia Immune Globulin personContraindications and Precautions

  • History of prior severe reaction following IV or IM administration of human immunoglobulin preparations

  • Selective IgA deficiency

  • Vaccinial keratitis?

  • Severe allergy to thimerosal (IM formulation only)

Vaccinia immune globulin administration
Vaccinia Immune Globulin personAdministration

  • Dose 0.6 ml per kg (approximately 42 ml for a 70 kg adult)

  • IM formulation administered in buttock or anterolateral thigh

  • Doses >10 ml should be divided and injected at separate sites

  • IV formulations same weight based dose, also IND

Cidofovir person

  • Nucleotide analogue of cytosine

  • Broad spectrum of activity against herpesviruses

  • Activity against orthopoxviruses in cell-based and animal models

  • Currently approved for treatment of CMV retinintis in persons with AIDS

  • Available for treatment of vaccinia under IND

Cidofovir indications
Cidofovir Indications person

  • Second line treatment of complications of smallpox vaccination

  • Use if patient fails to respond to VIG treatment

  • Consult with CDC before use under IND

  • Manufacturer recommends use with probenicid

Cidofovir adverse events
Cidofovir Adverse Events person

  • Renal toxicity

  • Neutropenia

  • Proteinuria

  • Anterior uveitis/iritis

  • Metabolic acidosis

  • Possible carcinogenicity and teratogenicity

  • Probenicid adverse events

Cidofovir administration
Cidofovir Administration person

  • 5 mg/kg IV during a 60 minute period

  • Second dose one week later may be considered

  • Baseline and post-administration assessment of renal function

  • Intravenous hydration

  • Extensive follow-up protocol required by IND

Cdc consultation
CDC Consultation person

  • Clinicians should contact State Public Health authorities

  • State Health Departments will contact CDC Emergency Operations Center

  • IND requirements must be fulfilled by clinican and State Health Department

For more information
For More Information person

  • CDC Smallpox website


  • National Immunization Program website


Certain images supplied by: person

Dr. John Leedom

Dr. J. Michael Lane

Dr. Vincent Fulginiti

World Health Organization

University of Rochester

National Institutes of Health

Logical Images, Inc.