Management, Evaluation, 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 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
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
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*
Symptom/sign Time after Vacc
Papule
2-5 days
Pustule
7-10 days
Maximum erythema 8-10 days
Scab
14 days
Scab separation
21 days
*typical response in a nonimmune person
Progression of smallpox vaccination site in a
non-immune person
Smallpox Vaccine Local Reactions
Among Susceptible Adults
Local sign
Pustule
Mean Diameter
12 mm
Erythema
16-24 mm
Induration
11-16 mm
Smallpox Vaccine Local Reactions
Among Susceptible Adults
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
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
Local edema at vaccination site
Lymphangitis
Regional lymphadenopathy
(nonfluctuant)
Satellite lesions
Lymphangitis following smallpox vaccination
Satellite lesions
Local Reactions Following
Smallpox Vaccine
Allergic reactions to bandage and
tape adhesives
Large primary vaccination reactions
(robust primary takes RPT)
Secondary bacterial infection
Allergic reaction to tape
Local Reactions to Adhesive
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)
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 take
Robust Primary Takes (RPT)
Observe carefully
Supportive therapy
Rest affected limb
Analgesia (non-aspirin)
NSAIDs
Usually improve in 24-48 h
Secondary bacterial infection of vaccination site
Secondary Bacterial Infection
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
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
Inadvertent inoculation
Eczema vaccinatum
Generalized vaccinia
Progressive vaccinia (vaccinia
necrosum)
Post-vaccinial encephalitis
Other dermatologic conditions
Smallpox Vaccine Adverse
Reaction Rates*
Reaction
Primary
Vaccination
Inadvertent inoculation
25-529
Generalized vaccinia
23-242
Eczema vaccinatum
10-39
Progressive vaccinia
0.9-1.5
Post-vaccinial encephalitis
Death
*Rates per million primary vaccinations
3-12
1
Smallpox Vaccine Adverse Reactions
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
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 following smallpox vaccination
Erythema Multiforme
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
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 inoculation
Inadvertent Inoculation
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
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
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 vaccinia
Generalized Vaccinia
Differential diagnosis
Erythema multiforme
Eczema vaccinatum
Inadvertent at inoculation multiple
sites
Early progressive vaccinia
Disseminated herpes
Severe varicella
Generalized Vaccinia
Generally self-limited
Most cases do not require therapy
VIG may be considered for recurrent
disease or severe disease
Lesions contain vaccinia
Eczema Vaccinatum
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 Vaccinatum
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 vaccinatum
Eczema Vaccinatum
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
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 Vaccinia
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 vaccinia
Progressive Vaccinia
Requires aggressive therapy with VIG
Antiviral therapy?
Surgical debridement?
Lesions contain vaccinia virus
Post-vaccinial Encephalitis
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 Encephalitis
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 Encephalitis
Treatment is supportive
VIG not effective
Anticonvulsive therapy and
intensive care may be required
Fetal vaccinia
Fetal Vaccinia
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 Vaccinia
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
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
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 Globulin
CDC is only source
IND Protocol
Limited stockpile currently available
Intravenous product being produced
Vaccinia Immune Globulin
Adverse Reactions
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
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
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
Nucleotide analogue of cytosine
Broad spectrum of activity against
herpesviruses
Activity against orthopoxviruses in cellbased and animal models
Currently approved for treatment of
CMV retinintis in persons with AIDS
Available for treatment of vaccinia
under IND
Cidofovir Indications
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
Renal toxicity
Neutropenia
Proteinuria
Anterior uveitis/iritis
Metabolic acidosis
Possible carcinogenicity and teratogenicity
Probenicid adverse events
Cidofovir Administration
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
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
CDC Smallpox website
www.cdc.gov/smallpox
National Immunization
Program website
www.cdc.gov/nip
Certain images supplied by:
Dr. John Leedom
Dr. J. Michael Lane
Dr. Vincent Fulginiti
World Health Organization
University of Rochester
National Institutes of Health
Logical Images, Inc.