# Presentation: 122316

## Smallpox Vaccine Adverse EventsPublic Health Guidance for Clinicians

- A Teaching Set Reviewing Key Points in the MMWR Report

**Notes:**
The MMWR report “Smallpox Vaccine Adverse Events:  Public Health Guidance for Clinicians” was released on January 24, 2003.  This presentation goes through the recommendations in that report.

Citations and references are at the bottom of the speaker’s notes.

## Expected Vaccination Site Reaction

**Notes:**
Smallpox vaccine is administered using the multiple–puncture technique with a bifurcated needle. The vaccinia virus replicates in the dermis of the skin; 3-5 days later, a papule forms at the vaccination site of immunocompetent vaccine-naïve persons (also referred to as “first time” or “primary” vaccinee). The papule becomes vesicular (approximately day 5-8), then pustular, and usually enlarges to reach maximum size in 8-10 days. The pustule dries from the center outward and forms a scab, which separates 14-21 days after vaccination, usually leaving a pitted scar. ========================================
Annotation:  Expected vaccination site reaction, (a ‘take’) in a first-time vaccinee demonstrating the progression from papule (day 4), to pustule (days 7-14), to scab (day 21).  
Source:  CDC 2001 ACIP Smallpox Recommendations

## Normal ReactionDay 7

**Notes:**
Formation by days 6-8 post-vaccination of a papule, vesicle, ulcer, or crusted lesion, surrounded by an area of induration signifies a response to vaccination; this event is referred to as a major reaction or a  “take,” and usually results in a scar. During the smallpox eradication era, individuals with a scar had much lower attack rates when exposed to smallpox cases than did unvaccinated individuals.  Therefore, a take has been a surrogate correlate of immunity to smallpox. Although the level of antibody that protects against smallpox infection is unknown, >95% of first-time vaccinees (i.e., persons receiving their first dose of smallpox vaccine) have increased neutralizing or hemagglutination inhibition antibody titers. 
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Annotation:  Normal reaction (taken day 7 post-vaccination)
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Normal ReactionDay 12

**Notes:**
Here is the normal smallpox reaction around day 12.  Note how the pustule is drying from the center outward.
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Annotation:  Normal reaction (taken day 12) heaped up border with pustule drying from center outward.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Major ReactionFirst time vaccinee, Day 6

**Notes:**
Vaccination site reactions are classified into two categories, “major reactions” and “equivocal reactions”.  A major reaction indicates a successful vaccine take, and is characterized by a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which might be a scab or an ulcer.  All other responses are equivocal reactions and are “non-takes.”  Equivocal reactions may be due to poor vaccination technique, use of subpotent vaccine, or residual vaccinial immunity in previously vaccinated individuals.  Persons with equivocal reactions cannot be presumed to be immune to smallpox and revaccination is recommended. 
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Annotation:  Example of a major reaction in a first time vaccinee at 6 days post-vaccination
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionFirst time vaccinee, Day 10

**Notes:**
The World Health Organization (WHO) has recommended that response to vaccination be evaluated on post-vaccination day 6, 7, or 8. These are the days of peak viral replication, and the period during which take should be assessed in both first-time vaccinees and re-vaccinees.  If the response to vaccination is evaluated too early, <6 days post-vaccination, some equivocal responses will look reactive due to dermal hypersensitivity to vaccinial proteins.  These were sometimes called “immediate reactions” but are not successful takes. 
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Annotation:  Example of a major reaction in a first time vaccinee at 10 days post-vaccination
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionFirst time vaccinee, Day 15

**Notes:**
Here is another example of a major reaction.
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Annotation:  Example of a major reaction in a first time vaccinee at 15 days post-vaccination
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionRevaccinee, Day 4

**Notes:**
If the response to vaccination is evaluated too late, >8 days post-vaccination, the vaccination take may be missed in those individuals with prior immunity to vaccinia who may experience a more rapid progression of the vaccination site. 

Responses in revaccinees that resolve in fewer than 6 days were sometimes called “accelerated reactions,” and are not successful takes. 
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Annotation:  Example of a major reaction in a re-vaccinee at 4 days post-vaccination.  This is in contrast to an equivocal reaction (non-reaction) in a first-time vaccinee.
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionRevaccinee, Day 8

**Notes:**
Here is another example of a major reaction in a re-vaccinee.  Note how it differs from a major reaction in the first time vaccinee.
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Annotation:  Example of a major reaction in a re-vaccinee at 8 days post-vaccination.  This is in contrast to an equivocal reaction (non-reaction) in a first-time vaccinee.
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionRevaccinee, Day 10

**Notes:**
This is another example of a major reaction in a re-vaccinee.
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Annotation:  Example of a major reaction in a re-vaccinee at 10 days post-vaccination.  This is in contrast to an equivocal reaction (non-reaction) in a first-time vaccinee.
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Major ReactionRevaccinee, Day 15

**Notes:**
Annotation:  Example of a major reaction in a re-vaccinee at 15 days post-vaccination.  This is in contrast to an equivocal reaction (non-reaction) in a first-time vaccinee.
Source:  Vaccination reactions in vaccinia-naïve and previously vaccinated volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louis University in 2002.

## Fatigue
Headache
Myalgia
Lymphadenopathy
Lymphangitis
Pruritis
Edema at the vaccination site
Satellite Lesions

- Headache
- Myalgia
- Lymphadenopathy
- Lymphangitis
- Pruritis
- Edema at the vaccination site
- Satellite Lesions

**Expected Range of Vaccine Reactions**

**Notes:**
A range of expected reactions occurs following vaccination.  These normal reactions do not require specific treatment, and may include fatigue, headache, myalgia, regional lymphadenopathy, lymphangitis, pruritis and edema at the vaccination site, as well as satellite lesions (1, [i]).  

## Rates of Expected Reactions

- 21% complications required physician consult
- Most Common Symptoms
- Fatigue (50%)
- Headache (40%)
- Muscle aches and Chills (20%)
- Nausea (20%)
- Fever  37.7 oC or 100 oF (10%)

**Notes:**
Historically, approximately 21% of complications associated with first-time vaccination were reactions that caused the vaccinee to consult a physician (1).   In a recent vaccination trial of 680 adult, first-time vaccinees, Frey et al reported the most common symptoms during the first 2 weeks following vaccination were fatigue (50%), headaches (40%), muscle aches and chills (20%), nausea (20%), and fever described as a temperature greater than or equal 37.7oC or 100°F  (10%).  Most local symptoms were reported during the second week following vaccination and included pain at the vaccination site (86%), and regional lymphadenopathy (54%). More than a third of vaccinees were sufficiently ill to miss school, work, recreational activities, or have trouble sleeping.  These signs and symptoms have been reported to be self-limited, requiring only symptomatic care. 

A fever following vaccination is common and approximately 70% of children experience >1 days of temperatures >100 F for 4--14 days after primary vaccination, and 15%--20% of children experience temperatures >102 F.  After revaccination, 35% of children experience temperatures >100 F, and 5% experience temperatures of >102 F. Fever is less common among adults after vaccination or revaccination.
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References:[i] Dryvax® [package insert]. Marietta, Pennsylvania: Wyeth Laboratories; 1994.
[ii] Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, Atmar RL, Edelman R, Nolan CM,Belsche RB,.  Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002;347(17):1265-74.
[iii] McIntosh K, Cherry JD, Benenson AS, et al.  Standard percutaneous revaccination of children who received primary percutaneous vaccination.  J Infect Dis 1977;135:155-66.
[iv] CDC smallpox diary card database 2001, unpublished.
[v] CDC unpublished data.

## Satellite LesionsNaïve Patient, Day 7

**Notes:**
Satellite lesions occasionally occur at the perimeter of the vaccination site and should not be confused with the early discrete vesicles that eventually coalesce into a central pox-like lesion. Satellite lesions are a benign finding and do not require treatment. 
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Annotation:  Examples of satellite lesions.  Satellite lesions in a naïve patient, day 7 post-vaccination.
Source:  “Vaccination reactions in vaccinia-naïve volunteers in a clinical study of diluted Dryvax smallpox vaccine enrolled at the NIAID-supported Vaccine Treatment and Evaluation Units at Saint Louise University, University of Maryland and University of Rochester and the Respiratory Pathogens Unit at Baylor College of Medicine in 2001.”

## Satellite Lesions

**Notes:**
Annotation:  Examples of satellite lesions.  More numerous satellite lesions.
Source:  CDC, “CDC Bioterrorism Update:  Smallpox Preparedness” broadcast.

## Large Vaccination Reactions and Robust TakesRobust take with lymphangitis

**Large Vaccination Reactions and Robust Takes****Robust take with lymphangitis**

**Notes:**
Large vaccination reactions, greater than 10 cm in diameter, at the site of inoculation occur in 10% of first-time vaccinees and are expected variants of the typical evolution of the vaccination site.  However, sometimes these large vaccination reactions have been reported as adverse events.  In the 1968 national surveillance of the United States for smallpox vaccine complications, 13 out of 572 adverse event reports were for unusually large and painful robust takes, formerly referred to as “primary takes.”  Fluctuant enlarged lymph nodes are not expected, and warrant further evaluation and treatment.  
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References:[i] Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis 1970; 122(4):303-309
[ii] Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. National surveillance in the United States. N Engl J Med 1969; 281:1201-1207.
Annotation:  Robust take with lymphangitis; Extensive erythema and induration with a linear streak posteriorly on day 9.
Source:  New England Journal of Medicine.  NEJM, Frey et al, 346(17), April 25, 2002.  Copyright©2002  Massachusetts Medical Society.  All rights reserved.

## Large Vaccination Reactions and Robust TakesRobust take with lymphangitis

**Notes:**
This is the same patient as in the previous slide.  Note the extensive erythema and induration.
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Annotation:  Robust take with lymphangitis; Extensive erythema and induration with a linear streak posteriorly on day 9.  Same patient, full view showing vaccination site.
Source:  New England Journal of Medicine.  NEJM, Frey et al, 346(17), April 25, 2002.  Copyright©2002  Massachusetts Medical Society.  All rights reserved  NIH – Personal communication

## Large Vaccination Reactions and Robust TakesLarge Local Reaction

**Notes:**
Here’s another example of a large local reaction.  There is an extensive area of erythema.
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Annotation:  Large local reaction.  Note the extensive area of erythema.
Source:   NIH – Personal Communication