1. Smallpox Vaccine: Overview for Health Care Response Teams
Thomas G. Franck, MD, MPH
Regional Physician Consultant
Office of Emergency Preparedness & Response
Virginia Department of Health
January 2003

2. Objectives To briefly review smallpox disease
To gain an in depth understanding of smallpox vaccine, including:
history of smallpox vaccination
overview of vaccinia
indications
contraindications
normal response
complications
1.To briefly review smallpox disease;
2.To provide an in depth review of smallpox vaccine, including:
brief history of smallpox vaccination
overview of vaccinia
vaccinia vaccine indications and contraindications
normal response to vaccinia vaccination
adverse events from vaccinia vaccination

3. Taxonomy Family: Poxviridae Genus: Orthopoxviruses Smallpox (variola)
Cowpox
Monkeypox
Vaccinia
Although there are several other members of the genus of viruses called orthopoxviruses, the four listed here represent those that can infect humans.
These four viruses have about 93% of their DNA in common, which accounts for their cross-reactivity and the ability to employ one as a vaccination that protects against the others.
93% DNA Homology

4. Smallpox Caused by Variola virus Unique to humans
Person-to-person spread
usually via close contact - droplets
contaminated materials (uncommon)
aerosolized droplet nuclei spread (rare)
30% case-fatality rate on average
Let’s begin by reviewing some major aspects of smallpox disease.
Here is an electron micrograph of variola major virus.
It’s a large, enveloped, brick-shaped DNA virus belonging to the family Poxviridae and the genus of Orthopoxviruses.

5. Smallpox: Clinical Features
Incubation: days (range 7-17)
Prodrome: lasts 2-4 days
fever, malaise, headache, backache, vomiting
Eruptive stage (Rash):
Oral cavity/pharynx  face, hands, forearms  lower extremities  trunk
Synchronous progression: maculopapules  vesicles  pustules  scabs
Lesions on palms /soles
Infectious stage (especially 1st week)
Smallpox disease can be divided into 3 phases: the incubation period, the prodrome, and the eruptive stage.

6. This series of photographs demonstrates the typical progression and distribution of smallpox rash.

7. Here is a fairly classic presentation of a child with smallpox.
This is smallpox due to variola major, ordinary type, which is the most common form.

8. Smallpox - Treatment Treatment Prevention/Prophylaxis Supportive care
No treatment proven effective
Experimental treatment with antivirals, e.g., Cidofovir
Prevention/Prophylaxis
Vaccination - protective if given within 3 days of exposure

9. Smallpox: Why the Concern Now?
Last case in US in 1949
Last naturally acquired case in 1977
Disease declared eliminated by WHO in 1980
Stocks of Variola virus held by U.S. & Russia
Bio Weapons programs in several countries
Recent Intelligence review: 4 countries may have covert stocks of smallpox virus – Russia, Iraq, North Korea, and France

10. Smallpox Vaccine: History
1796: Edward Jenner develops vaccine (cowpox)
1805: Use of cows to produce vaccine
1940s: Freeze-drying of Vaccinia
1965: Licensure of bifurcated needle
1972: Routine vaccination stopped in U.S.
1983: Vaccine removed from civilian market
1990: U.S. Military vaccination stops

11. Edward Jenner (1749–l823) the “father” of vaccination.
In the background is a dairymaid (or milkmaid) working with some cows.
(Courtesy of the Institute of the History of Medicine, The Johns Hopkins University, Baltimore, MD.)

12. Jenner transferred “matter” from the hand of an infected dairymaid to 8 year-old James Phipps on 14 May 1796.
It turns out this matter was cowpox virus. Jenner demonstrated that a person inoculated and infected with cowpox was protected against smallpox. The procedure, which he called vaccination, represented the first use of a vaccine in the prevention of disease.

14. English engraving by James Gillray, 1802
Here we see Jenner vaccinating someone with cowpox.
It’s an excellent capture of the anxiety felt by the population at the time, similar to what some of us may be experiencing today.

15. Compare the results of variolation with vaccination.
(Captain C. Gold, 1801, Courtesy of the Library, London, Wellcome Institute for the History of Medicine.)

16. Smallpox Vaccine Live virus called “Vaccinia”
An orthopoxvirus, genetically distinct from other orthopoxviruses such as cowpox, monkeypox, and variola (cause of smallpox)
Origin unknown: May be a virus now extinct in nature

17. Vaccinia Vaccine “Dryvax” (Wyeth Laboratories)
Contains NY City Board of Health strain
2.7 million doses licensed (phase 1)*
Enough vaccine “to vaccinate every single person in the country in an emergency”*
*December 2002

18. Vaccine Efficacy: Pre-Exposure
Reduces chance of getting infected (i.e., decreases secondary attack rate)
91%-97% reduction in cases among case contacts with vaccination scar
For those infected, reduces fatality rate and severity of disease
How well does the vaccine protect someone if it is given prior to any exposure to smallpox?

19. Just to review: The case-fatality rate tells you this: once I am infected and become a case, what are my chances of dying.
You can see from the graph that if you have been vaccinated, then you are relatively well-protected compared to those never having been vaccinated. And you are especially well-protected if vaccinated within the last 10 years.
Mack, J. Inf Dis, 1972

20. Vaccine Efficacy: Post Exposure
Generally prevents smallpox, or significantly decreases severity, if given within 3 days of exposure
Vaccination 4 to 7 days post-exposure still offered protection to many people, but significantly less than vaccination before 4 days
We have just seen that smallpox vaccination protects us when given in advance, prior to an exposure.
But it can also be very effective even after you are directly exposed to smallpox, if given early enough.
When estimates for prevention and disease modification are combined, fewer than 5% of all persons vaccinated within 3 days after exposure would be at risk for disease of normal severity

21. Vaccine Efficacy: Post Exposure
Smallpox AR %
29.5
47.6
75.0
96.3
1.9
21.8
(Madras)
(Pakistan)
Postexp vacc
Never vacc
Vacc <10 days
Vacc <7 days
Another way to look at post-exposure vaccination efficacy is to examine secondary attack rates.
In these 3 studies, the secondary attack rates varied considerably.
What these studies demonstrate is that the risk of developing smallpox depended on whether or not you received any vaccination post-exposure.
What is not quite so evident from these studies is the important finding that how quickly you received the vaccine after exposure to smallpox is critical to predicting your chances of survival.

22. Duration of Immunity
High level of protection (95-100%) for 3-5 years following vaccination
Immunity wanes after 5 years, but some residual protection evident at 10 and even 20+ years
Reduction in disease severity with any history of vaccination
However, best protection if vaccinated <3-5 yrs ago; we cannot rely on previous vaccinations to protect our population and we should consider the population to lack immunity to smallpox.

23. Smallpox Vaccine Indications: Non-Emergency
Current Indications:
Laboratory workers who handle cultures or animals infected with non-highly attenuated vaccinia or other Orthopoxviruses
New Recommendations:
Public health, hospital, and other personnel, generally years of age, who may have to respond to a smallpox case or outbreak

24. Smallpox Vaccine Indications: Emergency Situations
Ring Vaccination
Persons exposed to initial release
Close contact with confirmed or suspected case
Direct care or transportation of confirmed or suspected case
Laboratory personnel
Persons with risk of contact with infectious materials from case
Mass Vaccination of entire populations?
There are basically 2 major strategies at our disposal when it comes to managing a smallpox outbreak.
Some advocate ring vaccination and others advocate mass vaccination.
Ultimately, it may depend on the nature of the smallpox outbreak.

25. Contraindications: Non-Emergency Situations
Eczema/atopic dermatitis (active or history of) or household contact with eczema/atopic dermatitis
Other active skin conditions (allergic rash, burns, impetigo, chickenpox, shingles, herpes,psoriasis, severe acne, etc.) or household contact with acitve skin condition
Immunosuppression or household contact with immunosuppression
Pregnancy or pregnant household contact
Breastfeeding
Infants (not advised in children < 18)
Severe allergic reaction to prior vaccination or vaccine component

26. Contraindications: Immunodeficiency
Conditions causing immunodeficiency:
HIV, leukemia, lymphoma, other cancers, agammaglobulinemia, certain autoimmune disorders (e.g., SLE), other immune disorders
Treatments causing immunodeficiency:
Chemotherapy, radiation treatment, antimetabolites, alkyltating agents, organ transplant meds, high-dose corticosteroids
Immunomodulatory medications? Unknown
According to CDC, cancer chemotherapy or radiation treatment, current or within the past 3 months, is a contraindication.
High dose corticosteroids: Equivalent to 2 mgm/kg or greater of oral prednisone daily, or 20 mgm/day, particularly if given for longer than 14 days.
For certain immunomodulatory therapies, e.g., DMARDs for Rheumatoid Arthritis, there currently are no specific recommendations. According to the American College of Rheumatology, it may be prudent to avoid vaccination of such patients for now until further information becomes available. For those potential vaccinees with questionable contraindications or possible contraindications, we recommend consultation with a specialist in the appropriate field.

27. Contraindications: Eczema/Atopic Dermatitis
Eczema: a red, itchy rash that lasts at least two weeks and then comes and goes
It is estimated that at least 15 million people in U.S. have atopic dermatitis
These people are at risk of a serious complication, eczema vaccinatum
Here is one definition of eczema, as defined by an experienced group of dermatologists on the American Academy of Dermatology’s Bioterrorism Taskforce.

28. Contraindications: Emergency Situations
Exposed persons – no contraindications
Unexposed persons – generally same as non-emergency situations w/ some modifications, depending on situation
Example: if there were a smallpox outbreak in the U.S., the category of children 1-17 years old would probably be eliminated as a contraindication.

29. Vaccine Administration
Surgical needle
Vaccinostyle
Rotary lancet
Jet injector
Bifurcated needle*
*Only administration technique currently in use.

30. Vaccination Technique

31. Invented by Dr. Benjamin A
Invented by Dr. Benjamin A. Rubin of Wyeth Laboratories, patented in July Developed in conjunction with Reading Textile Machine Company. Bifurcation holds exactly 1 mg of water, slightly more vaccine because of increased viscosity. WHO procured about 50 million bifurcated needles between 1967 and The 1970 price was about US$5 per 1000.

32. This photo demonstrates good vaccination technique.

33. Vaccination Site Care
Remember – live vaccinia virus is present at site of vaccination until scab falls off on its own, usually 2-3 weeks.
Dressing
Health care setting: 3 layers of protection – gauze, semipermeable dressing, shirt
Non-health care setting: 2 layers of protection – gauze & shirt
Avoid salves and ointments
Avoid touching/scratching site and picking scab

34. Post-Vaccination Follow-up
Semipermeable dressing: change dressing at least every 3-5 days and as needed
Gauze dressing secured by tape: change dressing every 1-3 days and as needed
“Take” evaluation: 7 days after vaccination (+/- 1 day)
If significant side effects or adverse event, follow-up with designated health care provider

35. Clinical Response to Vaccination*
Sign/symptom
Papule
Vesicle
Pustule
Maximum erythema
Scab
Scab separation
Time after Vacc
3 days
5-6 days
7-11 days
8-12 days
14 days
21 days
*typical response in a nonimmune person

36. Clinical Response to Vaccination
Major (primary) reaction
Indicates viral replication has occurred and vaccination was successful
No reaction or equivocal reaction
No immunity and vaccination must be repeated

37. Let’s look at what the expected response to vaccination should be.
Here we see the typical progression of vaccinia.
On day 7 we see here a “major reaction”, also known as a “take”.

38. Major Reaction* (6-8 days after vaccination)
Primary vaccination
Vesicular or pustular lesion
Area of definite palpable induration surrounding a central crust or ulcer
Revaccination
Less pronounced and more rapid progression
Pustular lesion or induration surrounding a central crust or ulcer
*WHO Expert Committee on Smallpox, 1964

39. Primary
Revaccination
Day 3

40. Primary
Revaccination
Day 7

41. Primary
Revaccination
Day 10

42. Revaccination
Primary
Day 14

43. Normal Variants: Satellite Lesions

44. Normal Variants: Cellulitis & Lymphangitis

45. Smallpox Vaccination: Normal Side Effects
Fever: 10% of adults
Localized soreness: 35-47%
Headache/muscle aches: 40-50%
Redness/swelling > 3 inches: 15%
1/3 may feel bad enough to miss work, school, activity, or have trouble sleeping
In a recent study, about one-third of vaccinees felt sick enough to miss work, school, social activity, or have disturbed sleep.
In recent clinical trials, only about 5-10% of vaccinees actually missed work.

46. Smallpox Vaccination: Adverse Events
Contact transmission: spread vaccinia to others
Inadvertent autoinoculation: spread to other sites on body
Generalized vaccinia: spread throughout body
Eczema vaccinatum: severe skin reaction
Progressive vaccinia (vaccinia necrosum)
Postvaccinial encephalitis
Death

47. Accidental Inoculation
Accidental auto-inoculation of cheek with vaccinia virus, approximately 5 days old. Primary take on arm, days old. Photo courtesy of John M. Leedom, MD.

48. Accidental Inoculation

49. Generalized Vaccinia
Generalized vaccinia in an apparently normal child. Recovered without sequelae. Photo courtesy of John M. Leedom, M.D.

50. Generalized Vaccinia

51. Eczema Vaccinatum This is a more severe complication.
This child had a history of atopic dermatitis when he was vaccinated.

52. Eczema Vaccinatum
Again, you can see how severe this reaction can be. In fact, it can be fatal.
Do not receive smallpox vaccination if you have any history of atopic dermatitis or “eczema.”

53. Progressive Vaccinia
One of the worst complications is progressive vaccinia, which almost always occurs in someone with immunosuppression, and often this is a defect in cell-mediated immunity.

54. Post-Vaccinial Encephalitis
Autoimmune process
No predictors of susceptibility
Supportive care; no specific therapy
Vaccinia Immune Globulin is not effective and is not recommended.
15-25% mortality; and
25% had permanent neurological sequelae
Any patient with an evolving central nervous system disorder should not receive a vaccination.

55. Vaccinia Keratitis
This is caused by Vaccinia virus being deposited onto cornea, which leads to corneal infection or ulceration and subsequent clouding.
Treatment – VIG is contraindicated.
Combination of a topical antiviral and interferon speeds healing.
Vidarabine
Trifluridine
Acyclovir

56. Vaccine Adverse Events
Complication
# per million
Household transmission 27
Accidental autoinoculation
25-530
Generalized vaccinia
23-242
Eczema vaccinatum
10-39
Progressive vaccinia
1-1.5
Encephalitis
3-12
Death
1-2
Looking at the worst case scenario, these rates translate to the following:
For generalized vaccinia: 1 per 4,000
For eczema vaccinatum: 1 per 26,000
For post-vaccinial encephalitis: 1 per 83,000
For progressive vaccinia: 1 per 667,000
Death: 1 per 1 million primary vaccinations
1 per 4 million revaccinations

57. Postvaccinal Encephalitis Inadvertent Autoinoculation
Complication Rates of Vaccination Rates (per million vaccinations) U.S., 1968 (ten state survey)
Complication
108
1254
Total 2 12
Postvaccinal Encephalitis 3
1.5
Progressive Vaccinia 39
Eczema Vaccinatum 9
242
Generalized Vaccinia 42
529
Inadvertent Autoinoculation
Revaccination
Primary
Vaccination
Complication
Primary
Vaccination
Revaccination
Inadvertent Autoinoculation
529 42
Generalized Vaccinia
242 9
Eczema Vaccinatum 39 3
Progressive Vaccinia
1.5 3
Postvaccinal Encephalitis 12 2
Total
1254
108

58. VIG: Vaccinia Immune Globulin
Indicated:
Eczema vaccinatum
Progressive vaccinia
Generalized vaccinia (if severe or recurrent)
Accidental implantation (ocular or extensive lesions)
Not Recommended:
Accidental implantation (mild instances)
Generalized vaccinia (mild or limited - most instances)
Erythema multiforme
Encephalitis
Contraindicated:
Vaccinia keratitis
VIG is the Immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine.

59. Issues for Discussion HIV testing Pregnancy testing
Vaccination site care – who, how often?
Should healthcare provider continue to work?
Liability & workers’ compensation
HIV testing – do we recommend or simply offer the test?
Pregnancy – do we test?
Site care for vaccinated site
Gauze +/- semi-permeable bandage?
How often to change dressing? Who?
Who assesses for a “take” at 7 days?
Can healthcare provider continue to work?
CDC says “yes”, Wyeth says “no”
Options: furlough vs reassignment vs normal duty

60. “…it now becomes too manifest to admit of controversy, that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the final result of this practice.”
-Edward Jenner, 1801