1. Smallpox Vaccination

2. History of Vaccination in the US
Before 1972, smallpox vaccination required for all children at age 1 year
Most states required smallpox vaccination before school entry

3. Vaccine DryVax©, a lyophilized, live vaccinia virus
Store at -17oC to -20oC (-4 to - 1oF)
Re-constituted store 30 days at 2–8oC (36 – 46oF)
Contains
polymyxin B sulfate
dihydrostreptomycin sulfate
chlortetracycline hydrochloride
neomycin sulfate
Aventis vaccine kept for emergencies
Notes:
The vaccine uses Vaccinia virus, not variola, and so it is not possible to get smallpox from the vaccine
The Vaccine contains a number of antibiotics, and so persons with hypersensitivity to these components should avoid the vaccine, unless there has been an exposure and then only use with great care, and facilities to deal with an anaphylactic reaction. The tissue culture vaccines will not contain antibiotics
the Acambis vaccine is grown on tissue culture.

4. Supply of Vaccine (12/5/2002) Existing Supply:
Dryvax: 15 million doses (2.7 million doses are approved for distribution as a licensed vaccine)
Aventis Pasteur: 85 million doses
In Production:
Acam 1000: 54 million doses
Acam 2000: 155 million doses
Approximately half of the 2.7 million doses are for the military and the other half are for public health and medical civilian staff

5. Strains of Vaccinia
New York City Board of Health (NYCBOH) used in the DryVax and Aventis vaccine
Lister strain used by many Europeans and the Israelis
Both were used by the WHO
The Lister strain is reported to have fewer side effects

6. Immune Response
Neutralizing and HI antibodies appear about 10 days after vaccination
>95% of primary vaccinees have antibody titres ≥ 1:10
Cell mediated response (DTH) can be detected as early as 2 days after vaccination
Antibody response is about 4 – 8 days earlier than with natural variola infection, therefore vx after exposure can modify infection
Almost everyone will have detectable antibodies by 14 days after vaccination
Delayed type hypersensitivity (DTH) reactions have been demonstrated within 2 days as an erythema with possibly development of a pustule.
Ref: Source: Henderson & Moss. In Vaccines Eds Plotkin & Orenstein 3rd Ed p. 81
Source: Henderson & Moss. In Vaccines Eds Plotkin & Orenstein 3rd Ed 1999

7. Duration of Immunity
Neutralizing antibodies (NA) can be detected > 20 years after Vx
Anamnestic (memory) response seen upon re-vaccination, with significant elevation in NA by day 7
Notes
NA = neutralizing antibodies
Source: Henderson & Moss. In Vaccines Eds Plotkin & Orenstein 3rd Ed 1999

8. Smallpox vaccination
Administered using a bifurcated needle and 15 punctures delivered into the skin
Positive “take” can be seen after about 7 days
The package insert states that only 3 punctures should be made when vaccinating persons who have never received smallpox vaccine previously. CDC has requested a revision of this recommendation so that all vaccinations are administered using 15 punctures. As of this date (12/16/2002) persons receiving vaccine for the first time should only receive 3 punctures.

9. Bifurcated needle with and without the vaccine dose

10. Vaccination site immediately after vaccination
                                         
Vaccination site immediately after vaccination
Note: small amount of blood which should appear at the site if punctures were sufficiently deep into the skin

11. Vaccination Site Management
Blot excess vaccine off the site
Cover with non-occlusive bandage – this is to prevent maceration of the site
If patient contact use gauze covered by a semi-occlusive bandage – to prevent transmission to others
Site should be examined every day

12. Normal Primary Vaccination
Vaccinia virus proliferates in the basal cells of the epidermis
By day 3….. Papule
Day 5-6 Vesicle with surrounding erythema – so called Jennerian pustule
Note the Jennerian pustule (whitish, umbilicated, multilocular, containing turbid fluid and surrounded by an erythematous areola

13. Normal Primary Vaccination
Day 8 – 9 Well formed pustule
This is a major reaction – a POSITIVE TAKE

14. Normal Primary Vaccination
◄ Normal reactions - 5 days
Normal reaction - 8 days 

15. Normal Primary Vaccination
Day 12 +
Pustules break down and crust over
This is a major reaction – a POSITIVE TAKE

16. Normal Primary Vaccination
Day 14

17. Normal Primary Vaccination
Day 16
Scabs begin to dry completely and then fall off by day 21 leaving a visible circular scar
This is a major reaction – a POSITIVE TAKE

18. Normal Vaccine Reactions Among Primary Vaccinees
Low grade fever > 37.7oC – 16%
Swelling of regional lymph nodes %
Myalgia, chills, headache, fatigue %
&/or nausea
These are normal and should not be considered as adverse events
They occur usually about 3-10 days after vaccination

19. Vaccine reactions among re-vaccinees
Among those for whom 25 years or more has elapsed since last vaccination, essentially all should experience a "major reaction"

20. Vaccine reactions among re-vaccinees
Level of response depends upon level of immunity
Persons with some residual CMI can develop an erythema and even a pustule, BUT there may not be sufficient immunity to inhibit viral replication
Those with substantial immunity may experience no more than a minor DTH reaction

21. Reactions in re-vaccinees
Accelerated reaction – major reaction.
Note the position next to an old smallpox vaccination scar.
Day 3: Note small vesicles have already formed
The reactions in persons who have been vaccinated previously are not very different in appearance from stages in a normal vaccination, but they appear earlier and are limited to a few vesicles and
Source: CDC web page

22. Vaccine reactions among re-vaccinees
It is impossible to distinguish clinically between an equivocal reaction which is due to residual immunity and one which is due to an allergic reaction
Therefore all reactions, other than a major reaction, should be read as a no-take and repeated using a different batch of vaccine

23. Types of reaction at the vaccination site
Re-Vaccination
Primary
Primary
Types of reaction at the vaccination site
Types of local reaction which may follow smallpox vaccination. Red dots represent erythema.
However, please note that it is impossible clinically to determine if the Re-Vaccination reaction is due to immunity or if it is a hypersensitivity reaction.
Time is in days after vaccination unless otherwise noted
Note: it is impossible to distinguish clinically between a re-vaccination reaction due to residual immunity and one due to a hypersensitivity reaction
After Burdon KL. Textbook of Microbiology 1948

24. Equivocal Reaction Small area of erythema Possibly a small pustule
Should be re-vaccinated
After two unsuccessful re-vaccinations seek consultation
Could result from
residual immunity or
reaction to vaccine components rather than a viral replication –
but cannot distinguish between the two
An equivocal reaction can occur when a person has residual immunity from a previous successful vaccination, and then this can interrupt vaccinia virus replication at a relatively early stage, so there has been some replication but not sufficient for the development of a well developed pustule, OR
An equivocal reaction can occur if there is sensitivity to one of the vaccine components and this sensitivity is seen as an erythema.

25. Equivocal reaction - Allergic
Erythema and a small, evanescent papule are present within several days
Symptoms resolve quickly
These are “sensitivity” reactions that can be evoked with vaccine virus that is no longer viable.
Revaccination is indicated.

26. Equivocal reaction – No Reaction
In some individuals, no take is seen after revaccination, even at long intervals after a primary vaccination.
Usually this is due to poor technique, low potency vaccine, or inactivation of the virus at the skin site (e.g. if alcohol is used to prepare the site).
Revaccination is indicated using vaccine of assured potency.

27. Normal Variant Satellite Lesions
The frequency of satellite lesions varies from study to study and ranges from 2.4 to 6.6 %.
No treatment other than symptomatic relief

28. Lymphangitis and cellulitis
Viral cellulitis can be confused with bacterial infection.

29. Normal Variant Cellulitis

30. Serious Adverse Reactions
Usually occur about 7 days after vaccination
These are not the normal reactions to a smallpox vaccination
Can be minimized by careful screening of vaccinees for contraindications

31. Serious Adverse Events
Potential adverse events should be referred to the designated Hospital Assigned Physician who can evaluate adverse events
All adverse events should be reported to both the state health department and to the Vaccine Adverse Events Reporting System (VAERS)
Do NOT report normal reactions to smallpox vaccination

32. Smallpox Vaccination: Complications▲
Eczema vaccinatum ►

33. ◄ Generalized vaccinia
Note: young vaccinees have a higher proportion of adverse events
Erythema multiforme ►

34. ◄ Accidental transfer from mother to 2-year old
Because of the high levels of close contact between parents and infants, the risk of inadvertent transfer of vaccinia is increased.

35. Rates of Complications of Smallpox Vaccination Per Million Doses, USA, 1968†, ††
All doses
Primary doses
Post-Vaccinal Encephalitis
1.1
2.9
Progressive Vaccinia
0.8
0.9
Eczema Vaccinatum
8.9
10.4
Accidental Infection
13.6
25.4
Death
0.6
Note: it is unclear how extensive was the pre-vaccination screening of vaccinees
† Excludes contact cases
†† Source: From N. Engl J Med, 1969; 281:

37. Treatment for Serious Adverse Reactions
VIG and cidofovir available only from CDC via state health departments
Cidofovir (Vistide) may be used under an Investigational New Drug (IND) protocol to treat serious smallpox vaccine

38. Vaccinia Immune Globulin
Contains thimerosal
Dosage:
Usual dosage 0.6ml/kg IM dose may be divided
For severe cases 1 – 10 ml/kg
700 doses of IM VIG are available now
Approximately 3300 doses of the new IV VIG will be available by the end of December 2002.

39. Inadvertent inoculation of other body sites
Indications for Use of Vaccinia Immunoglobulin (VIG) for Treatment of Adverse Reactions Associated With Smallpox Vaccination
Inadvertent inoculation of other body sites
— Usually not required — Indicated for inoculation of eye or eyelid — BUT contraindicated for vaccinial keratitis because increased scarring can occur
Generalized vaccinia—Indicated if patient is toxic or if patient has serious underlying illness
Source: Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR 2001;50(RR10):1-25

40. Eczema vaccinatum—Indicated for severe cases
Indications for Use of Vaccinia Immunoglobulin (VIG) for Treatment of Adverse Reactions Associated With Smallpox Vaccination - II
Eczema vaccinatum—Indicated for severe cases
Progressive vaccinia—Indicated for severe cases
Postvaccinial encephalitis — Not effective

41. Contraindications to Vaccine in the Absence of Exposure or Potential Exposure to Smallpox

42. Contraindications: Pre-Event
Eczema and atopic dermatitis and other chronic skin conditions: 28 million in the US at risk for eczema vaccinatum
[Has the patient had an itchy, scaly rash that lasts more than 2 weeks and which comes and goes? – this should be considered as atopic dermatitis]
Eye disease of the cornea or conjunctiva, especially if pruritic or inflammatory
While the question about an itchy scaly rash that lasts more than 2 weeks and comes and goes probably is broader than is necessary, a specialized panel of dermatologists felt that this would error on the side of caution in detecting atopic dermatitis in potential vaccinees.
Atopic dermatitis is thought to be a manifestation of an immune deficiency in the skin which leads to a failure to contain viral replication within the skin. This could be a reduction or absence of antimicrobial peptides within the skin.
Topical steroids for skin conditions

43. Contraindications: Pre-Event
Immunosuppression (organ transplants, HIV and cancer): 10 million individuals (3.6 percent) may be at increased risk for progressive vaccinia
≥2mgm/kg/ day prednisone or ≥20mgm/day for 14 or more days
Pregnancy
Any of the previous conditions in a member of the household
Persons should consider deferring vaccination also if they are likely to have intimate relations with a person with any of the previous conditions, even if they are not in the same household, because of the risk of transfer during intimate contact until the scab drops off.

44. Contraindications: Pre-Event
Breast feeding because of risk of inadvertent inoculation
Hypersensitivity to any of the vaccine components
Hypersensitivity to thimerosal
Breast feeding women could pump breast milk and have someone else feed the baby, as it is the close contact with the baby that is the risk. In addition, although the risk is considered to be very low, data are not available to assure that vaccinia virus is not transmitted via breast milk. Similarly, women who are bottle-feeding a baby, should consider if they can assure barriers between herself and the baby to prevent inadvertent inoculation of the baby, although the risk is not as high as with breast feeding.
If a vaccinee has a serious adverse reaction to the vaccine, hypersensitivity to thimerosal could rule out this treatment with serious consequences

45. Contraindications: Post Event
None if a person is exposed or at potential exposure

46. Risk of Transmission to Contacts
Transmission in virtually all cases from persons who were primary vaccinees
16.8 – 20 cases of contact EV per 106 primary vaccinations
62% of contacts cases in children < 5 years
1.8% of contact cases in persons > 20 years
EV = eczema vaccinatum
Source: Neff et al. Contact Vaccinia – Transmission of Vaccinia From Smallpox Vaccination. JAMA 288;(15) Oct 16, 2002

47. Recent Israeli Experience
Lister strain, considered to have fewer side effects
Total full reaction among vaccinated – 76 % ( n= 929 )
Side Effects:
Fever - 5 % • Headaches - 28 %
Muscle pain - 18 % • Nausea - 12 %
Fatigue and weakness - 31 % • Shivering - 9 %
Other - 13 %
There was one case of suspected encephalitis. The physicians in that case wanted to do a spinal tap, though the patient refused
(Israeli Ministry of Health records, 2002)

48. Efficacy of Post-Exposure Vaccination
" Vaccination within 3 days of exposure will completely prevent or significantly modify smallpox in the vast majority of persons
Overall, 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.  
Vaccination 4 to 7 days post-exposure still offered protection to many people, but significantly less than vaccination before 4 days."
Source: Ray Strikas, MD, CDC. Dec 13, 2002

49. Q & A: Vaccine and Pregnancy
Q. What if a woman is vaccinated and then finds out that she is pregnant?
A. Vaccination during pregnancy does not appear to increase the risk of miscarriage or stillbirth. Fetal vaccinia is rare. (Plotkin & Orenstein p. 85). VIG may be indicated, contact the HAP.
Women who may be pregnant should consider taking a pregnancy test the day of the vaccination or very close to that date.
HAP= hospital assigned physician

50. Q & A: VIG and Immunity Q. If VIG is administered for a severe
reaction, will this affect my immunity?
No, the fact that there is a severe
reaction indicates that there has been a strong immune response. The VIG will have no impact on the immune system and its memory.

51. Q & A: Steroids Q. A person who is on steroids should not receive
the vaccine in a pre-event situation because of immunosuppression. What is the dose of steroid that should be the cutoff for deciding immunosuppression or not?
A. 20mg/day prednisone for 14 days
2mg/kg/day prednisone
These are similar to the levels of steroid that are
used for the cutoff for other live virus vaccine such as MMR or varicella.
For a person who has been on these high levels of prednisone, they can be vaccinated 3months after their last dose of steroid
Other drugs which lead to immunosuppression severe enough to be a contraindication to vaccinai vaccination include alkylating agents, antimetabolites
Other conditions which would disqualify a person for vaccinia vaccination in a pre-event situation include leukaemia, lymphomas, organ and stem cell transplants

52. Q & A: Re-Vaccination
Q. What is the recommended timeframe for revaccination on non-takers?
A. If their vaccination site is looked at on Day & found to be a non-take, re- immunize immediately or any time thereafter. (Note the patient receives a new PVN number)
PVN = Pre-event Vaccination Number

53. Q & A: Swimming Pools
Q. Can I swim in the pool before the vaccination scab has dropped off?
A. No, even with a dressing, this is probably an inappropriate activity

54. References
Henderson & Moss.Vaccines 3rd Ed. Eds Plotkin & Orenstein 3rd Ed 1999
CDC. Vaccinia (Smallpox) Vaccine Recommendations of the Advisory Committee on Immunization Practices. MMWR 50 No. RR-10. June 22, 2001
Neff et al. Contact Vaccinia – Transmission of Vaccinia From Smallpox Vaccination. JAMA 288;(15) Oct 16, 2002

55. Supplemental Slides

57. Criteria for Determining Risk of Smallpox
High Risk for Smallpox  report immediately
Febrile prodrome (see below) AND
Classic smallpox lesions (see below and photo at right) AND
Lesions in same stage of development (see below)
Moderate Risk for Smallpox  urgent evaluation
One MAJOR smallpox criterion (see below) OR
>4 MINOR smallpox criteria (see below)
Low Risk for Smallpox  manage as clinically indicated
No viral prodrome OR
Febrile prodrome and <4 MINOR smallpox criteria (no major criteria)
(see below)

58. Major Smallpox Criteria
FEBRILE PRODROME: occurring 1-4 days before rash onset: fever >102°F and at least one of the following: prostration, headache, backache, chills, vomiting or severe abdominal pain. All smallpox patients have a febrile prodrome. The fever may drop with rash onset.
CLASSIC SMALLPOX LESIONS: deep, firm/hard, round, well-circumscribed; may be umbilicated or confluent
LESIONS IN SAME STAGE OF DEVELOPMENT: on any one part of the body (e.g., the face, or arm) all the lesions are in the same stage of development (i.e. all are vesicles, or all are pustules)
Minor Smallpox Criteria
Centrifugal distribution: greatest concentration of lesions on face and distal extremities
First lesions on the oral mucosa/palate, face, forearms
Patient appears toxic or moribund
Slow evolution: lesions evolve from macules to papulespustules over days
Lesions on the palms and soles (majority of cases)

59. Conditions With Vesicular or Pustular Rashes
Clinical Clues
Varicella (primary infection with varicella-zoster virus)
Most common in children <10 years; children usually do not have a viral prodrome
Disseminated herpes zoster
Prior history of chickenpox; immunocompromised hosts
Impetigo (Streptococcus pyogenes, Staphylococcus aureus)
Honey-colored crusted plaques with bullae are classic but may begin as vesicles; regional not disseminated
Drug eruptions and contact dermatitis
Exposure to medications; contact with possible allergens
Erythema multiforme (incl. Stevens Johnson Sd)
Major form involves mucous membranes and conjunctivae
Enteroviruses incl. Hand, Foot and Mouth disease
Summer and fall; fever and mild pharyngitis at same time as rash; distribution of small vesicles on hands, feet and mouth or disseminated
Disseminated herpes simplex
Lesions indistinguishable from varicella; immunocompromised host
Scabies; insect bites (incl. fleas)
Pruritis; in scabies, look for burrows (vesicles and nodules also occur); flea bites are pruritic, patient usually unaware of flea exposure
Molluscum contagiosum
Healthy afebrile children; HIV+ individuals
Bullous Pemphigoid
Bullous lesions. Positive Nikolski sign.
Secondary syphilis
Rash can mimic many diseases; rash may involve palms and soles; 95% maculo-papular, may be pustular. Sexually active persons
Conditions With Vesicular or Pustular Rashes

60. How to Collect a Specimen for DFA or IFA Testing
Laboratory Testing for Varicella: Collect at least 3 good specimens from each patient
Direct fluorescent antibody (DFA)—rapid, depends on adequate specimen (see below)
Indirect fluorescent antibody (IFA) —rapid, depends on adequate specimen (see below)
Polymerase chain reaction (PCR)--available in research labs, some tertiary care centers
Serologic testing: an IgG (collected at time of rash) provides evidence of prior varicella, and makes acute varicella infection unlikely but does not rule out herpes zoster in persons at risk of dissemination. IgM is not useful for diagnosis.
VZV culture—results delayed, useful only if processed in-house
EM (electron microscopy)—can identify herpes viruses
How to Collect a Specimen for DFA or IFA Testing
Unroof (open) vesicle or pustule with a sterile lancet
Swab base of vesicle vigorously with a sterile swab
Smear swab onto 3 areas (or wells) of a microscope slide
Allow slide to air dry
Transport to lab for immediate fixing and staining
VZV positive specimens are seen with varicella (chickenpox) and herpes zoster (shingles)
The hospital lab performs _________________ test
For DFA/IFA , call ________________ (specimen is tested at outside lab)

61. A suspected case of smallpox is a public health and medical emergency!
Clinical case definition of smallpox:
an illness with acute onset of fever >101°F followed by a rash characterized by vesicles or firm pustules in the same stage of evolution without other apparent cause.
Report ALL suspected cases (without waiting for lab results) to:
1. Hospital Infection Control ( ) ___-____ or ( ) ___-____ Pager
2. (Local) health department ( ) ___-____ or ( ) ___-____ Pager
3. (State) health department (517) or (517)
Questions? Centers for Disease Control and Prevention:
(404) days; Nights/weekends/holidays: (770)