Smallpox Immunization Screening for Risk Factors Safety Surveillance Adverse Events Recognition

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Smallpox ImmunizationScreening for Risk
FactorsSafety Surveillance Adverse Events
Recognition Management

• COL Renata J. M. Engler, MC, USA
• Director, National Vaccine Healthcare Center
  (VHC) Network
  
• Chief, Allergy-Immunology Department, WRAMC
• Uniformed Services University of the Health
  Sciences
  
• Consultant to the Army Surgeon General for
  Allergy-Immunology
  
• DoD Representative to the National Vaccine
  Advisory Committee

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Learning ObjectivesImprove Understanding of . .

• Importance of vaccine safety - from prevention to
  treatment and management
  
• Risk communication and management
• Smallpox vaccine benefits and risks
• Understanding side effects can be significant
• Smallpox vaccine adverse events
• Expected and unexpected diagnose Rx
• Importance of VAERS, safety surveillance

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Immunization Threats to Success

• Public Perception
• High anxiety
• Diseases prevented NOT visible
• Rare adverse events HIGHLY visible
• Fear of vaccine adverse event vs evidence
• Low trust in safety surveillance
• Governmental agencies policies perceived as
  indifferent to individual risk suffering
  
• VAERS or vaccine adverse events reporting system
  considered inadequate insensitive

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Vaccine Safety

• National international focus for improvement
• Vaccine safety clinical assessments
• New specialty recognized by CDC VHC CISA
• Defining medical exemptions optimizing use
• Special needs in setting of a coercive program
• Risk assessment, education management
• Adverse events surveillance
• Initial VAERS no barriers, better provider use
• Follow-up VAERS outcomes and disability issues
  related to adverse events linked with vaccines
  
• Process for developing new case definitions and
  then evaluating relevance and significance
  (evidence for causality, risk factors for future
  screening)

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Congressional Challenge to DoD

• Enhance vaccine safety surveillance
• Enhance vaccine safety through improved screening
  process education of vaccinees and vaccinators
  access to expert review
  
• Increase provider knowledge in vaccine safety
  assessment and medical exemptions
  
• Regional centers of excellence to support
  mission
  
• Improve vaccine adverse events reporting
• Break down barriers to reporting
• Improve quality of adverse events reporting
• CDC-DoD collaboration in support of VAERS
• Role of the Vaccine Healthcare Center Network

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Risk Perception
? Fear of Shot Consequences
? Fear of Disease Consequences
What is my personal risk for an adverse reaction?
Is the risk of disease real for me?
Patient
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Fall 2001
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Smallpox VaccineLive Vaccinia Immunization

• Effective in a smallpox endemic world
• Complications are significant compared to other
  vaccines in a smallpox free world
  
• Rates of serious reactions in a population of
  adult primary vaccinees largely unknown
  
• Rare adverse events not well characterized
• 21st century vaccination need for adverse events
  surveillance crucial in order to
  
• Modify risk management strategies as needed
• Define disability and outcomes credibly
• Collect outcomes data
• Liability implications for secondary contact
  injury and civilian employee workmans
  compensation

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Vaccinia Immunization Goal Serious Adverse
Events Prevention

• Avoid immunizing high risk populations
• Contraindication ? medical exemption
• Balance with potential benefits to individual
• Optimize circumstances surrounding vaccination
  encounter
  
• Proper vaccine handling and administration
• Proper patient and close contact education
• Avoidance of contact spread of virus
• Handwashing, handwashing, handwashing
• Covering vaccination site appropriately

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Prevention of VacciniaComplications

• Staged screening for risk factors predictive of
  more serious adverse events
  
• Define the risks
• Evaluate the degree of risk
• Contraindication absolute or relative
• Define what is not a contraindication
• Manage the risks defined
• Patient education
• Further evaluation with specialist
• Establish medical exemption status

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Vaccinia Contact ComplicationRisk Management
Challenge

• Main route of secondary infection
• Contact with lesion or unwashed hands that had
  contact with vaccination site
  
• Virus can be cultured from top of permeable
  bandage, particularly if moist
  
• Respiratory transmission unlikely (like HIV
  risk) no evidence of transmission but not well
  studied
  
• Risk management, liability questions
• Clinical considerations

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Managing Contact Risk

• Screening of close contacts
• Cumbersome with reliability of questions unclear
• Responsibilities of vaccine program versus
  vaccinee
  
• 1968 Ten State Survey
• 27 infections/million 44 children aged years
  
• Transmission from recently vaccinated military
  recruits reported before 1990
  
• Report of 6 cases from one vaccine recipient
• Eczema vaccinatum many cases (50) due to
  secondary contact with vaccinee rather than due
  to primary vaccination

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Managing Contact Risk

• Contact vaccinia complications
• Rare encephalitis or vaccinia necrosum
• Most common inoculation with severity of
  reaction based on location
  
• Eye can be serious if ocular complications
  arise
  
• Genital area lesions caution with false positive
  FTA screening
  
• Eczema vaccinatum severe outcomes if atopic
  dermatitis risk factor present
  
• Progressive vaccinia
• Risk ? Infancy or immunosuppressed state

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Smallpox Vaccine Serious Adverse Event Rates
United States rates may be higher due to more
persons with immune defects ? Cancer, cancer t
herapy, organ transplantation, etc.
? Chronic illness with immune suppression, such
as HIV/AIDS, ? Eczema or atopic dermatitis.
Rates may be lower for persons previously
vaccinated.
Lane JM, Ruben FL, Neff JM, Millar JD.
Complications of smallpox vaccinations, 1968
national surveillance in the United States. New
Engl J Med 19692811201-1208.
Lane JM, Ruben FL, Neff JM, Millar JD.
Complications of smallpox vaccination, 1968
results of ten statewide surveys. J Infect Dis
1970122303-309.
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Adverse Reaction Rates to Smallpox Vaccine (per
Million)

• Estimates reviewed Military Medicine 2000
  1654287
  
• Encephalitis 0.2-8 with 0 in healthy
  revaccinees
  
• Lower rates related to age/re-vaccinees
• Vaccinia necrosum 1-4 per million
• Eczema vaccinatum 2-15 with highest in Israel
  Defense Force (IDF) experience 91-96
  
• Generalized vaccinia 2-30 (highest in Puerto
  Rico experience 1967-68)
  
• E multiforme 3-24 (Puerto Rico ?)
• Inadvertent inoculation 2-13
• Secondary infection 6 (in IDF experience)
• US Total 46 per million

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Vaccinia ScreeningSensitivity over Specificity -
1

• Does anyone you live with or have close contact
  with have a chronic (lasting longer than 3
  months) or serious illness including skin
  problems?
• Do you live with or have close contact with
  anyone being treated by a doctor for a disease?
  
• Are you being treated by a doctor for a disease?
  (Debated question, too sensitive?)
  
• Do you have a history (childhood, teenager,
  adult) of chronic or recurrent skin rashes?

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Vaccinia ScreeningHigh Sensitivity Skin Disease
Screen

• Do you have a history of longstanding or on/off
  (chronic) rashes during infancy, childhood,
  adolescence or adulthood (no matter how severe or
  mild the rash)?
• Do you have a history of skin rashes with redness
  and flaking or scaling, oozing or crusting?
  
• Did the the chronic or recurrent rashes itch?
• Where was your rash located?
• Face/head/neck folds of arms legs
  arms/legs/not trunk all over trunk, arms, legs

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Vaccinia ScreeningHigh Sensitivity Skin Disease
Screen

• Do you have a history of cancer, transplantation,
  or immune deficiency?
  
• Do you have a history of recurrent infections?
• In the past 3 months, have you taken any
  medications by mouth or on your skin that could
  suppress your immune system?
  
• Corticosteroids, anti-cancer drugs, specific
  immunosuppressive therapies
  
• X-ray treatments, UV phototherapy?
• Other
• Do you have a bleeding problem or take blood
  thinners?

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2002 ACIP Final RecommendationsScreening for
Atopic Dermatitis

• Secondary screening tool 2/5 YES ? STOP
• Has a doctor ever diagnosed eczema in the
  patient?
  
• Has the patient had itchy rashes that last more
  than 2 weeks?
  
• Has the patient ever had itchy rashes in the
  folds of the arms or legs?
  
• Did the patient have eczema with food allergies
  during infancy and childhood?
  
• Has a doctor ever diagnosed asthma or hayfever in
  the patient and/or first degree relative?

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Pregnancy Exclusion

• Need for sensitive specific screening
• Could you be pregnant?
• Is your menstrual cycle regular?
• Date of last menstrual period?
• Is there a chance that you could become pregnant
  in the next month?
  
• Would you like birth control counseling or a
  referral to OB-GYN?
  
• Laboratory testing not required but should be
  offered if indicated or requested

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Contact Screening

• Contact risk issues
• Infant
• Breast feeding
• Pregnancy
• Immune deficient close contact
• Ability to avoid contact with household member?
• Logistics and resources to support?
• Degree of contact that is acceptable?
• Separate bathroom, sleeping arrangements
• Bandaging wound, handwashing compliance?

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Anaphylaxis Vaccines

• Rare event for most vaccines (1 per million)
• Exception Japanese encephalitis vaccine
• 1 in 10,000 with onset up to 1 week after dose
• Some reactions linked with gelatin
• Vaccinia rare with NO deaths reported
• Egg allergy and vaccines no egg in Dryvax
• Not a risk for measles, mumps or rubella
  vaccines
  
• Influenza and yellow fever primarily
• Gelatin (porcine more than bovine)
• Linked with anaphylaxis to MMR, other vaccines

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Anaphylaxis RiskScreening for Vaccinia (US)

• Vaccine contains
• Neomycin
• Polymyxcin B
• Streptomycin
• Tetracycline
• Preservative phenol
• Glycerin 50
• Latex rubber in stopper so assume risk

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Anaphylaxis TreatmentNew Standard of Care

• Early recognition and treatment with epinephrine
  linked to improved outcomes
  
• TIME is critical particularly in setting of
  rapidly progressive systemic anaphylaxis
  
• Epinephrine 11000 SQ
• Same blood levels as saline injection
• Optimum delivery highest blood levels
• IM in the anterolateral thigh deltoid SQ
• Repeat every 1-5 minutes if rapidly progressive
  systemic anaphylaxis

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Screening for Prior Smallpox Vaccination
Reactions

• Lower risk with future vaccinia doses IF healthy
• Have you ever received the smallpox vaccination?
• How many doses?
• Do you have a smallpox scar?
• Did you have a serious reaction to the smallpox
  vaccine?
  
• How many weeks did the smallpox reaction last?
• Did a doctor tell you to avoid future smallpox
  vaccination?

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Duration of Immunity

• Limited data available suggests
• Persistent protection for many decades in some
  but not all long term memory T cells
  
• Probably better if more than 1 dose
• Rates of smallpox in early 1900s increased the
  longer out from vaccination but NOT to levels of
  unvaccinated individuals
  
• Antibody measurements not predictive of degree of
  protection but data limited
  
• Intercurrent illness with immune compromise may
  adversely affect response

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How Protective Was Childhood Vaccination ?

• Mortality from smallpox infection
• Overall mortality in unvaccinated 30
• Vaccinated within 10 years 1.4
• Vaccinated 20 years ago 11
• Age 30-49 unvaccinated 50
• Age 30-49, vaccine in infancy 3.7
• Aged 50, vaccine in infancy 5.5
• More than one dose of vaccine ??
• Probably lower than for only infant dose

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40 with prior vaccine dose (1 or more)
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History of PriorSmallpox Vaccine Reaction

• ALERT for medical exemption evaluation
• Any systemic reaction lasting longer or more
  severe than expected
  
• Doctor advised avoidance of future vaccine
• Encephalitis or neurologic complication
• Eczema vaccinatum, generalized vaccinia
• Anything that concerns the patient!

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Contraindications

• Immunodeficiency disorders
• Primary/congenital
• IgA deficiency 1 in 500-700 blood donors?
• Some have functional humoral defects
• Not all are the same in risk but excluded?
• Acquired immune deficiency
• HIV infection even if asymptomatic
• Disease or drug related immune suppression
• Complex evaluation process
• Key offer screening no barriers to testing

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Secondary Immune Defects

• Acute illness with or without fever
• Standard screening for all vaccines
• Malnutrition most common cause of IMD
• Anergy in ranger training students lasting
  months linked to diet and sleep deprivation
  
• Lifestyle factors poorly understood
• Sleep hygiene
• Tobacco use

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Screening for Contraindications to Vaccinia

• Initial high sensitivity, low specificity
• WRAMC scantron questionnaire contains series of
  questions developed by CISA/CDC/VHC working
  groups
  
• Used for SRP screening of 1900
• Further evaluation to determine specific need for
  medical exemption derm, allergy
  
• Develop consensus 1st and 2nd level tool

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Screening for Smallpox Immunization

• Preliminary Results for WRAMC N1946
• 7 with YES response to skin disease screening
  questions
  
• 1.9 with YES to possible immune deficiency
  questions
  
• 32 answered NO to all screening question
• Challenge precise identification of vaccine
  candidates requiring evaluation for medical
  exemption

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Screening Good and Bad

• Document issues identified in initial screen
• Detail additional history or evaluation that
  clarifies degree of risk
  
• Difficult contact/household risk
• Document medical exemption criteria
• Risk of screening process false Neg
• Incentive to conceal high risk history?
• Understanding of screening process?
• Patient specific barriers to learning?
• Questions NOT validated

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Moses AE, Cohen-Poradosu R. Eczema Vaccinatum -
A Timely Reminder.
NEJM 2002 346(17)1287.
Outcome after 3 weeks of hospitalization VIG
administration and 3 weeks in ICU Deep facial
and chest scarring. Could earlier administration
of VIG have reduced morbidity?
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Fear Inversion
? Fear of Disease Consequences
? Fear of Shot Consequences
What is my personal risk for an adverse reaction?
Is the risk of disease real for me?
Patient
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From anti-vaccination website, accessed 21 Oct
2002
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Smallpox Vaccination in DoD

• The challenges for optimizing Smallpox Vaccine
  Risk Management apply to all vaccines but carry
  higher stakes for vaccinia because of the more
  serious and higher rates of serious adverse
  events.
•  Lessons learned, competence and infrastructure
  developed in the context of reintroduction of the
  smallpox vaccine will benefit all vaccine
  programs in the Department of Defense, whether
  for future new vaccine insertions or improvements
  on established vaccine programs.

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Standard 1 Information EducationStandard 2
Storage HandlingStandard 3 Screening Medical
History - Medical exemptions when
indicated!Standard 4 Contraindications
Standard 5 Record keeping Standard 6 Vaccine
AdministrationStandard 7 Adverse
EventsRemember This is the minimum for quality!
Complexity of Immunizations Minimum Standards For
Non-Traditional Sites MMWR March 2000 (On CDC w
ebsite)
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Smallpox Vaccination in DoD

• The Challenge
• How well high-risk personnel are exempted from
  vaccinia immunization in a pre-smallpox event
  world and how well the military healthcare system
  identifies and cares for individuals with serious
  adverse events will be the yardstick by which DoD
  and the military healthcare system will be judged
  when someone dies or is seriously injured by a
  direct or indirect (contact) vaccinia
  complication.

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Smallpox Vaccine Adverse EventsSerious and Rare
AssociationsRecognition and Evaluation
Management and Reporting

• New Clinical Challenges
• Anticipating the Unexpected

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Special issues vaccines against bioterrorism
And biowarfare
How real is the threat?
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Smallpox Vaccine Material

• U.S. stockpiles dose estimates vary 12/-
  million doses vaccine (Dryvax? calf lymph, not
  human cell culture derived)
  
• New York City Board of Health strain of vaccinia
  produced by Wyeth Laboratories in 13 separate
  lots lyophylized in glass vials with rubber
  stoppers, sealed w/ metal band
• Rehydrated vial 100 doses with a potency of at
  least 108 plaque-forming units (pfu)/ml
  
• 90 of susceptible persons respond to 110
  dilution, 70 re-vaccinees NEJM 2002 15 OK
  
• Increasing supplies identified

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Licensed Vaccine

• FDA approval of 2 million doses of Dryvax? but
  with new diluent
  
• Anticipate start of vaccination by 2003
• Different from Israeli vaccine (cell culture)
• Vaccinia strain in US
• Less virulent with lower side effect profile than
  strains used in other countries
  
• Efficacy for prevention of smallpox
• New vaccines cell culture, inactivated

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Innate Immune System

• Neutrophil function
• Critical role in vaccinia response
• Quantitative and qualitative defects would be
  expected to have higher risk of complications
  
• Diseases and neutrophil function?
• Complement
• 50 do not develop vaccinia CF antibody
• Role in vaccinia response?
• Defects may tolerate vaccinia as long as antibody
  and cellular responses are normal

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Humoral Immunity Vaccinia

• Antibody deficiency linked with vaccinia
  complication risk neutralizing Ab importance
  
• Quantitative immunoglobulins
• Dysproteinemias monoclonal gammopathy?
• Agammaglobulinemia
• IgA deficiency not addressed
• Functional humoral immunodeficiency
• Requires specific antigen challenge
• May have normal total antibody levels
• B cell numbers functional assays
• 2002 Ab defects NOT a contraindication for
  varicella IF cellular immunity OK

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Adaptive Immune Response Cytotoxic T Cells Int
erferon-gamma generation Neutralizing antibodies

Innate Immune Response Neutrophils Natural kil
ler cells Gamma delta T cells ?? Toll-like recep
tors
?? Anti-microbial peptides
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Complexity of Immune DisordersAdditional Risk
Management Challenge

• Infectious diseases
• HIV infection contraindication
• Asymptomatic, early disease experience in early
  1980s no adverse effects seen except in 1 out
  of 700 recruits later found with HIV
  
• Reactivation of tuberculosis described
• Collagen vascular diseases
• SLE
• Rheumatoid arthritis
• Other vasculitis, etc
• Others patient specific risk assessments

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Corticosteroid (CS) UseHow much is too much?

• Biologic variability in CS effect
• Degree of immune suppression?
• ACIP Guidelines for contraindication to live
  virus vaccination in general (MMWR Feb 2002)
  
• Prednisone or equivalent 2 mg/kg of body weight
  or a total of 20 mg/day for children who weigh
  10 kg, when administered for 2 weeks
  
• Greater than physiologic doses for longer ??
• Wait 1 month after discontinuation of therapy
  before administering a live-virus vaccine
  
• If chronic illness is also linked to ? immunity
• Consider anergy panel to determine cellular
  immunity

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Interferon-? NK FunctionFirst Line Defense for
Vaccinia

• Humans deficient in NK cells
• Highly susceptible to herpetic viral infection
• No early resistance to Listeria (mouse)
• MHC Class I expression defect
• Similar loss of functional first line of defense
• Atopic dermatitis skin
• Th2 cytokine responses do not facilitate innate
  antiviral immune responses
  
• Lack of IL-12 stimulation of NK cells IFN-?
  production ? reduced NK function

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Cellular ImmunityIn-Vivo Anergy Panel

• Functional assessment of CD4 T cell responses in
  the skin
  
• Delayed type hypersensitivity skin testing with
  recall antigens familiar to population
  
• Tetanus, candida, mumps
• 99 of health population responds to 2/3 or more
  antigens with induration at 48-72 hours 5 mm
  
• Partial anergy 1/3 Complete anergy 0/3
• Predictive of increased sepsis risk after
  surgery
  
• Prognostic significance in HIV
• Used as screening for primary cellular IMD

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Local Reactions to Rashes

• How big is too big?
• Range of normal reactions where symptomatic
  care is adequate
  
• Pain
• Wound care
• Secondary infection
• Lymphangitis, adenopathy
• Generalized Rash what is normal and what is
  not?

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Smallpox Vaccination Complications
Toxic Erythema
Autoinnoculation
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Eczema Vaccinatum
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Vaccinia Post-Recovery
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Vaccinia Gangrenosum
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Smallpox Vaccine Risks

• Autoinnoculation, secondary scarring
• Secondary infections covering site?
• Autoimmune Vaccinia
• Vaccinia vaccinatum vaccinee contacts
• Vaccinia Gangrenosum
• Myocarditis, other problems
• Risk factor of particular concern
• Eczema, atopic dermatitis remote hx?
• Other skin conditions ?
• Immune compromise, age
• Extreme exertion with ? CMI

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Serious Complications

• Early recognition screening risk factors
  missed?
  
• Encouraging vaccinee to recognize symptoms that
  are serious, persistent or unexpected
  
• Rapid evaluation to rule out other causes
• Illness happens at any time in some people
• Attitude of openness as to cause
• Vaccinia specific diagnosis culture, other?
• Treat symptoms and follow-up
• Consultation available to support PCP
• Learning curve for the organization, the provider
  and the vaccinee cognitive complexity!

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Neurologic Complications

• Encephalitis CISA workgroup definition
• Acute generalized disturbance of brain function
  requiring hospitalization consisting of coma or
  stupor that cannot be attributed to medication or
  post-ictal state. Must include altered
  consciousness, delirium, obtundation and/or
  confusion
• Diagnosis of exclusion for other causes
• Data elements required for better understanding
  of cases that occur
  
• See questionnaire developed by CDC working group

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Neurologic Complications

• Encephalomyelitis
• Evidence of acute neurologic involvement
  presenting with non-specific signs such as fever,
  seizures, altered consciousness, headache,
  vomiting, meningismus, anorexia, with multifocal
  involvement of CNS and with CFS evidence of
  inflammation (7 white cells).
• Exclusion of other criteria required.
• Onset of symptoms after 8-15 days
• EEG generalized high voltage slow waves from
  both hemispheres
  
• Target white matter of CNS - post mortem
  histology shows perivenous microglial
  proliferation involving the white matter of
  cerebral hemispheres and brain stem

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Defining Encephalitis

• Reyes syndrome Clinical symptoms of acute
  encephalopathy with altered level of
  consciousness plus
  
• Absence of inflammatory changes in CSF with 5WBC/mm3 or brain histology showing cerebral
  edema without perivascular or meningeal
  inflammation
• Absence of other etiologies for cerebral or
  hepatic abnormalities
  
• Labyrinthitis as isolated finding?

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Neurologic Complications

• Polyneuritis or polyneuropathy or peripheral
  neuropathy (n28 cases)
  
• Clinical acute, intense pain, paresthesias,
  muscle paralysis and wasting (proximal or
  distal), hypotonia (involved limb), loss of
  tendon reflexes, objective sensory disorders
  (stocking glove anesthesia)
• Guillain-Barre
• Brachial neuritis
• Facial nerve palsy's

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Deaths Vaccine in US

• What we know
• Primary vaccinees (68 cases)
• Vaccinia necrosum (n13) majority in age year
  
• Post-vaccinia encephalitis (n34) primary
  vaccinee age peaks
  
• Contact eczema vaccinatum (n12) age spread with highest in age 1-4 years
  
• Stevens Johnson reaction (n1)
• What we do not know
• Risks in older primary vaccinees

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Deaths Vaccine in US

• What we know
• Revaccination deaths (8 cases) 7 30 yrs
• Vaccinia necrosum (n6/8)
• Underlying disease AML, Hodgkins, CLL,
  scleroderma on steroids
  
• Encephalitis (n2) no risk factors
• What we do not know about revaccinees
• Risks in older individuals with other chronic
  disorders such as diabetes, collagen vascular
  disease, cancer survivors

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Severe Generalized Vaccinia

• Very rarely a generalized vaccinial rash,
  sometimes covering the whole body, occurred 6-9
  days after vaccination. The course of the
  individual skin lesions resembled that of the
  lesion at the vaccination site, but if the rash
  was profuse the lesions sometimes varied greatly
  in size. The generalized eruption usually did not
  have the centrifugal distribution which was
  characteristic of the rash of smallpox. (Fenner,
  299)
• When systemic signs and symptoms lead one to
  suspect blood-borne virus dissemination, VIG may
  be of benefit. (Lane et al, 258-9)

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Severe Generalized Vaccinia

• There is general enlargement of the lymphatic
  glands, and the lesions normally commence in the
  abnormal areas of the skin, but in this malignant
  form always involve normal skin as well. Usually
  large areas of the skin are infected
  simultaneously, with a uniform development of the
  rash, not at all unlike that of malignant
  smallpox. Although in some areas the rash may be
  confluent, in closely adjoining areas of the skin
  there may be no rash at all, and the
  characteristic centrifugal distribution of
  smallpox is absent, although the rash may be more
  characteristic than anything else. Although the
  rash on the face at first sight resembles
  smallpox, the absence of rash on the tip of the
  nose compared with the density of the cheeks
  rules this out. (Dixon, 151-152)

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Vaccinia ComplicationsThe Eye

• Clinical presentation
• Vesicular lesions with inflammation swelling of
  eyelid and conjunctiva
  
• Cornea affected in 6 (22/334)
• Keratitis permanent sequellae frequent
• Corneal, eyelid, eyelash abnormalities
• Iritis rare event
• Treatment option besides local care
• VIG (except for keratitis)
• Triflurothymidine (Viroptic? for herpetic
  keratitis)

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Myocarditis After Vaccinia Immunization

• 237 Finish conscripts
• Mumps, polio, tetanus,smallpox, diphtheria and
  type A meningococcal disease
  
• 8 demonstrated serial ECG changes
• ST segment elevation and T wave inversion
• 3 asymptomatic evidence of myocarditis atopy as
  risk factor raised as question?
  
• 127 consecutive recruits myocarditis cause
• Serial ECG, fourfold titer increase
• Etiologic vaccinia, mononucleosis, Mycoplasma,
  Chlamydia, Coxsackie B4
  
• Adenovirus and influenza A usually asymptomatic

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Myocarditis After Vaccinia Immunization

• What is risk in adult primary vaccinees?
• Largely unknown, varies from country to country
• Less frequent with US vaccine strain than
  others?
  
• Clinical recognition avoidance of risk
• Onset of chest pain, dyspnea, fatigue 8-16 days
  after vaccination
  
• ECG ST segment elevation with T wave inversion
• Management
• Some case reports suggest prompt response to
  prednisone therapy
  
• Role of VIG less well defined but if severe may
  be justified under compassionate IND

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Vaccinia and Bone Infection

• Vaccinia has been localized to arthritis synovial
  fluid and to clavicle periostium
  
• Rare cases of osteomyelitis reported
• Mostly from other countries but mentioned in some
  of older US literature
  
• Expect the unexpected!
• Rotavirus vaccine and intussusception
• Smallpox vaccine will surprise and challenge us
  clinically

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Rare Adverse EventsVaccinia Complications?

• Case reports with clinical correlation
• Asthma interstitial pneumonitis
• Diabetes insipidus irreversible
• Flare of herpes zoster post vaccination
• Tuberculosis flare post vaccination
• Glomerulonephritis
• Post-vaccinia arthritis syndrome

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Rare Adverse EventsVaccinia Exposure Association

• Case reports with clinical correlation?
• Leukemia following smallpox vaccination
• Genital syphilis-like lesion and false positive
  FTA
  
• Other case reports raising questions?
• May or may NOT be causally linked
• Increased risk of adverse events
• Blood groups A, B, AB, M, Rho(D)?

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Vaccinia ComplicationsTreatment Challenges

• Specific versus symptomatic therapies Role of
• Vaccinia Immune Globulin?
• Cidofovir?
• Triflurothymidine for the eye?
• Interferons?
• Immunomodulatory IVIG?
• Corticosteroids?
• Peripheral neuropathy?
• Myocarditis?
• Others encephalitis, Stevens Johnson?

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Interferons in Viral Infections

• Antiviral effector molecules IFN-? ?
• Bind to common interferon receptor, Janus-family
  tyrosine kinase signaling pathway
  
• Interfere with viral replication in tissue
  culture cells via destruction of mRNA
  
• Synthesis induced by DS-RNA (synthetic and
  viral), then induces endoribonuclease - degrades
  viral RNA
  
• Serine threonine kinase P1 kinase inhibits
  translation preventing viral protein synthesis
  
• Induce MHC class I expression facilitate
  cytotoxic T cell (CD8) killing
  
• Activate NK cells
• Block spread of virus to uninfected cells

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Atopic Dermatitis

• Complex immune dysregulation
• Atopic dermatitis phenotype a factor of
• Genotype
• Environment
• Immunomodulation over time
• Clinical challenges to a simple view
• Case report of improved AD following accidental
  immunization of a child with active disease
  
• Vaccinia was used to suppress herpetic oral
  leasions (cold sores)
  
• Dose response determines type of immune response
  to vaccinia exposure Th1 versus Th2?
  
• Higher dose, ? more rapid IFN-? NK response?

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Atopic Dermatitis History

• Are CDC exemption criteria too strict?
• Particularly with currently asymptomatic skin
  disease AND prior history of immunization?
  
• Are there interventions that could modify risk if
  vaccine benefit exceeds risk?
  
• Vaccination under informed consent?
• Medical practice provider-patient decision?
• NEED Registry of vaccinees who had a history of
  AD in childhood but received vaccine without
  problems
  
• What are criteria for risk stratification?

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Smallpox VaccineExemption Management

• In an emergent setting
• Nothing is an absolute contraindication complex
  issues surrounding risk stratification versus
  benefit plus ability to manage the risk
  
• How should eczema patients be managed?
• Do prior vaccinees need lower dose for booster
  effect does this lower risks?
  
• Hyperimmune globulin for vaccine complications?

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Vision Develop a network of regional VHCs that s
upport continuous quality improvement of
immunization healthcare delivery, education,
research and case management of complex adverse
events for DoD beneficiaries.
Mission and Goals To provide clinical, educationa
l, research quality assurance leadership for
immune readiness through outreach in support of
the goals of enhanced vaccine safety, efficacy,
knowledge, trust and services to include
diagnosis management of adverse events.
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Additional Background SlidesSmallpox Vaccine
Challenges
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Evaluating Side Effects After Vaccination
Temporal versus Causal Association

• Adverse event (AE) causally attributed to vaccine
  if
  
• Exact chronology of immunization AE is known
• AE corresponds to previously associated AE
• Event conforms to a specific clinical syndrome
  whose association with vaccination has a strong
  biologic plausibility (anaphylaxis)
  
• Lab result confirms association (e.g., vaccine
  strain such as varicella isolate from skin
  lesion)
  
• Positive rechallenge with worsening of
  reaction
  
• Controlled clinical trial or epidemiologic study
  shows greater risk of AE among vaccinated vs
  unvaccinated (control) groups database vaccine
  safety links

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2002 ACIP Final RecommendationsScreening for
Atopic Dermatitis

• Have you, or a member of your household ever been
  diagnosed with eczema or atopic dermatitis
  
• IF YES, you may NOT receive the smallpox
  (vaccinia) vaccine due to the risk that you or
  your household contact might develop a severe and
  potentially life-threatening illness called
  eczema vaccinatum

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2002 ACIP Final RecommendationsScreening for
Atopic Dermatitis

• Eczema/atopic dermatitis usually is an itchy red,
  scaly rash that lasts more than 2 weeks and often
  comes and goes.
  
• IF YOU or a member of your household have EVER
  had a rash like this you should NOT receive the
  smallpox (vaccinia) vaccine at this time UNLESS
  you and a healthcare provider are sure that this
  rash is not atopic dermatitis or eczema.
• Additional screening ? exclusions

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2002 ACIP Final RecommendationsScreening for
Atopic Dermatitis

• Secondary screening tool 2/5 YES ? STOP
• Has a doctor ever diagnosed eczema in the
  patient?
  
• Has the patient had itchy rashes that last more
  than 2 weeks?
  
• Has the patient ever had itchy rashes in the
  folds of the arms or legs?
  
• Did the patient have eczema with food allergies
  during infancy and childhood?
  
• Has a doctor ever diagnosed asthma or hayfever in
  the patient and/or first degree relative?

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Cutaneous Conditions Immunization Exclusions

• Skin Conditions excluded
• Atopic dermatitis current or past
• Neurofibromatosis, active contact dermatitis,
  furunculosis, urticaria pigmentosa, lichen
  planus, psoriasis, keratodermia, epidermolysis
  bullosa, dermatitis herpetiforme, acrodermatitis
  chronica, keratosis follicularis, Darier disease,
  morphea, discoid lupus, any inflammatory

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Jenner Vaccination 1878 Paris Exhibit
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The Take-Home Messages

• Life is uncertain it always has been!
• Nothing is promised cherish today!
• What is the best defense at an individual level?
  Knowledge, developing ways to meet the
  challenges, enhance immune readiness!
  
• Love Caring being there to share the stress
  and the grief - essential elements of quality
  living, of nurturing our community ourselves
  
• Stop being afraid! Explore ways to love better,
  to care more, whether in our patient care or in
  the way we live our lives and serve our country
  
• Be thankful for each moment! Rejoice always!