Smallpox

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Smallpox

• Dr. Kristy Murray Lillibridge
• Asst. Professor, Epidemiology
• Center for Infectious Diseases
• University of TexasHouston, School of Public
  Health

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Poxvirus family large, complex, double stranded
DNA viruses

• Subfamilies
• Chordopoxvirinae (vertebrate poxviruses)
• Entomopoxvirinae (insect poxviruses)
• Chordopoxvirinae genera
• Orthopoxvirus (cowpox, vaccinia, monkeypox,
  variola, racoonpox, camelpox, skunkpox, volepox,
  ectromelia)
• Parapoxvirus (orf, pseudocowpox, )
• Avipoxvirus (canarypox, fowlpox)
• Capripoxvirus (goatpox, lumpy skin disease)
• Leporipoxvirus (myxoma, fibroma)
• Molluscipoxvirus (molluscum contagiosum)
• Yatapoxvirus (tanapox, Yaba monkey tumor)

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Current orthopoxvirus diagnostics

• Orthopoxvirus viral detection
• Single gene PCR, RFLP
• Species specific 12 hours
• real time PCR in development
• Species specific, generic 3-4 hours
• Culture
• Electron microscopy, immunoelectronmicroscopy
• Immunohistochemistry
• Serologic
• IgM capture, neutralization antibodies, IgG ELISA

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Variola

• Two strains
• Variola major 25-30 CFR
• Variola minor lt1 CFR

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Selected Aspects of Smallpox History

• Variola from the Latin Varius, meaning spotted,
  introduced in 569 A.D. by Marium, Bishop of
  Avenches
• Deaths
• Marcus Aurelius, AD180
• William II of Orange, 1650
• Emperor Joseph of Austria, 1654
• Tsar Peter II of Russia, 1730
• King Louis XV of France, 1774

Pediatr Inf Dis J 1999 1885 - 93
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Fenner F et al
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Protection from Smallpox

• Folklore in Europe that milkmaids rarely
  pockmarked
• Belief that protection from smallpox resulted
  from infection acquired from cows
• Edward Jenner observed that some with history of
  cowpox resisted variolation

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Jenners Experiment

• Transferred matter from the hand of an infected
  dairymaid to 8 year-old James Phipps on 14 May
  1796
• Variolation unsuccessful on 1 July 1796
• Phipps did not respond to variolation 5 years
  after original vaccination

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History of Smallpox Eradication

• 1950 - Pan American Sanitary
  Organization decides to
• undertake eradication hemisphere-wide
• 1959 - World Health Assembly adopts
  goal to eradicate smallpox
• 1966 - World Health Assembly decides
• to intensify eradication and provide more
  funds

Henderson DA, Moss B, Smallpox and Vaccinia in
Vaccines, 3rd edition, 1999
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Burden of Smallpox

• 1950s 50 million smallpox cases and an estimated
  6 million deaths per year
• 1960s 15 million smallpox cases and 2 million
  smallpox deaths per year
• Sequelae pockmarks, blindness, skeletal
  deformities

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Factors Which Facilitated Smallpox Eradication

• Clinical characteristics made clinical diagnosis
  easy
• No carrier state no animal reservoir
• No subclinical illness
• Maximal communicability at time of substantial
  illness, not prodrome
• Vast majority of cases could be traced to face to
  face contact

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Smallpox Eradication Strategy

• Mass vaccination campaigns in each country, using
  vaccine of ensured potency that would reach gt80
  of population
• Development of a system to detect and contain
  cases and outbreaks

Henderson DA, Moss B, Smallpox and Vaccinia in
Vaccines, 3rd edition, 1999
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Search and Containment Strategy

• Principal global eradication strategy was search
  for cases and containment of spread by locating
  and vaccinating contacts

Contacts to Contacts
Contacts to Case(s)
Case(s)
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Eradication of Smallpox

• 1977 - Last case in Somalia
• Intensive search over next 2 years
• 1980 World Health Assembly recommended all
  countries stop vaccination declared eradicated
• Stockpiles remain in Atlanta (CDC) and Moscow
  (Institute of Virus Preparations)

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Last Cases of Smallpox
Rahima Banu 16 October 1975 Variola
Major-Bangladesh
Ali Maow Maalin 26 October 1977 Variola
Minor-Somalia
Two laboratory acquired cases occurred in UK
in 1976
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Why the Concern Today?

• Ken Alibek, a former deputy director of the
  Soviet bioweapons program reported beginning in
  1980, the Soviet government had a successful
  program to produce the smallpox virus in large
  quantities and adapt it for use as a bioweapon.
  The program had an industrial capacity of
  producing many tons of smallpox virus annually.
• Concerns with decreasing financial support,
  smallpox could fall into other hands

JAMA 1999 281 2127-2137
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Biological Agent Priority CategoriesCategory A

• Variola virus
• Bacillus anthracis
• Yersinia pestis
• Francisella tularensis
• C. botulinum toxins
• Filo and Arenaviruses

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Caveats Why It Might Be Worse

• Higher population susceptibility
• Deliberate introduction of smallpox likely to
  differ from natural introduction
• Smallpox virus could be altered
• Lack of familiarity with disease could delay
  recognition
• Public health workforce not vaccinated
• Vaccine supply limited

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SmallpoxClinical Features

• ID50 10-100 particles
• disease is spread by secretions from the
  patient's mouth and nose, and by material from
  pocks or scabs
• It is transmitted directly from one person to the
  next. Close contact with patients, or their
  clothing or bedding, is thus required for
  infection
• 7-17 day incubation period
• Prodrome acute symptoms - fever, malaise,
  headache
• Eruptive stage
• case fatality - 35

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1st day of Rash Macules/Papules
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2nd day of rash More papules
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Day 3 fluid accumulating in papules to form
vesicles
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Day 4 Vesicles more distinct firm to the touch
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Day 5 Fluid becomes cloudy vesicles become
pustules
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Day 7 Pustular rash
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Day 8 Pustules larger firm and deeply embedded
in the skin
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Days 10-14 Pustules dry up and become scabs.
Scabs separate and fall off.
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Day 20 scabs have separated
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Complications

• Bacterial infection of the skin, e.g., boils,
  impetigo (2-5 in dirty environment) blood
  stream infection (septicemia)
• Corneal ulceration and blindness corneal opacity
  (4.4), corneal ulcer (1)
• Bronchitis and pneumonia probably due to
  secondary infection
• Encephalitis 1 in 1000 cases

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Mortality Risk Factors

• Community vs Hospital Diagnosis
• Type of Virus (Major vs. Minor)
• Vaccination Status
• Environmental sanitation (soap and water)
• Treatment (antibiotics)
• Antivirals ????

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Smallpox Vs. Chickenpox
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Smallpox VaccineVaccinia Virus

• Origin of vaccinia virus unknown
• Genetically distinct from cowpox and variola
• May be a virus now extinct in nature
• U.S. vaccine (Dryvax, Wyeth Laboratories)
  contains New York City Board of Health strain

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in Fenner F et al. Smallpox and its
Eradication, pp 570
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Clinical Response to Vaccination

• Jennerian vesicle at inoculation site
• Swelling and tenderness of axillary lymph nodes,
  usually during 2nd week
• 15-20 of primary vaccinees
• 0-15 of revaccinees
• Fever and malaise common
• Primary vaccination (6-8 days later)
• Vesicular or pustular lesion
• Area of definite palpable induration surrounding
  a central crust or ulcer

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Primary vaccination, day 3
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Primary vaccination, day 7
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Primary vaccination, day 10
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Primary vaccination, day 14
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Immunity Following Vaccination

• Nearly 100 protection for morbidity for 10 years
• 80 protection for morbidity at 20 years
• 90 protection against mortality at 50 years

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Adverse Reaction Rates
Adapted from CDC.Vaccinia (smallpox vaccine)
recommendations of the ACIP, 2001. MMWR
200150(RR-10)
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Risk Factors

• Eczema (contact too)
• Age less than 1 yr
• Anaphylaxis
• Neomycin, Streptomycin, Tetracycline
• Immunosuppression
• Cancer (disease or therapy)
• HIV
• Iatrogenic (transplant)

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Facial autoinocuation
12-F-15
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Autoinoculation
12-F-17
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Generalized Vaccinia
12-E-12
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Eczema Vaccinatum
12-D-17
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Eczema Vaccinatum
12-D-25
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Progressive Vaccinia
12-C-14
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Progressive Vaccinia
12-C-16
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Fetal Vaccinia
12-H-11
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Contraindications and PrecautionsNonemergency
Situations

• Severe allergic reaction to prior dose or vaccine
  component
• Eczema, history of eczema, or household contact
  with eczema or history of eczema
• Other skin conditions
• Immunosuppression or immuno-suppressed household
  contact
• Pregnancy
• Age lt18 years

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Goals of Outbreak Investigation

• Identify contacts of cases to limit further
  spread of disease
• Identify source of initial exposure
• Identify the population at risk
• Identify any unexpected epidemiologic features of
  the outbreak
• Improve containment strategies

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Expected Epidemiologic Features of Smallpox

• Incubation period 12 days (range 7-17 days)
• Transmission most common among face-to-face
  contacts via droplet spread
• Period of highest transmission during first 7-10
  days after the onset of rash
• Expected case-fatality rate of 30
• Secondary attack rate among susceptible household
  contacts 60

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Suggested Readings

• Fenners book Smallpox and its Eradication
• ACIP MMWR Vaccinia Vaccine
• JAMA article by DA Henderson et al., Smallpox as
  a biological weapon, June 9, 1999, Vol. 281, pp
  2127-2137