Smallpox Vaccine Performance: Efficacy, Effectiveness and Vaccination Strategies

1
Smallpox Vaccine Performance Efficacy,
Effectiveness and Vaccination Strategies
Harold S. Margolis, MD Centers for Disease
Control and Prevention
Advisory Committee on Immunization Practices
Smallpox Work Group Meeting Atlanta, GA May 8,
2002
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General Limitations

• Most data not derived from controlled clinical
  trials
• Most conclusions are derived from clinical and
  epidemiologic studies conducted 30 years ago
• No good animal models of smallpox from which to
  extrapolate outcomes

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Pre-Exposure Immunization
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Estimates of Efficacy of Vaccination

• No controlled clinical trials
• Protection estimated from comparisons of
  secondary attack rates among vaccinated and
  unvaccinated family contacts of cases
• Vaccination status determined by presence of a
  scar and did not account for
• vaccine potency
• scar secondary to skin infection rather than
  vaccine take
• on-time vaccination
• The general medical opinion was that successful
  vaccination or revaccination within the previous
  3 years provided virtually certain protection
  against smallpox

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Effectiveness of Smallpox Vaccination
From Fenner et al, WHO 1988, p.591
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Types of Smallpox Lesions and Case-Fatality
Rates, Bombay, 1972
Rao, Smallpox in Bombay, Kothari, Bombay, 1972,
6942 cases
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Post-exposure Protection
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Effectiveness of Post Exposure Vaccination
From Fenner F et al. Smallpox and its
Eradication, pp 591
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Post-Exposure Vaccine Efficacy

• Secondary attack rates reduced up to 91 compared
  to unvaccinated contacts
• Lowest disease rates among persons vaccinated lt7
  days after exposure
• Disease generally less severe (modified type) in
  persons receiving post-exposure vaccination
• Difficult to define period of highest efficacy
  from available data earlier is probably better
  as with other post exposure immunization

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Duration of Protection
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Antibody Persistence After VaccinationIsraeli
Defense Forces, 1989

• Group I
• Recruits 18 years of age (N65), serum _at_ 0, 23
  days
• Previously vaccinated at 1 year and 8 years of
  age
• Group II
• Reservists (N20 per age group after exclusions)
• Vaccination at 0, 8, 18 years of age
• No data on clinical takes
• Excluded travel to countries requiring smallpox
  vaccine
• Vaccine
• Elstree strain (Lister)
• Usually vaccinated by jet injector, some by
  scarification
• Neutralizing antibodies - plaque reduction assay

Baruch El-Ad, et al J Infect Dis 1990161446-8.
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Antibody Persistence After VaccinationIsraeli
Defense Forces, 1989
2
Group I prevaccination
1.8
1.6
1.4
Group II
1.2
Log titer
1
0.8
0.6
0.4
0.2
0
0
5
10
15
20
25
30
Time (years)
Baruch El-Ad, et al J Infect Dis 1990161446-8.
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Long-term Persistence of Cell Mediated Immune
Memory to Vaccinia

• Vaccinia virus specific CD4 and CD8 CTL in
  person immunized 4 years earlier
• J Virology 1993 671538-1544
• No vaccinia virus specific CTL activity in
  persons vaccinated 20 years previously
• 50 of persons vaccinated lt3 yrs previously had
  CD8 CTL activity and low level CD4 activity
• J Gen Virol 1993 74751-754
• CD4 and CD8 memory vaccinia virus specific CTL
  activity in persons vaccinated 35-50 years
  previously 1/66,000 cells
• J Virology 1996 702627- 2631

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Long-term Protection from Infant Smallpox
Immunization, Liverpool, 1902-1903
Hanna, W. 1913, Studies in smallpox and
Vaccination. Bristol, Wright.
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Smallpox Fatality Rate by Time Since Vaccination
- Europe, 1950-1971
Mack TM. J Infect Dis 1972125161-9.
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Summary Estimated Protection from Smallpox
Vaccination
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Surveillance and Containment Effectiveness of
the Control Strategy Used to Eradicate Smallpox
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Characteristics of Smallpox

• Clinically evident disease - no subclinical
  illness
• No carrier state
• Transmission does not occur during prodrome
• Maximum transmission at time of substantial
  illness
• Vast majority of cases traced to face-to-face
  contact

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Strategies for Smallpox Eradication
Strategy
Year
Mass vaccination
1950s
Mass vaccination and coverage surveys
1966
Search and containment
1968
Monthly assessments
1973
House to house searches
1974
Rewards for finding cases
1974
Rash surveillance
1975
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Surveillance and Containment (Ring Vaccination)

• Worked for multiple cases in multiple places
• Used to eradicate smallpox

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Smallpox Eradication in West and Central Africa

• Estimated 200,000 - 400,000 cases annually among
  20 countries when corrected for underreporting
• Cases continued to occur among unvaccinated
  persons despite mass vaccination campaigns
• Surveillance was initially thought to be most
  useful in maintenance phase of program after
  mass vaccination
• Accumulating evidence suggested that surveillance
  and containment was of greater than mass
  vaccination

Foege WH, Millar JD, Henderson DA. Bull WHO 1975
52 209-222
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Effect of Search and Containment on Reported
Smallpox Cases, West and Central Africa
1968-1969
Surveillance Containment Initiated
population not vaccinated
Smallpox cases reported/expected ratio
Foege WH, Millar JD, Henderson DA. Bull WHO 1975
52 209-222
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Exposure Factors for SmallpoxWest Pakistan,
1968-1970

• Punjab Province -- 6 study villages
• Index case first case of smallpox in compound
• Contact any person regularly sleeping in same
  house or compound as index case excluded
  persons with previous smallpox
• Exposures
• Constant sleeping in same house or compound and
  remaining there during the day
• Daily left the house or compound during the day
  

Heiner et al. Amer J Epidemiol 1971 91316-326
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Exposure Factors for SmallpoxWest Pakistan,
1968-1970
Heiner et al Amer J Epidemiol 1971 91316-326
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Operational Aspects of Surveillance and
Containment

• Intense surveillance for case detection
• Delineation of functional and geographic
  boundaries around cases or outbreaks
• Outbreak control activities with first priority
  given to vaccination of contacts of cases (family
  and community contacts)
• Communications between areas about cases