Vaccine Evaluation

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Vaccine Evaluation
Kathryn M. Edwards, M.D. Professor of
Pediatrics Vice Chair for Clinical
Research Vanderbilt University Nashville, TN
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Case Presentation

• 9 month old child presents to ED
• Has fever to 102o F, irritability
• Physical examination shows stiff neck
• Lumbar puncture shows cloudy spinal fluid
• Gram stain of fluid reveals bacteria
• Haemophilus influenzae, type b grown
• Child dies within 24 hours of admission

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• Haemophilus influenzae type b,
• Incidence by age group

Rate per 100,000 population
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• Estimated Incidence of Invasive Hib Disease,
  1987-2000

Rate per 100,000 children lt5 years of age
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Historical Perspective
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Vaccination 101Definition of Vaccination

• Active protection against disease produced by
  administration of a foreign substance
• Goal to induce immunity and memory similar to
  natural infection but without disease

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Principles of Vaccination
The more similar a vaccine is to the natural
disease, the better the immune response to the
vaccine and the better the protection afforded.
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Classification of Vaccines

• Live attenuated
• Inactivated

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Live Attenuated Vaccines

• Attenuated (weakened) form of the "wild" virus or
  bacteria
• Must replicate to be effective
• Immune response similar to natural infection
• Usually effective with one dose
• However, they carry a risk of disease

except those administered orally
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Inactivated Vaccines

• Cannot replicate
• Generally not as effective as live
• Generally require 3-5 doses
• Antibody titer diminishes with time
• Very safe

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Selection of Vaccine Candidates

• Public Health Need
• Vaccine has sound scientific rationale
• Expectation of safety
• Animal studies show immunogenicity
• Can be made in a practical formulation
• Commercial development possible

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Clinical Testing of Vaccines
Phase 1 Safety and Immunogenicity -Small
studies -Begin in Adults -Proceed to
successively younger children Phase 2 Safety,
immunogenicity, dose -Prospective, randomized,
blinded, controlled -Several hundred
children Phase 3 Efficacy -Prospective,
randomized, blinded, controlled -Size depends on
disease attack rate Lot-to-Lot Consistency
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Roles of Different Groups

• Manufacturer Applies for Licensure
• FDA Issues License based on Studies
• ACIP Issues guidelines for Public Sector
• AAP / AAFP Guidelines for Constituents

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Post-licensure Safety Surveillance

• VAERS
• Vaccine Safety Data Link
• Center Immunization Safety Assessment
• Phase IV Trials

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Vaccine Safety IssuesRotavirus and
Intussusception
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Clinical Trials

• 27 Trials (5 efficacy studies)
• 9 Countries
• 150 investigators at 320 sites
• 10,000 infants received Rotashield
• Cost hundreds of millions of
• 15 years

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Intussusception in RV Vaccinees,Pre-licensure
Study Vaccine Dose Day 307-US RV-S1 2 15
316-F Rotashield 3 7 320-US Rotashield 2 51 32
1-US RV-TV (tab) 2 6 325-US RV-TV (tab) 3 7
5 / 10,054 vaccinees vs. 1 / 4638 controls
(P0.45, Poisson)
Adapted from Rennels M, et al. PIDJ 199817924
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Licensure and Use Decisions

• Pre-licensure cases discussed widely
• Vaccine Licensed and Recommended
• Put in package insert
• Included in ACIP / AAP recommendations
• FDA established a search code
• Early look at VAERS reports planned

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VAERS Intussusception Reports 7/16/99

• 15 infants (1.8 million doses distributed)
• Median Age 3 months
• 13 followed 1st dose of Rotashield
• 12 within 1 week of Rotashield dose

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AAP Member Alert Possible Association of
Intussusception with Rotavirus Vaccination
1. Suspend vaccination summer season and
rotavirus not present 2. Advise parents to
promptly seek medical attention for
symptoms 3. Report all cases following
vaccination to VAERS
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Time from RRV-TV to IS
n45/74
Dose 1
n10/47
Dose 2
Dose 3
n3/25
CDC
October 8, 1999
Days
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Intussusception in RV Vaccinees,Pre-licensure
Study Vaccine Dose Day 307-US RV-S1 2 15
316-F Rotashield 3 7 320-US Rotashield 2 51 32
1-US RV-TV (tab) 2 6 325-US RV-TV (tab) 3 7
Adapted from Rennels M, et al. PIDJ 199817924
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How Much Safety Data is Enough?
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SAMPLE SIZES NEEDED TO DETECT RARE EVENTS
Adapted from Ellenberg 1997, Davis 2000
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Challenges for Safety Assessment

• The complexity of the safety issues are difficult
  to communicate to both the public and to the
  medical community at large
• The concepts of causation are difficult
• Recruitment of larger numbers of children into
  pre-licensure trials are problematic
• Post-licensure studies are complicated by the
  lack of vaccine registries, absence of
  unimmunized control groups, and funding

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Natural History of an Immunization Program
Prevaccine Increasing Loss of Resumption
Eradication Coverage Confidence of Confidence
Immunization Stopped
Disease
Outbreak
Vaccine Coverage
Eradication
Adverse Events
ic1
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The Bottom Line about Vaccines

• Vaccines are all about Risks and Benefits
• The best vaccines prevent bad diseases
• If a vaccine offers little or no benefit, no risk
  is acceptable
• If the market for the vaccine is small, then
  industry cannot afford to develop it
• When disease is reduced, adverse events may occur
  more often than disease
• To insure appropriate vaccine supplies, industry,
  government, and academia must collaborate

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Challenges that Remain

• Distributing vaccines to all that need them
• Developing vaccines for malaria, HIB, TB
• Ensuring vaccine safety
• Maintaining public confidence in vaccines
• Educating the new generation of scientists
• Educating a responsible public

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