Immunization Safety Review: An Update

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Immunization Safety ReviewAn Update

• National Immunization Conference
• March 17, 2003
• Kathleen Stratton

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Process

• 14 member committee
• Meets three times per year to discuss a specific
  safety concern
• Issues report on each topic approximately 60-90
  days after holding public workshop
• Funded by CDC and NIH
• Topics chosen by Inter-agency Group on Vaccines

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Reports

• Measles-mumps-rubella vaccine and autism
• Thimerosal-containing vaccine and
  neurodevelopmental disorders
• Multiple immunizations and immune dysfunction
• Hepatitis B vaccine and demyelinating
  neurological disorders
• SV40 contamination of polio vaccine and cancer
• Sudden unexpected death in infancy and vaccines
• Influenza vaccines and neurological disorders

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Why are some people worried?

• VAPP and OPV
• Rotavirus and intussecption
• Swine Flu and Guillain-Barre syndrome
• High Fevers (febrile seizures)
• Hypotonic-Hyporesponsive Episodes
• DTwP and acute encephalopathy
• Mumps meningitis (not used in US)
• Smallpox vaccine
• Studies for licensure are not large enough to
  detect rare events

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What will some people never stop worrying about?

• SIDS
• Autism
• Multi-symptom neuro-immunologic dysfunction

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What drives some concerns?

• Themes from media coverage in Australia
• Cover-up
• Excavation of the facts
• Unholy alliance for profit
• Towards totalitarianism
• Us versus Them
• Vaccines as poisonous chemical cocktails
• Vaccines as cause of idiopathic ills
• Back to nature (from Leask and Chapman,
  2000)

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Policy Analysis And Review
Research
Communications
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Reviewing Causality Evidence

• Evidence favors rejection of a causal
  relationship
• Evidence is inadequate to accept or reject a
  causal relationship
• Evidence favors acceptance of a causal
  relationship
• Evidence establishes a causal relationship

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Causality Evidence

• Blinded, controlled studies of safety are rare
• The numbers of subjects are often small
• Case reports are rarely useful but get inordinate
  attention via VAERS analyses
• Published data weighs more heavily
• Ecological analyses are easy but frustrating
• Administrative data are useful but not perfect
• Quality can easily outweigh quantity
• Schedule is complicated and growing
• When is enough, enough?

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Use of Biological Evidence Review

• Strengthen epidemiological understanding
• Raise questions re epidemiological understanding
• Is an open question worth keeping open? Can it be
  put to rest?
• Research agenda
• Use in the courts.

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Changing terminology

• MMR fragmentary
• Thimerosal biologically plausible
• All others strength of the evidence that
  biological mechanisms are operative

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Three Categories of EvidenceBiological Mechanisms

• Theoretical only
• Experimental evidence (in vitro, in vivo animal,
  humans)
• Weak,
• Moderate,
• Strong

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Theoretical only

• A reasonable mechanism can be hypothesized that
  is commensurate with scientific knowledge and
  that does not contradict known physical and
  biological principles, but it has not been
  demonstrated in humans or animal models.

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Experimental evidence

• Evidence can be derived under highly contrived
  conditions.
• Other experimental evidence is derived under less
  contrived conditions.
• Experience in humans with other vaccines or with
  wild-type disease is consistent

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Conclusions HBVx and MS

• The evidence favors rejection of a causal
  relationship between HB vaccine and incident and
  relapse MS in adults (despite the few numbers of
  studies).
• Cannot extend the conclusion to children.
• Evidence for all other C/PNS conditions was
  inadequate to accept or reject causality
• Biological evidence is (very?) weak

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Conclusions SV40-contaminated polio vaccine
and cancer

• The evidence is inadequate to accept or reject a
  causal association between SV40-contaminated
  polio vaccine and cancer
• DESPITE
• A large number of negative studies
• Strong association between SV40 presence and
  human cancers
• Definite contamination definite transforming
  properties

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Conclusions Vaccines And SUDI

• The evidence favors rejection of a causal
  relationship between DTwP and SIDS (and probably
  DTaP?)
• The evidence favors acceptance of a causal
  relationship between DwP and fatal anaphylaxis
• The evidence is inadequate.HBVx and neonatal
  death, other Vx and SIDS, Vx and SUDI
• Biological mechanisms (other than anaphylaxis)
  are theoretical only

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Summary of Causality Conclusions
Favors rejection Inadequate Favors acceptance
MMR ASD X
TMS NDD X
Multiple Allergy X
Autoimmune infection X
HBVx MS (incident relapse) X
Other C/PNS X
SV40-IPV Cancer X
D-wP Fatal anaphylaxis X
DTwP(aP) SIDS X
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Summary of Evidence Causality
Uncontrolled studies Controlled studies Causality
MMR ASD 2 5 FR
TMS NDD 1 (unpub.) I
Multiple Allergy 1 5 I
Autoimmune infection 3 -- 5 6 FR
HBVx MS (incident relapse) 3 1 FR
Other C/PNS 1 p 4 un-p (CDD) I
SV40-IPV Cancer 8 4 I
D-wP Fatal anaphylaxis 2 infants FA
Infant Vx SIDS (DTP others) FR I
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Causality x Biological Categories
Inadequate to Accept/Reject Favors Rejection Favors Acceptance Establishes
Theoretical SUDI and Vx HBVx and neonatal death MMR ASD (fragmentary?) SIDS and DTwP (DTaP)
Weak Mult Imm Allergic Disease (Asthma) Hep B 1st episode CNS DD, ADEM, ON, TM, GBS, and BN. Thimerosal and autism and other NDD, (plausible?) Mult Imm Autoimmune disease (Diabetes) Hep B MS (incident and relapse)
Moderate SV40 (exposure could lead to cancer in humans under natural conditions and is related to SV40 infection in humans)
Strong SV40 (is a transforming virus) Mult Imm Heterologous Infection Fatal anaphylaxis from DwP e.g. OPV and VAPP
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Policy Analysis and Review Recommendations
Report Recommendation
Thimerosal Review assessment of how public health policy decisions are made under uncertainty
Thimerosal Review of the strategies used to communicate rapid changes in Vx policy, recommends research on how to improve those strategies.
Multiple Immunizations More explicit strategy for developing recommendations for the use of vaccines.
SV40 Develop a Vaccine Contamination Prevention and Response Plan.
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Unanswered Questions

• Are there idiosyncratic effects in individuals?
• Are there very small effects in population?
• Can/should you study effects on ill-defined
  physical symptoms?
• What is the role of genetic factors?
• What will it take to stop the anger?
• Will this ever end? Will it ever get resolved?

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Immunization Safety Review Committee

• WWW.IOM.EDU\ImSafety
• ImSafety_at_nas.edu
• 202/334-1342