Immunization Safety Review:An Update

National Immunization ConferenceMarch 17, 2003

Kathleen Stratton

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

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

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

What will some people never stop worrying about?

• SIDS

• Autism

• Multi-symptom “neuro-immunologic” dysfunction

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)

Policy AnalysisAnd Review

Research Communications

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

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?

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….

Changing terminology

MMR: fragmentary

Thimerosal: biologically plausible

All others: strength of the evidence that biological mechanisms are operative

Three Categories of EvidenceBiological Mechanisms

• Theoretical only • Experimental evidence (in vitro, in vivo

animal, humans)Weak, Moderate, Strong

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.

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

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

Conclusions SV40-contaminated polio vaccine and

cancerThe 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

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

Summary of Causality ConclusionsFavors rejection

Inadequate Favors acceptance

MMR ASD XTMS NDD XMultiple Allergy X

Autoimmune; infection XHBVx MS (incident; relapse) X

Other C/PNS XSV40-IPV Cancer XD-wP Fatal anaphylaxis XDTwP(aP) SIDS X

Summary of Evidence: CausalityUncontrolled studies

Controlled studies

Causality

MMR ASD 2 5 FRTMS NDD 1 (unpub.) IMultiple Allergy 1 5 I

Autoimmune; infection 3; -- 5; 6 FRHBVx MS (incident; relapse) 3; 1 FR

Other C/PNS 1 p; 4 un-p (CDD) I

SV40-IPV Cancer 8 4 ID-wP Fatal anaphylaxis 2 infants FAInfant Vx SIDS (DTP; others) FR; I

Causality x Biological Categories Inadequate to Accept/Reject Favors Rejection Favors

AcceptanceEstablishes

Theoretical SUDI and VxHBVx 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]

Policy Analysis and Review Recommendations

Report RecommendationThimerosal Review & assessment of how public health policy

decisions are made under uncertaintyReview 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.

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?

Immunization Safety Review Committee

WWW.IOM.EDU\ImSafety

ImSafety@nas.edu

202/334-1342