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Summary
Congress passed the National Childhood Vaccine Injury Act (P.L. 99-660)
in 1986. The legislation was intended to bolster vaccine research and devel-
opment through federal coordination of vaccine efforts in government by
providing relief to vaccine manufacturers who reported at the time that
financial burdens from awards in the tort system threatened their financial
viability. The legislation was also intended to address concerns about the
safety of vaccines through a multipronged approach involving instituting
a compensation program financed by an excise tax on covered vaccines,
setting up a passive surveillance system for vaccine adverse events, and
providing information to consumers.
Sections 312 and 313 of the legislation required the secretary of the
U.S. Department of Health and Human Services to consult with the Institute
of Medicine (IOM) to conduct a review of the scientific literature related
to a set of serious adverse events1 following immunizations recommended
for use in children. Two reports were issued (IOM, 1991, 1994). These
reports contain a framework for causality assessment of adverse events
following vaccination. The reports embraced all vaccines covered by the
National Vaccine Injury Compensation Program (VICP) up to that point:
diphtheria- and tetanus-toxoids and whole cell pertussis (DTwP) vaccine2
and other tetanus toxoid–containing vaccines; measles, mumps, and rubella
1 Adverse events are distinguished from adverse effects in that an event is something that
occurs but may not be causally associated, whereas an adverse effect implies causation. All
adverse effects are adverse events, but not all adverse events are adverse effects.
2 Acellular pertussis vaccine (aP) has replaced whole cell pertussis vaccine in the United States.
1
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2 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
(MMR) vaccines; Haemophilus influenzae type B vaccine; hepatitis B vac-
cine; and both inactivated and oral polio vaccines.3 The reports informed
the secretary’s review of the Vaccine Injury Table. The reports have also
been referenced extensively as a source of definitive scientific understanding
of the evidence by Special Masters in decisions regarding injuries not listed
on the Vaccine Injury Table.
The IOM was subsequently asked to review specific vaccine safety
concerns in a series of reports requested by the Centers for Disease Control
and Prevention (CDC). These reports (IOM, 2001a,b, 2002a,b, 2003a,b,
2004a,b) included causality assessments similar to the previous IOM re-
ports, but included other conclusions and recommendations regarding re-
search, communications, and policy review.
CHARGE TO THE COMMITTEE
In 2009 the IOM entered into a contract with the Health Resources
and Services Administration (HRSA)4 to convene a committee of experts
to review the epidemiologic, clinical, and biological evidence regarding ad-
verse health events associated with specific vaccines covered by the VICP.
The committee was composed of individuals with expertise in pediatrics,
internal medicine, neurology, immunology, immunotoxicology, neurobiol-
ogy, rheumatology, epidemiology, biostatistics, and law.
The vaccines to be reviewed included varicella zoster vaccine; influ-
enza vaccines;5 hepatitis B vaccine; human papillomavirus vaccine (HPV);
tetanus toxoid–containing vaccines other than those containing the whole
cell pertussis component; measles, mumps, and rubella vaccines; hepatitis
A vaccine; and meningococcal vaccines. It is expected that the report will
provide the scientific basis for review and adjudication of claims of vaccine
injury by the VICP.
HRSA presented a list of specific adverse events for the committee
to review (see Table S-1). The selection criteria was described at the first
committee meeting (Johann-Liang, 2009) as including the vast majority of
adverse events in the claims for compensation. The committee added ad-
verse events to the list if it identified epidemiologic studies or case reports
for an adverse event not originally assigned by HRSA. These additions were
all-cause mortality and seizures following influenza vaccine; optic neuritis
3 Vaccines are included in the VICP if they are recommended by the CDC for routine ad-
ministration in children and are subject to an excise tax. Adults who experience an adverse
reaction to one of these “childhood” vaccines are also covered by the program.
4 The CDC and the National Vaccine Program Office also provided funds for the project via
the contract with HRSA.
5 The 2009 H1N1 influenza vaccine is covered by the Countermeasures Injury Compensation
Program, and evidence about its safety is not covered in this report.
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TABLE S-1 Adverse Events and Causality Conclusions Included in the Vaccine Chapters
DT–, TT–,
and aP– Injection-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
Disseminated Oka VZV CS
without Other Organ
Involvement
Disseminated Oka VZV CSa
with Subsequent Infection
Resulting in Pneumonia,
Meningitis, or Hepatitis
Vaccine Strain Viral CS
Reactivation without Other
Organ Involvement
Vaccine Strain Viral CS
Reactivation with
Subsequent Infection
Resulting in Meningitis or
Encephalitis
Measles Inclusion Body CSa,b
Encephalitis
Encephalitis I I I I I
Encephalopathy I I I I I I
Infantile Spasms I
3
continued
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4
TABLE S-1 Continued
DT–, TT–,
and aP– Injection-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
Febrile Seizures CS
Afebrile Seizures I
Seizures I Ic I I
Meningitis Ic
Cerebellar Ataxia I
Ataxia I I
Autism FR I
Acute Disseminated I I I I I I I I
Encephalomyelitis
Transverse Myelitis I I I I I I I I
Optic Neuritis Ic Ic Ic Ic
Neuromyelitis Optica Ic I I I
Multiple Sclerosis Onset in I I I I
Adults
Multiple Sclerosis Onset in I I
Children
Multiple Sclerosis Relapse I I I
in Adults
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Multiple Sclerosis Relapse I I
in Children
Multiple Sclerosis I I I
First Demyelinating Event I
in Adults
First Demyelinating Event I
in Children
Guillain-Barré Syndrome I I I I I I I I
Chronic Inflammatory I I I I I I I
Disseminated
Polyneuropathy
Opsoclonus Myoclonus I I
Syndrome
Bell’s Palsy FR I I
Brachial Neuritis I I I I
Amyotrophic Lateral I
Sclerosis
Small Fiber Neuropathy Ic I
Anaphylaxis CS CS CS I CSd FA CSe CS
Chronic Urticaria I
Serum Sickness I
5
continued
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6
TABLE S-1 Continued
DT–, TT–,
and aP– Injection-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
Inactivated Influenza FR
Vaccine and Asthma
Exacerbation or Reactive
Airway Disease Episodes in
Children and Adults
Live Attenuated Influenza I
Vaccine and Asthma
Exacerbation or Reactive
Airway Disease Episodes in
Children Younger Than 5
Years of Age
Live Attenuated Influenza I
Vaccine and Asthma
Exacerbation or Reactive
Airway Disease Episodes
in Persons 5 Years of Age
or Older
Erythema Nodosum Ic
Systemic Lupus I I
Erythematosus
Vasculitis I I
Polyarteritis Nodosa I I
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Psoriatic Arthritis I
Reactive Arthritis I
Rheumatoid Arthritis I
Juvenile Idiopathic I
Arthritis
Transient Arthralgia in FAf
Women
Transient Arthralgia in FA
Children
Transient Arthralgia I
Chronic Arthralgia in I
Women
Chronic Arthritis in I
Women
Chronic Arthropathy in I
Children
Arthropathy in Men I
Arthropathy I I I
Type 1 Diabetes FR I FR
Autoimmune Hepatitis I
Myocarditis I
Pancreatitis I
7
continued
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8
TABLE S-1 Continued
DT–, TT–,
and aP– Injection-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
Hepatitis I
Thromboembolic Events I
Stroke Ic I
Hypercoagulable States I
Myocardial Infarction I
Chronic Fatigue Syndrome I
Chronic Headache I
Fibromyalgia I I I I
Sudden Infant Death I
Syndrome
Hearing Loss I
All Cause Mortality Ic
Oculorespiratory Syndrome FAg
Thrombocytopenia I
Immune Thrombocytopenic I
Purpura
Complex Regional Pain I
Syndrome
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Deltoid Bursitis CS
Syncope CS
NOTE: CS = convincingly supports a causal relationship; FA = favors acceptance of a causal relationship; FR = favors rejection of a causal relation-
ship; I = inadequate to accept or reject a causal relationship.
a The committee attributes causation to individuals with demonstrated immunodeficiencies.
b The committee attributes causation to the measles component of the vaccine.
c Although not originally charged to the committee by the sponsor, the committee considered this adverse event in its review of the literature.
d The committee attributes causation to yeast-sensitive individuals.
e The committee attributes causation to the tetanus toxoid vaccine. The evidence is inadequate to accept or reject a causal relationship between
anaphylaxis and diphtheria toxoid or acellular pertussis vaccine.
f The committee attributes causation to the rubella component of the vaccine.
g The committee attributes causation to two particular vaccines used in three particular years in Canada.
9
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10 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
following MMR, influenza, hepatitis B, and DTaP vaccines; neuromyelitis
optica and meningitis following MMR vaccine; erythema nodosum follow-
ing hepatitis B vaccine; and stroke and small fiber neuropathy following
varicella vaccine.
It is important to note that the committee was not tasked with assess-
ing the benefits (effectiveness) of vaccines or any policy issues related to
vaccination. The committee’s task is focused only on an assessment of the
risk of vaccines.
ASSESSING THE WEIGHT OF EVIDENCE
Two streams of evidence support the committee’s causality conclusions:
epidemiologic evidence derived from studies of populations (most often
based on observational designs but randomized trials when available), and
mechanistic evidence derived primarily from biological and clinical studies
in animals and individual humans (see Figure S-1). Some studies provide
evidence capable of addressing both epidemiologic and mechanistic ques-
tions. Drawing from both sources of evidence to support causal inference
is well established in the literature.
The committee made three assessments for each relationship reviewed.
The first assessment applies to the weight of evidence from the epide-
miologic literature; the second applies to the weight of evidence from the
mechanistic literature. Each individual article (or findings within an article
if more than one outcome or vaccine was studied) was evaluated for its
strengths and weaknesses. The committee then synthesized the body of evi-
dence of each type (epidemiologic or mechanistic) and assigned a “weight-
of-evidence” for each. These weights-of-evidence represent the committee’s
assessment of the quality and quantity of evidence. The two weight-of-
evidence assessments contributed to the third assessment, a conclusion
about the causal relationship.
Weight of Epidemiologic Evidence
Each peer-reviewed epidemiologic study was evaluated for its methodo-
logic limitations (e.g., flawed measurement of either vaccine administration
or adverse event, or failure to adequately control confounding variables)
and for the precision of the reported results (e.g., the width of the 95%
confidence interval around an effect estimate, reflecting the statistical power
to detect a significantly increased risk of an adverse event). A specific study
involving multiple outcomes or vaccines could have fewer limitations for
the analysis of some vaccines or some outcomes than for others. Small clini-
cal studies can be well conducted but the low number of subjects may limit
the ability to detect most adverse events. Although most efficacy studies
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ORIGINAL RESEARCH IN HUMANS OTHER LITERATURE
Controlled Uncontrolled Reviews of
Animal and
Observational Studies and Clinical Studies and Case Reports Consequences of the
In Vitro Studies
Randomized Trials Surveillance Studies Natural Infection
Included studies Excluded reports Included reports
Excluded studies Excluded studies with case descriptions that did not meet with case descriptions
with very serious with very serious that met minimum minimum attribution that met minimum
limitations from limitations from attribution elements elements for attribution elements
the Epidemiologic the Epidemiologic in the Mechanistic Mechanistic in the Mechanistic
Evidence Evidence Evidence Evidence Evidence
Studies Included in the Studies Included in the
Weight of Epidemiologic Evidence Weight of Mechanistic Evidence
High Moderate
Strong Intermediate Weak Lacking
Limited
(increased or (increased or
null/decreased) null/decreased)
CAUSALITY CONCLUSION
11
FIGURE S-1 Epidemiologic and mechanistic evidence reviewed by the committee.
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16
EPIDEMIOLOGIC ASSESSMENT MECHANISTIC ASSESSMENT CAUSALITY CONCLUSION
Inadequate
Low-
High Moderate Favors Favors Convincingly
Inter- to Accept
Inter-
(decreased risk (decreased risk
High Moderate
(increased risk) (increased risk) Limited Strong Rejection Acceptance Supports
mediate Weak Lacking or Reject
mediate
High
(increased risk)
Convincingly
Supports
Strong
Moderate
(increased risk)
Favors
Acceptance
Inter-
mediate
High Favors
(decreased risk
Rejection
*
Moderate ,
Inadequate
to Accept
or Reject
Low-Intermediate,
Weak, or Lacking***
* Causality conclusion is favors rejection only if mechanistic assessment is not strong or intermediate.
** Causality conclusion is inadequate to accept or reject only if mechanistic assessment is not strong or intermediate.
*** Causality conclusion is inadequate to accept or reject only if epidemiologic assessment is not
FIGURE S-2 Strength of evidence that determined the causality conclusions.
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17
SUMMARY
health. The focus of this particular committee is only on the question of
what particular vaccines can cause particular adverse effects.
The framework also had to accommodate known strengths and limi-
tations of both types of evidence. Mechanistic evidence can only support
causation, but epidemiologic evidence can support a causal association
or can support the absence of (“rejection of”) a causal association in the
general population. Mechanistic evidence, particularly that emerging from
case reports, occasionally provides compelling evidence of an association
between exposure to a vaccine and an adverse event in the individual be-
ing studied, but it provides no meaningful information about the risk to
the population. Epidemiologic analyses are usually unable to detect an in-
creased or decreased risk that is small, unless the study population is very
large or the between-group (e.g., vaccinated vs. unvaccinated) difference in
risk is very high (e.g., smoking increases the risk of lung cancer by at least
10-fold). Epidemiologic analyses also cannot identify with certainty which
individual in a population at risk will develop the condition.
The committee does not consider a single epidemiologic study—regard-
less of how well it is designed, the size of the estimated effect, or the nar-
rowness of the confidence interval—sufficient to merit a weight of “high”
or, in the absence of strong or intermediate mechanistic evidence, sufficient
evidence to support a causality conclusion other than “inadequate to ac-
cept or reject a causal relationship.” This requirement might seem overly
rigorous to some readers. However, the Agency for Healthcare Research
and Quality advises the Evidence-based Practice Centers that it has funded
to produce evidence reports on important issues in health care to view an
evidence base of a single study with caution (Owens et al., 2010). It does so
due to the inability to judge consistency of results, an important contribu-
tor to a strength of evidence, because one cannot “be certain that a single
trial, no matter how large or well designed, presents the definitive picture of
any particular clinical benefit or harm for a given treatment” (Owens et al.,
2010). It is acknowledged by the committee and others (Owens et al., 2010)
that policy makers must often make decisions based on only one study.
However, the committee is not recommending policy, rather evaluating the
evidence using a transparent and justifiable framework.
CAUSALITY CONCLUSIONS
Convincingly Supports
The framework allows for a causality conclusion of “convincingly sup-
ports” based on an epidemiologic weight-of-evidence assessment of high in
the direction of increased risk (which requires at least two well-conducted
epidemiologic studies). Strong mechanistic evidence, which requires at least
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18 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
one case report in which compelling evidence exists that the vaccine indeed
did cause the adverse event, always carries sufficient weight for the com-
mittee to conclude the evidence convincingly supports a causal relationship.
The committee considered the detection of laboratory-confirmed, vaccine-
strain virus compelling evidence to attribute the disease to the vaccine-strain
virus and not other etiologies. This conclusion can be reached even if the
epidemiologic evidence is rated high in the direction of no increased risk
or even decreased risk.
The simplest explanation in this circumstance is that the adverse effect
is real but also very rare. Stating this another way, if the vaccine did cause
the adverse effect in one person, then it can cause the adverse effect in
someone else; however, the isolated report of one convincing case provides
no information about the risk of the adverse effect in the total population
of vaccinated individuals compared with unvaccinated individuals.
The committee concluded the evidence convincingly supports 14 spe-
cific vaccine–adverse event relationships. In all but one of these relation-
ships, the conclusion was based on strong mechanistic evidence with the
epidemiologic evidence rated as either limited confidence or insufficient.
The convincing evidence regarding varicella vaccine and disseminated Oka
varicella zoster virus (VZV) and Oka VZV viral reactivation depended on
identification of vaccine-strain virus as documented by polymerase chain
reaction, as was the evidence regarding MMR vaccine and measles inclu-
sion body encephalitis. Epidemiologic evidence, as well as mechanistic
evidence, convincingly supported the causal relationship between MMR
vaccine and febrile seizures. Clinical evidence from case reports and a well-
identified mechanism of hypersensitivity reactions convincingly supported
the conclusions regarding anaphylaxis and six vaccines (MMR, varicella,
influenza, hepatitis B, meningococcal, and tetanus toxoid vaccine). Mecha-
nistic evidence provided the convincing support for the conclusion that
injection of vaccine, independent of the antigen involved, can lead to two
adverse events: syncope and deltoid bursitis (see Table S-2).
Favors Acceptance
A conclusion of “favors acceptance of a causal relationship” must be
supported by either epidemiologic evidence of moderate certainty of an
increased risk or by mechanistic evidence of intermediate weight. The com-
mittee concluded the evidence favors acceptance of four specific vaccine–
adverse event relationships. These include HPV vaccine and anaphylaxis,
MMR vaccine and transient arthralgia in female adults, MMR vaccine and
transient arthralgia in children, and certain trivalent influenza vaccines used
in Canada and a mild and temporary oculorespiratory syndrome. The con-
clusion regarding anaphylaxis was supported by only mechanistic evidence.
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TABLE S-2 Summary of Causality Conclusionsa
Studies Cases
Contributing Contributing
to the to the
Epidemiologic Epidemiologic Mechanistic Mechanistic Causality
Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
b
5 Varicella Disseminated Oka Insufficient None Strong – Convincingly
VZV without Other Supports
Organ Involvement
5 Varicella Disseminated Oka Limited (subsequent 1 Strong 9 Convincingly
VZV with Subsequent infection resulting in (in individuals Supportsc
Infection Resulting pneumonia) with demonstrated
in Pneumonia, immuno-
Insufficient (subsequent None
Meningitis, or deficiencies)
infection resulting in
Hepatitis
meningitis or hepatitis)
b
5 Varicella Vaccine Strain Insufficient None Strong – Convincingly
Viral Reactivation Supports
without Other Organ
Involvement
5 Varicella Vaccine Strain Viral Limited (subsequent 1 Strong 6 Convincingly
Reactivation with infection resulting in Supports
Subsequent Infection encephalitis)
Resulting in Meningitis
Insufficient (subsequent None
or Encephalitis
infection resulting in
meningitis)
19
continued
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TABLE S-2 Continued
20
Studies Cases
Contributing Contributing
to the to the
Epidemiologic Epidemiologic Mechanistic Mechanistic Causality
Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
4 MMR Measles Inclusion Insufficient None Strong 1 Convincingly
Body Encephalitis (measles; in Supportsc,d
individuals with
demonstrated
immunodeficiencies)
Lacking None
(mumps or rubella)
4 MMR Febrile Seizures High (increase) 7 Intermediate 12 Convincingly
Supports
4 MMR Anaphylaxis Insufficient None Strong 43e Convincingly
Supports
5 Varicella Anaphylaxis Limited 1 Strong 76f Convincingly
Supports
6 Influenza Anaphylaxis Limited 1 Strong 22 Convincingly
Supports
8 Hepatitis B Anaphylaxis Insufficient None Strong 10 Convincingly
(in yeast-sensitive Supportsg
individuals)
10 Tetanus Anaphylaxis Insufficient None Strong 6 Convincingly
Toxoid Supports
11 Meningococcal Anaphylaxis Insufficient None Strong 1 Convincingly
Supports
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12 Injection- Deltoid Bursitis Limited 1 Strong 16 Convincingly
Related Event Supports
12 Injection- Syncope Insufficient None Strong 35h Convincingly
Related Event Supports
9 HPV Anaphylaxis Insufficient None Intermediate 36 Favors
Acceptance
4 MMR Transient Arthralgia in Moderate (increase) 4 Intermediate 13 Favors
Women (rubella) (rubella) Acceptancei
Insufficient None Lacking None
(measles or mumps) (measles or mumps)
4 MMR Transient Arthralgia in Moderate (increase) 7 Weak None Favors
Children (rubella) Acceptance
Lacking None
(measles or mumps)
j
6 Influenza Oculorespiratory Moderate (increase) 3 Intermediate – Favors
Syndrome Acceptancek
4 MMR Autism High (null) 4 Lacking None Favors
Rejection
6 Influenza Inactivated Influenza High (null) 2 Lacking None Favors
Vaccine and Bell’s Rejection
palsy
21
continued
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TABLE S-2 Continued
22
Studies Cases
Contributing Contributing
to the to the
Epidemiologic Epidemiologic Mechanistic Mechanistic Causality
Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
6 Influenza Inactivated Influenza High (null) 9 Weak 6 Favors
Vaccine and Asthma Rejection
Exacerbation or
Reactive Airway
Disease Episodes in
Children and Adults
4 MMR Type 1 Diabetes High (null) 5 Lacking None Favors
Rejection
10 DT, TT, or aP Type 1 Diabetes High (null) 5 Lacking None Favors
containing Rejection
a All other causality conclusions are the evidence is inadequate to accept or reject a causal relationship.
b Due to the use of the same surveillance systems in some publications it is likely that some of the cases were presented more than once; thus, it
is difficult to determine the number of unique cases.
c The committee attributes causation to individuals with demonstrated immunodeficiencies.
d The committee attributes causation to the measles component of the vaccine.
e Some cases were from passive surveillance systems; however, it is not possible to know how many represent unique cases or were reported
elsewhere.
f In addition, at least 30 cases were reported to passive surveillance systems; however, it is not possible to know how many represent unique cases
or were reported elsewhere.
g The committee attributes causation to yeast-sensitive individuals.
h In addition, hundreds of cases have been reported to passive surveillance systems; however, it is not possible to known how many represent
unique cases or were reported elsewhere.
i The committee attributes causation to the rubella component of the vaccine.
j Due to the use of the same sample population in some studies it is likely that some of the cases were presented in more than one publication;
thus, it is difficult to determine the number of unique cases.
kThe committee attributes causation to two particular vaccines used in three particular years in Canada.
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23
SUMMARY
The other conclusions were supported by both epidemiologic evidence and
by mechanistic evidence (see Table S-2).
Favors Rejection
The framework allows the committee to “favor rejection” of a causal
relationship only in the face of epidemiologic evidence rated as high or
moderate in the direction of no effect (the null) or of decreased risk and
in the absence of strong or intermediate mechanistic evidence in support
of a causal relationship. The committee concluded the evidence favors
rejection of five vaccine–adverse event relationships. These include MMR
vaccine and type 1 diabetes, diphtheria, tetanus, and pertussis (DTaP) vac-
cine and type 1 diabetes, MMR vaccine and autism, inactivated influenza
vaccine and asthma exacerbation or reactive airway disease episodes, and
inactivated influenza vaccine and Bell’s palsy. The evidence base for these
conclusions consisted of epidemiologic studies reporting no increased risk;
this evidence was not countered by mechanistic evidence (see Table S-2).
Inadequate to Accept or Reject
The committee identified two main pathways by which it concludes
that the evidence is “inadequate to accept or reject” a causal relationship.
The most common pathway to this conclusion occurs when the epidemio-
logic evidence was of limited certainty or insufficient and the mechanistic
evidence was weak or lacking. Another pathway occurs when the epidemio-
logic evidence is of moderate certainty of no effect but the mechanistic evi-
dence is intermediate in support of an association. The committee analyzed
these sets of apparently contradictory evidence and ultimately depended
upon their expert judgment in deciding if a conclusion to favor acceptance
based on the intermediate mechanistic data was warranted, or if the con-
clusion remained as “inadequate to accept or reject” a causal relationship.
The vast majority of causality conclusions in the report are that the
evidence was inadequate to accept or reject a causal relationship. Some
might interpret that to mean either of the following statements:
• Because the committee did not find convincing evidence that the
vaccine does cause the adverse event, the vaccine is safe.
• Because the committee did not find convincing evidence that the
vaccine does not cause the adverse event, the vaccine is unsafe.
Neither of these interpretations is correct. “Inadequate to accept or
reject” means just that—inadequate. If there is evidence in either direction
that is suggestive but not sufficiently strong about the causal relationship, it
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24 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
will be reflected in the weight-of-evidence assessments of the epidemiologic
or the mechanistic data. However suggestive those assessments might be,
in the end the committee concluded that the evidence was inadequate to
accept or reject a causal association.
A list of all conclusions, including the weights of evidence for both
the epidemiologic evidence and the mechanistic evidence, can be found in
Appendix D.
SUSCEPTIBILITY
The literature supporting several of the causality conclusions discussed
in the previous section indicates that individuals with certain characteristics
are more likely to suffer adverse effects from particular immunizations.
Individuals with an acquired or genetic immunodeficiency are clearly recog-
nized as at increased risk for specific adverse reactions to live viral vaccines
such as MMR and varicella vaccine. Age is also a risk factor; seizures after
immunization, for example, are more likely to occur in young children.
Thus, the committee was able at times to reach more limited conclusions
that did not generalize to the entire population.
CONCLUDING COMMENT
Committee members spent an enormous amount of time reading thou-
sands of articles. The committee makes 158 causality conclusions in this
report. It tried to apply consistent standards when reviewing individual
articles and when assessing the bodies of evidence. Some of the conclusions
were easy to reach; the evidence was clear and consistent or, in the extreme,
completely absent. Some conclusions required substantial discussion and
debate. Inevitably, there are elements of expert clinical and scientific judg-
ment involved.
The committee used the best evidence available at the time. The com-
mittee hopes that the report is sufficiently transparent such that when new
information emerges from either the clinic or the laboratory, others will be
able to assess the importance of that new information within the approach
and set of conclusions presented in this report.
REFERENCES
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of the committee to review the adverse consequences of pertussis and rubella vaccines.
Washington, DC: National Academy Press.
IOM. 1994. Adverse events associated with childhood vaccines: Evidence bearing on causality.
Washington, DC: National Academy Press.
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25
SUMMARY
IOM. 2001a. Immunization safety review: Measles-mumps-rubella vaccine and autism.
Washington, DC: National Academy Press.
IOM. 2001b. Immunization safety review: Thimerosal-containing vaccines and neuro-
developmental disorders. Washington, DC: National Academy Press.
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