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Appendix A
immunization Safety Review:
Measle s -Mump s -Rubella
Vaccine and Autism
Executive Summary
Immunization is widely regarded as one of the most effective and beneficial
tools for protecting the public's health. In the United States, immunization pro-
grams have resulted in the eradication of smallpox, the elimination of polio, and
the control and near elimination of once-common, often debilitating and poten-
tially life-threatening diseases, including measles, mumps, rubella, diphtheria,
pertussis, tetanus, and Haemophilus influence type b.
Along with the benefits of widespread immunization, however, have come
concerns about the safety of vaccines. No vaccine is perfectly safe or effective,
and vaccines may lead to serious adverse effects in some instances. Furthermore,
if a serious illness is observed after vaccination, it is often unclear whether that
sequence is coincidental or causal, and it can be difficult to determine the true na-
ture of the relationship, if any, between the vaccination and the illness.
Ironically, the successes of vaccine coverage in the United States have made
it more difficult for the public to weigh the benefits and complications of vac-
cines because the now-controlled diseases and their often-serious risks are no
longer familiar. However, because vaccines are so widely used and because
state laws require that children be vaccinated before entering daycare and
school, in part to protect others it is essential that safety concerns be fully and
carefully studied.
This report, the first of a series from the Institute of Medicine (IOM) Im-
munization Safety Review Committee, presents an assessment of the evidence
regarding a hypothesized causal association between the measles-mumps-rubella
(MMR) vaccine and autism, an assessment of the broader significance for soci-
95
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IMMUNIZATION SAFETY RE VIE W
ety of the issues surrounding the MMR-autism hypothesis, and the committee's
conclusions and recommendations based on those assessments.
OVERVIEW OF THE IMMUNIZATION SAFETY
REVIEW PROJECT
Since the mid-199Os, an increasing number of challenges to the safety of
vaccinations have gained attention in various settings. The Committee on Gov-
ernment Reform of the U.S. House of Representatives held seven hearings on
vaccine-safety issues during 1999-2000, and the media including news pro-
grams such as 60 Minutes, 20/20, and Nightline have covered these issues as
well. Also, many consumer and professional organizations have sponsored re-
lated conferences and scientific symposia, and the Internet is playing an in-
creasingly important communications role.
With these growing concerns about vaccine safety, the Centers for Disease
Control and Prevention (CDC) and the National Institutes of Health (NIH) rec-
ognized the need for an independent group to address safety concerns in a timely
and objective manner. In 1999, as a result of previous IOM work on vaccine
safety and the Institute's access to independent scientific experts, CDC and NIH
began a year of discussions with IOM to develop the Immunization Safety Re-
view project to address existing and emerging vaccine-safety concerns.
The Immunization Safety Review Committee, convened in the fall of 2000,
comprises 15 members with expertise in pediatrics, neurology, immunology,
internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk
perception and communication, decision analysis, public health, nursing, and
ethics. To preclude any reel or perceived conflicts of interest, committee mem-
bers were subject to strict selection criteria that excluded anyone who had finan-
cial ties to vaccine manufacturers or their parent companies, previous service on
vaccine advisory committees, or prior expert testimony or publications on issues
of vaccine safety.
The committee is charged with examining three vaccine-safety hypotheses
each year during the 3-year study period (2001-2003~. The Interagency Vaccine
Group (JAG) comprising officials from the National Vaccine Program Office at
the U.S. Department of Health and Human Services (DHHS), the National Im-
munization Program and the National Center for Infectious Diseases at the CDC,
the National Institute for Allergy and Infectious Diseases at the NIH, the De-
partment of Defense, the Food and Drug Administration, the National Vaccine
Injury Compensation Program at the Health Resources and Services Admini-
stration, the Health Care Financing Administration, and the Agency for Interna-
tional Development, will select the hypotheses to be examined by the commit-
tee. The committee's findings will be released to the public in a series of brief
consensus reports.
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APPENDIXA: MMR AND AUTISM
97
In contrast to previous IOM vaccine-safety studies (e.g. IOM, 1991, 1994a,b),
which limited their conclusions to causality assessments and recommendations on
future research directions, the Immunization Safety Review Committee has been
asked to assess not only the scientific plausibility of the hypothesized association
but also the significance of the issue in a broader societal context. The plausibility
assessment has two components: (1) an examination of the causal relationship
between the vaccine and the adverse event, and (2) an examination of any patho-
genic mechanisms that support the hypothesis. The significance assessment ad-
dresses such considerations as the burden of the adverse health event in question,
the burden of disease that the vaccine prevents, and the level and potential conse-
quences of public concern about the safety of vaccine use.
The findings of the plausibility and significance assessments provide the
basis for the committee's recommendations regarding public health response,
immunization policy review, current and future research, and effective com-
munication strategies for the specific immunization-safety questions.
The committee adopted the framework for assessing causality developed by
the committees previously convened by the IOM (IOM, 1991, 1994a) to address
questions of vaccine safety. To evaluate the hypothesis on MMR vaccine and
autism, the committee collected information from several sources, including a
review of the published, peer-reviewed scientific and medical literature, and
commissioned a background paper reviewing the epidemiological studies of
MMR vaccine and autism. The committee also held an open scientific meeting
in March 2001 (see Appendix B) to review the current understanding of the eti-
ology and epidemiology of autism and on-going investigations regarding the
MMR vaccine and autism hypothesis.
THE HYPOTHESIZED RELATIONSHIP
BETWEEN MMR AND AUTISM
Autism is a complex and severe developmental disorder characterized by
Impairments of social interaction, impairments in verbal and nonverbal commu-
nication, and restricted or repetitive and stereotyped patterns of behaviors and
interests (APA, 1994, Filipek et al., 1999~. Over time, research has identified
subtle differences in the onset and progression of autistic symptoms. The term
"autistic spectrum disorders" (ASD), synonymous with 'pervasive developmental
disorders" (PDD), refers to a continuum of related cognitive and neurobehavioral
disorders that reflects the heterogeneity of these symptoms. ASD includes autistic
disorder, childhood disintegrative disorder, Asperger's syndrome, Rett's syn-
drome, and pervasive developmental disorder not otherwise specified (PDD-NOS
or atypical autism). While the primary deficits are similar for all of these disor-
ders, patients vary in the severity of their symptoms and level of cognitive im-
pairment. Although Rett's syndrome is included in the diagnostic category of
ASD, it is considered by many to be a distinct neurologic disorder and this diag-
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IMMUNIZATION SAFETY RE VIE W
nosis is not included in most research which has evaluated the association of the
MMR vaccine with autism. In this report, the terms "autism," "autistic," and
"autistic spectrum disorders" are used interchangeably to refer to this broader
group of pervasive developmental disorders. The term "autistic disorder" refers to
a more narrow diagnosis defined by criteria in the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition (DSM-IV) (APA, 1994~.
Research has established a very strong genetic component in the etiology of
autism, but other factors, including infectious, neurologic, metabolic, immuno-
logic, and environmental insults, may play important roles. However, significant
gaps still remain in our understanding of the risk factors and etiologic mecha-
nisms of ASD.
Clinical descriptions of autism suggest two different types of presentation,
including early onset and regression, distinguished by the reported time-course
of the developmental abnormalities. Most cases of autism appear to be early
onset, resulting from prenatal or early postnatal insults (Bristol et al., 1996),
however, the diagnosis of early-onset cases is characteristically not made until
the second year of life, when symptoms become more pronounced. In a second
course, suggested in a minority of cases, apparently normal development is fol-
lowed by regression (or the sudden loss of previously established developmental
milestones), usually in the second year, which leaves open the possibility that
MMR vaccination precedes the onset of the disorder. However, there is no sci-
entifically established definition of regression.
Current attention to the possible relationship between MMR and ASD stems
primarily from a case series reported in 1998 (Wakefield et al., 1998~. Twelve
children with a history of normal development followed by loss of acquired
skills and gastrointestinal symptoms were referred to a London gastroenterology
clinic that was interested in the connection between measles virus and bowel
disease. For eight of these children, the onset of their behavioral problems was
associated, through retrospective accounts by their parents or physicians, with
MMR vaccination. The resulting report, and numerous other cases reported by
parents, have generated considerable interest and concern about a possible link
between MMR vaccination and ASD, and regressive autism in particular.
There are also more general concerns in the United States and the United
Kingdom that the introduction and wide-scale use of the MMR vaccine coincide
with an apparent increase in the occurrence of ASD. Information about the rates
of ASD in the United States and changes in incidence or prevalence is limited,
reflecting a lack of epidemiological research on ASD in this country. However,
a recent report by the California Department of Developmental Services (1999),
which shows a significant increase between 1987 and 1998 in its caseload of
children with ASD, is often cited as evidence of this increasing trend, although
the reported increases occurred well after the licensure and introduction of
MMR in the United States in 1971. Published studies of trends in ASD preva-
lence and incidence, in fact, have been unable to resolve how much of the ob-
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APPENDIXA: MMR AND AUTISM
99
served increase is real or due to other factors such as reporting bias, changes in
diagnostic criteria, or better case ascertainment over time (Fombonne, 1999,
2001 a, Gillberg and Wing, 1999~.
PLAUSIBILITY ASSESSMENT
The committee proceeded in order to answer the following question: What
is the causal relationship between MMR vaccine and ASD? The committee's
primary finding is that a number of epidemiological studies (both uncontrolled
and controlled) provide no support for an association on a population level be-
tween MMR immunization and ASD (Dales et al., 2001, Gillberg and Heijbel,
1998, Kaye et al., 2001, Patja et al., 2000, Peltola et al., 1998, Taylor et al.,
1999~. Findings from unpublished studies, which were shared with the commit-
tee publicly and through personal communications and which are in the process
of being submitted for publication (Fombonne, 2001b, Miller et al., 2001),
seemed to provide additional evidence of no association between MMR and
ASD, although the findings still need to be peer-reviewed, published, and sub-
jected to scrutiny by the broader scientific community.
Although these epidemiological studies do not support an association at a
population level, it is important to recognize the inherent methodological limita-
tions of such studies in establishing causality. Studies may not have sufficient pre-
cision to detect very rare occurrences on a population level. A poor understanding
of the risk factors and failure to use a standard case definition may also hamper the
ability of epidemiological studies to detect rare adverse events. In addition, since
MMR exposure is virtually universal in developed countries, elucidating any asso-
ciation with adverse outcomes requires the creative use of administrative and other
data sets and complex research designs. Furthermore, the rarity of the individual
autistic spectrum disorders and the difficulty in determining their exact onset, and
therefore the temporal relationship between onset and vaccination, make certain
epidemiological study designs (e.g., cohort studies) impractical.
Second, the committee concludes that the case series of children with ASD
and bowel symptoms (Wakefield et al., 1998) is uninformative with respect to
causality between MMR and ASD. The small number of cases, the potential
selection bias, the difficulty in diagnosing children with ASD, multiple diagno-
ses in the patients, and the lack of detail regarding the criteria for the behavioral
diagnoses of the children in the series limit the utility of this study in establish-
ing causality. Although parents or doctors made a temporal link between the
onset of their children's behavioral disorders and the MMR vaccine, the authors
of the resulting paper acknowledge that their findings do not prove an associa-
tion between MMR and the condition they describe. Furthermore, it is not possi-
ble to describe from this study the nature of any relationship among vaccine-
strain measles virus infection, ASD, and bowel symptoms. In addition, case re-
ports submitted to the Vaccine Adverse Event Reporting System, a national pas-
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IMMUNIZA TION SAFETY RE VIE W
save surveillance system in the United States, sometimes note a temporal asso-
ciation between MMR vaccination and the onset of symptoms, but these reports
vary substantially in their level of detail and supporting medical documentation.
The committee found them uninformative in assessing causality.
Third, the biologic model linking MMR and ASDis incomplete and frag-
mentary. Possible immunologic and metabolic mechanisms have been described
but have not been supported by validated and replicated controlled studies. While
some believe that disrupted viral immunity following administration of polyva-
lent vaccines could lead to atypical or persistent measles infection, possibly re-
sulting in ASD or bowel disease, there is no biological precedent or sufficient
evidence from existing research to support this scenario. Furthermore, with the
exception of the results from two groups (Kawashima 1996, 2000, Wakefield,
2001), there is no evidence to support persistent infection with vaccine-strain
measles virus except for individuals with compromised immunity. The groups'
findings, however, have not been adequately replicated and validated by con-
trolled studies. In the absence of such studies, the existence of persistent vaccine-
strain measles virus infection in ASD with bowel inflammation is uncertain.
Finally, there is no relevant animal model. The model based on Borna dis-
ease virus infection in rats may be useful for studying the induction of symp-
toms of ASD by insults, especially infectious, to brain development during the
prenatal and perinatal periods, but this model is not adequate for studying the
association between the MMR vaccine and the subsequent onset of ASD.Also,
primate models which are effective for the study of vaccine safety and immuno-
genicity or the neurobehavioral aspects of ASD do not adequately represent any
relationship between the MMR vaccine and ASD.
Thus, the committee concludes that the evidence favors rejection of a
causal relationship at the population level between MMR vaccine and autis-
tic spectrum disorders (ASD). The committee bases this conclusion on the
following evidence:
. A consistent body of epidemiological evidence shows no association at a
population level between MMR vaccine and ASD.
. The original case series of children with ASD and bowel symptoms and
other available case reports are uninformative with respect to causality.
Biologic models linking MMR vaccine and ASD are fragmentary.
There is no relevant animal model linking MMR vaccine and ASD.
However, the committee notes that its conclusion does not exclude the
possibility that MMR vaccine could contribute to ASD in a small number of
children, because the epidemiological evidence lacks the precision to assess
rare occurrences of a response to MMR vaccine leading to ASD and the
proposed biological models linking MMR vaccine to ASD, although far
from established, are nevertheless not disproved.
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APPENDIXA: MMR AND AUTISM
101
It is important to note that the committee evaluated the hypothetical asso-
ciation between MMR vaccine and ASD from a starting position of neutrality. A
shift from that position is possible only if sufficient evidence is available to con-
vince the committee that a causal association is either likely or unlikely.
SIGNIFICANCE ASSESSMENT
In its significance assessment, the committee considered the burden (i.e.,
the seriousness, risk, and treatability) of the vaccine-preventable diseases (mea-
sles, mumps, and rubella) and the potential adverse event (ASD), and the level
of public concern surrounding this issue. Measles, mumps, and rubella can lead
to significant morbidity and mortality, and treatment of these infectious diseases
and their associated complications is limited to symptomatic relief and physiol-
ogic support until the condition resolves.
Historically, concerns about the safety of vaccines have led to declines in
immunization coverage rates followed by outbreaks of disease, as observed with
pertussis in the United Kingdom during the 1970s. Similar outbreaks could eas-
ily occur were immunization rates to decline as a result of fears regarding MMR.
Yet, because MMR vaccine is a mandatory vaccine that is administered to
healthy children in part, as a public health measure to protect the health of
others the responsibility of the government to ensure the safety of this vaccine
is high, even if the adverse outcome is rare.
Thus, the significance of the hypothesized adverse event ASD, a group of
incurable and serious behavioral disorder requires consideration of all possible
etiologies. In addition, the level of public concern about MMR vaccine safety is
high.
RECOMMENDATIONS
Public Health Response
Although the committee has concluded that the evidence favors rejection of
the causal relationship at the population level between MMR vaccine and autis-
tic spectrum disorders, the committee nevertheless recommends that this is-
sue receive continued attention. It does so in recognition that its conclusion
does not exclude the possibility that MMR vaccine could contribute to ASD in a
small number of children, as well as the following factors: the identified limita-
tions of the evidence, the burden of ASD, the burden of the diseases prevented
by the vaccine, the immense concern of parents, and the prominence of the issue
in public debate.
Specific recommendations regarding policy review, research and surveil-
lance, and communication follow.
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IMMUNIZA TION SAFETY RE VIE W
Policy Review
. At this time, the committee does not recommend a policy review of the li-
censure of MMR vaccine or of the current schedule and recommendations for
administration of MMR vaccine.
Research Regarding MMR and ASD
The committee concludes that further research on the possible occurrence
of ASD in a small number of children subsequent to MMR vaccination is war-
ranted and has identified targeted research opportunities that could lead to a
clearer understanding of the relationship. The committee makes the following
research recommendations, recognizing that it has no basis for judging
whether the results of such research will alter the balance of evidence that led
to the committee's original conclusion:
.
Use accepted case definitions and assessment protocols for ASD to enhance
the precision and comparability of results from surveillance, epidemiological
studies, and biologic investigations.
Explore whether exposure to MMR vaccine is a risk factor for ASD in a
small number of children.
. Develop targeted investigation of whether or not measles vaccine-strain
virus is present in the intestines of some children with ASD.
Encourage all who submit reports to the Vaccine Adverse Event Reporting
System to provide as much detail and as much documentation as possible when
any diagnosis of ASD is thought to be related to MMR vaccine.
. Study the possible effects of different immunization exposures for exam-
ple, studying children whose families have chosen not to have them receive the
MMR vaccine.
. Conduct further clinical and epidemiological studies of sufficient rigor to
identify risk factors and biological markers of ASD in order to better understand
genetic or environmental causes.
.
Communications
The committee heard repeatedly in its open sessions and discussions with
parents and advocacy groups that obtaining unbiased and accurate information on
the possible relationship between MMR vaccine and ASD has been difficult. The
committee will address this issue more fully in the future. In the meantime, it
specifically recommends that government agencies and professional organi-
zations, CDC and the Food and Drug Administration (FDA) in particular,
review some of the most prominent forms of communication regarding the
hypothesized relationship between MMR vaccine and ASD, including infor-
mation they provide via the Internet and the ease with which Internet in-
formation can be accessed. They should especially be attentive to how commu-
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APPENDIXA: MMR AND AUTISM
103
nications are perceived and used by parents of children about to be immunized or
those who believe their child has been adversely affected by a vaccine. Direct
input from parents and other stakeholders would be invaluable in conducting a
systematic and effective evaluation of current communication tools.
General and Crosscutting Issues
In its discussion of recommendations related specifically to the MMR-ASD
question, the committee identified more general concerns that it could not ade-
quately or appropriately address in this report. These include deficiencies in the
available information on the risks and benefits of vaccines, inadequate discus-
sion on the ethics of providing information regarding the risks and benefits of
vaccinations, the role of public input into vaccine advisory committees, and in-
adequate clinical-provider information on vaccine safety or the Vaccine Adverse
Event Reporting System. The committee sees a need for a dialogue between
vaccine safety advocates of every kind, in order to come to common under-
standing of how to align the appropriate public health attention with a possibly
small vaccine safety risk. Finally, the committee did not have time to address
responsibly the appropriateness of alternative immunization schedules or prac-
tices, which might be requested in a clinical setting. These concerns will be
more completely considered in future reports. In the meantime, the committee
urges the CDC, FDA, NIH, American Academy of Pediatrics (AAP), and simi-
lar organizations to take to heart the serious concerns and earnest offers of help
on information exchange and communication from the members of the public
concerned about the safety of vaccines.
SUMMARY
The Immunization Safety Review Committee concludes that the evidence
favors rejection of a causal relationship at the population level between MMR
vaccine and ASD. However, this conclusion does not exclude the possibility that
MMR vaccine could contribute to ASD in a small number of children, because
the epidemiological evidence lacks the precision to assess rare occurrences of a
response to MMR vaccine leading to ASD and the proposed biological models
linking MMR vaccine to ASD, although far from established, are nevertheless
not disproved.
Because of the limitations of the evidence, the significant public concern
surrounding the issue, the risk of disease outbreaks if immunization rates fall,
and the seriousness of ASD, the committee recommends that continued attention
be given to this issue. Thus, the committee has provided targeted research and
communication recommendations. However, at this time, the committee does
not recommend a policy review of the licensure of MMR vaccine or of the cur-
rent schedule and recommendations regarding administration of MMR vaccine.
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Representative terms from entire chapter:
immunization safety
