Immunization Safety Review Measles-Mumps-Rubella Vaccine and Autism (2001) / Chapter Skim
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Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism
Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism
Pages 13-70
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From page 13... ...
However, because vaccines are so widely used and because state laws require Hat 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 Tom the Immunization Safety Review Committee, presents an assessment of He evidence regarding a hypothesized causal association between the measles-mumps-rubella (MMR)
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From page 14... ...
This legislation mandated the establishment of a National Vaccine Injury Compensation Program to handle related claims, and of the Vaccine Adverse Event Reporting System (VAERS) , which is a national passive surveillance system.
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From page 15... ...
In 1999, as a result of IOM's previous work and its access to independent scientific experts, CDC and NIH began a year of discussions win IOM to develop the Immunization Safety Review project to address vaccine-safety issues both existing and emerging. THE CHARGE TO THE COMMITTEE The Immunization Safety Review Committee is responsible for examining a broad variety of vaccine-safety concerns.
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From page 16... ...
The plausibility assessment has two components: (1) an examination of the causal relationship between the vaccine and the adverse event and (2)
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From page 17... ...
That is, there is no presumption that a specific vaccine does or does not cause the adverse event in question. The weight of He available evidence determines whether it is possible to shift that position toward causality ("the evidence favors acceptance of a causal relationship")
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From page 18... ...
UNDER REVIEW: THE MMR-AUTISM HYPOTHESIS The Immunization Safety Review Committee examined the hypothesized causal relation between MMR vaccination and autism. Autism is a complex and severe developmental disorder characterized by impairments of social interaction, impairments in verbal and nonverbal communication, and restricted or repetitive and stereotyped patterns of behaviors and interests (APA, 1994; Filipek et al., 1999~.
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From page 19... ...
of adequate size that did not detect a significant association between the vaccine and the adverse event. The balance of evidence Tom one or more case reports or epidemiological studies provides evidence for a causal relation that outweighs the evidence against such a relation.
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From page 20... ...
Subsequent epidemiological studies have investigated the possible relationships among the MMR vaccine, ASD, and bowel disease. Some studies have focused on ASD with no specific relation to bowel disease; other studies have focused on the bowel disease with no particular relationship to ASD.
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From page 21... ...
PLAUSIBILITY ASSESSMENT The Immunization Safety Review Committee undertook to answer the following question: What is the causal relationship between He MMR vaccine and ASD? The sources of evidence considered by the committee in its plausibility assessment include biological plausibility, reports of individual cases or series of cases, and epidemiological studies.
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From page 22... ...
and the latest version of the WHO's International Classification of Diseases, ICD-10 (Filipek et al., 1999; WHO, 1993~. Widespread acceptance of these diagnostic criteria is expected to produce more consistent identification and categorization of cases, which will be more conducive to research and comparative studies.
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From page 23... ...
Autistic disorder occurs more often in boys than girls and is thought to have multiple etiologies that are not well described. Genetic factors are known to have a very strong influence in the etiology (Rutter et al., 1997~.
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From page 24... ...
Not better accosted for by Rett's Disorder or Childhood Disintegrative Disorder. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
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From page 25... ...
PDD-NOS, or atypical autism, is a residual category for subtypes of autism that have many of the characteristics of other pervasive developmental disorders, such as abnormal social interaction and communication skills, but that do not meet the strict DSM-IV/ICD-10 diagnostic criteria for one of the previously described disorders. Atypical autism also includes autistic characteristics that develop after 36 months of age (VoL~nar and Lord, 1998~.
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From page 26... ...
estimate of the prevalence of autistic disorder is about 10 in 10,000 children (Gillberg and Wing, 1999~. These figures do not include other categories of ASD such as Asperger's syndrome, childhood disintegrative disorder, Rett's syndrome, or atypical autism.
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From page 27... ...
The biological plausibility of the potential association of MMR and ASD (~rough discussion of immunologic mechanisms and appropriate anunal models) and of MMR and autismibowel disease (through discussion of the opioid excess hypothesis, autoimmune mechanism, and isolation of Be vaccine-strain measles virus in the gut)
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From page 28... ...
Those that are relevant in the assessment of the causal relationship between MMR and ASD are noted here. First, the presence of an increased number of types of viral proteins from a combination vaccine may increase the potential for peptide competition for binding to major histocompatibility complex (MHC)
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From page 29... ...
The BDV-infected rat has been proposed as an adequate model of the neuroanatomical and behavioral aspects of autism induced by a persistent viral infection with a minimal inflammatory response (Carbone et al., 1991; Pletnikov et al., 1999, 2000; Rubin et al., 19991. However, BDV is not related to measles virus, and this model has not been shown to be useful in addressing the potential link between autism and the attenuated measles virus found in MMR vaccines.
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From page 30... ...
There are, however, concerns regarding the significance of ~ese f~ndings, because it has not been possible to detect measles virus genetic material using standard RT-PCR assays. Although unpublished studies (Wakefield, 2001)
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From page 31... ...
The majority of studies have found no evidence for the presence of measles virus or measles virus materials (either wild-type or vaccine swains in the gut of patients with inflammatory bowel disease (reviewed in Afzal et al., 2000~. Furthermore, large epidemiological studies investigating a potential relationship between measles virus (wild-type and vaccine-s~ain3 exposure and occurrence of inflammatory bowel disease have been inconsistent in their findings and unhelpfill in establishing or refuting an association (Ekbom et al., 1996; Morris et al., 2000; Pardi et al., 1999, 2000, Thompson et al., 1995~.
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From page 32... ...
In He absence of such studies, the evidence does not demonstrate persistent vaccine-s~ain measles virus infection in ASD, inflammatory bowel disease, or ASD with bowel inflammation. Furthermore, it is not possible win He available evidence to describe He direction of any relationship among vaccine-s~ain measles virus infection, autism, and enterocolitis i.e., is it possible Hat autism creates greater susceptibility to enterocolitis following a viral insult?
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From page 33... ...
No rechallenge cases for regressive autism in response to MMR vaccination were identified in the VAERS case reports provided to the committee. Possible rechallenge cases Mom another source are discussed in a subsequent section.
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From page 34... ...
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From page 35... ...
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From page 36... ...
The Working Party concluded that it was impossible to prove or refute the suggested associations between MMR vaccine and ASD or inflammatory bowel disease due to limitations such as selection bias and lack of a control. Based on the available evidence, the Working Party found that Here was no support for a causal association between MMR and autism, and there was no cause for concern about He safety of either He MMR or MR vaccine.
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From page 37... ...
In 1982 the Finnish National Board of Health and National Public Health Institute launched a long-term MMR vaccination program aimed at the elimination of measles, mumps, and rubella from Finland (Patja et al., 2000; Peltola et al., 1998~. All children were to be vaccinated twice with MMR, between the ages of 14 and 18 months and at 6 years.
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From page 38... ...
Vaccine coverage was around 95°/O, with almost 3 million doses distributed and approximately 1.8 million vaccines by 1996. Following introduction of MMR, a country-wide passive surveillance system, based on reporting by health care personnel, was established to gather information about the incidence and nature of all severe adverse events following MMR vaccination.
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From page 39... ...
. The California Department of Developmental Services provided data on regional service-center caseloads for children born between 1980 and 1994 and with an ICD-9 diagnosis of autistic disorder, which excludes other pervasive developmental disorders.
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From page 40... ...
The authors hypothesized that if MMR vaccine were a major cause of the increasing incidence of autism, then the risk of autism in successive birth cohorts would be expected to stop rising within a few years of the vaccine being widely used. However, because the incidence of autism among 2- to 5-year-olds increased markedly from 1988 to 1993 while MMR vaccine coverage was over 95% for successive birth cohorts, the authors conclude that the results do not support a causal association between MMR vaccination and the risk of autism.
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From page 41... ...
The analysis of actual numbers and the fitted trend showed a significant increase in cases for core and atypical autism but produced no evidence of a sudden "step up" after MMR vaccine was introduced in the United Kingdom in either Me number of cases or in the exponential trend. The second analysis focused on children born after 1987.
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From page 42... ...
Taylor and colleagues recently updated their study by reviewing all prevalent autism cases identified by the end of 2000 in five of the eight districts in the North Thames region. Their objectives were to test whether there has been an increase in the proportion of cases with regressive features associated with MMR vaccination and whether there was an association between bowel symptoms and MMR exposure in children with and without regressive symptoms.
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From page 43... ...
Although childhood disintegrative disorder, which is characterized by normal development until age 2 or older with a rapid degeneration' is rare (VoL~nar, 2001) , a pattern of apparently normal development followed by fluctuating skill acquisition is well krlown.
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From page 44... ...
study of 1999 reportedly found no increase in the proportion of autism cases with regressive features associated with MMR vaccination and no association between bowel symptoms and MMR exposure in children with and without regressive symptoms. Similarly, the unpublished findings from a case-control study that Dr.
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From page 45... ...
They cannot rule out the possibility of an unusual and rare response to an exposure because they do not have sufficient precision to detect very rare occurrences on a population level. A poor understanding of the risk factors and lack of a consistent case definition may also hamper the ability of epidemiological studies to detect rare adverse events.
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From page 46... ...
SIGNIFICANCE ASSESSMENT In contrast to previous IOM vaccine-safety studies, which limited their conclusions to causality assessments and their recommendations to fixture research directions, the Immunization Safety Review Committee has been asked to make recommendations regarding a broad range of actions—including potential policy reviews, for example, and changes in communication to the public and to health care providers about issues of vaccine safety. In so doing, the committee considers the significance of the hypothesized associations between vaccines and adverse events in a broader social context the context in which policy decisions must be made.
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From page 47... ...
, and subacute sclerosing panencephalitis (in .001-.018% of cases) (Read et al., 1999; Miller et al., 1992~.
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From page 48... ...
Prior to the ~ntroduci~on of the measles vaccine in the United States in 1963, an average of 400,000 measles cases were reported each year (CDC, 1998) (Figure 1~.
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From page 49... ...
By 1998, MMR vaccination coverage had reached its highest level ever, with an estimated 92% of children aged 19-35 months vaccinated (CDC, 2000d)
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From page 50... ...
(i.e., urban versus rural areas) , population movement, and immigration of individuals from countries with inadequate levels of immunization coverage may alter the vaccine coverage rates needed to eliminate indigenous cases (Fine, 1993; CDC, 2000b)
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From page 51... ...
. Level and Potential Consequences of Public Concern Regarding MMR and ASD Publication of reports hypothesizing an association between the MMR vaccine, bowel disease, and ASD (e.g., Thompson et al., 1995, Wakefield et al.
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From page 52... ...
held an independent scientific seminar with an ad-hoc committee of experts to review the evidence. The group reported finding no evidence to support a link with MMR and a change in MMR vaccination policy (MRC, 1998~.
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From page 53... ...
In 1998, MMR coverage in children aged 19-35 months was at its highest 92.1% (+/- 0.6, 95% CI - but * decreased slightly to 90.6% (+/-0.6, 95% CI)
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From page 54... ...
There also was publicity about risks of adverse events attributed to the vaccine, and some respected medical and public health leaders questioned the safety of Me vaccine. As the public's confidence in the protective effects of the vaccine decreased, use of the vaccine was either interrupted or declined markedly.
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From page 55... ...
The committee recognizes that there are conditions under which a conclusion favoring rejection of He hypothesized causal relationship would result in a recommendation that no further research, surveillance, communication, or policy attention be mounted. Those conditions include strong evidence against the relationship, an understanding that no further mechanistic or pathogenesis research could shift the balance of evidence; an adverse event of little medical or public health significance; a vaccine-preventable disease posing little danger of significant morbidity or mortality should immunization rates fall; and little public, political, or media attention to the problem.
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From page 56... ...
The committee is aware that a paper has been submitted for publication that will address this issue (Wakef~eld, 2001~. Furthennore, in conjunction with the CDC's National Immunization Program, the CPEA is beginning an autism regression and vaccination study Hat will assess the temporal association between MMR vaccination and autism, distinguishing between the early-onset and regressive fonns; and will replicate studies of persistent measles infection in children with autism compared to control children (Bristol-Power, 2001~.
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From page 57... ...
It is not clear, however, that such evidence would necessarily shift Be balance of evidence away from a causality determination favoring rejection of the relationship at Be population level with ASD. (See IOM, 1994a, for a discussion of the contribution of rechallenge cases in causality determinations.)
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From page 58... ...
The committee does so because of the burden of ASD and because some general research might one day shed additional light on the hypothesized relationship between MMR and ASD. As definitions or understanding of autism are enhanced and clarified, epidemiological studies are needed to document the prevalence and incidence of ASD, temporal trends, and the incidence and prevalence of different courses of ASD (e.g., regressive vs.
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From page 59... ...
First, a recurring dilemma in the minds of many concerned about vaccine safety focuses on how to align the appropriate public health attention with a possibly small vaccine safety risk. The committee had little difficulty recommending Mat continued attention be devoted to the hypothesized MMR and ASD link with the specific recommendation being for targeted research.
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From page 60... ...
1998. Absence of detectable measles virus genome sequence in inflammatory bowel disease tissues and peripheral blood lymphocytes.
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From page 61... ...
1999. Measles inclusion-body encephalitis caused by the vaccine strain of measles virus.
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From page 62... ...
1998. Measles virus RNA is not detected in inflammatory bowel disease using hybrid capture and reverse transcription followed by the polymerase chain reaction.
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From page 63... ...
1995. Passively administered antibody suppresses the induction of measles virus antibodies by vaccinia-measles recombinant viruses.
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From page 64... ...
2000. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammato~y bowel disease and autism.
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From page 65... ...
1995. Persistent measles virus infection of the intestine: Confirmation by immunogold electron microscopy.
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From page 66... ...
2000. Early measles virus infection is associated with the development of inflammatory bowel disease.
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From page 67... ...
1990. Age of symptom onset in young children with pervasive developmental disorders.
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From page 68... ...
1993. Evidence of persistent measles virus infection in Crohn's disease.
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From page 69... ...
1997. Association of measles infection and the occurrence of chronic inflammatory bowel disease.
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