Issue
Number 307
April 17, 2002
CONTENTS OF THIS ISSUE
- Research review by
Dr. Paul Offit puts concerns to rest: Autism is
not caused by MMR vaccine
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April 17, 2002
RESEARCH REVIEW BY DR. PAUL OFFIT PUTS CONCERNS TO REST:
AUTISM IS NOT CAUSED BY MMR VACCINE
On April 5, 2002, the Vaccine Education Center Newsletter
of the Children's Hospital of Philadelphia
published the following article by Dr. Paul
Offit, Center Director, in advance of a planned
speaking tour by British physician
and MMR critic Andrew Wakefield. The Immunization Action
Coalition (IAC) is republishing Dr. Offit's
article, simply titled "Vaccines and Autism," by
permission of the author in the
interest of reaching as many health care
professionals as possible with this important and timely
information.
The complete text of the article, including references,
reads as follows:
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VACCINES AND AUTISM
Andrew Wakefield is soon to embark on a multi-city tour to
promote his idea that the MMR vaccine
causes autism. Media coverage surrounding this
tour may increase parents' fears about the vaccine
and parents may come to you with questions.
This [article] may be used as a resource for
talking points. It provides a concise summary of:
- the studies used to support the hypothesis
that MMR causes autism
- the studies that refute this hypothesis
- other investigations into the causes of autism.
----------------------------------------------------
THE "WAKEFIELD" STUDIES: STUDIES HYPOTHESIZING THAT MMR
CAUSES AUTISM
Those who claim that MMR causes autism often cite two
papers by Andrew Wakefield and colleagues.
This section summarizes those studies and lists
their critical flaws.
The first Wakefield paper
In 1998, Andrew Wakefield and colleagues published a paper
in The Lancet titled "Ileal-lymphoid-
odular hyperplasia, non-specific colitis, and
pervasive developmental disorder in children."(1)
Wakefield's hypothesis was that the MMR
vaccine causes a series of events that include intestinal
inflammation, loss of intestinal barrier function,
entrance into the bloodstream of encephalopathic
proteins, and consequent development of
autism. In support of his hypothesis, Dr.
Wakefield described 12 children with
neurodevelopmental delay (8 with autism). All of these
children had gastrointestinal complaints
and developed autism within 1 month of receiving
MMR.
Critical flaws
- About 90% of children in England received MMR at the
time this paper was written. Because MMR is
administered at a time when many children are
diagnosed with autism, it would be expected that
most children with autism would
have received an MMR vaccine, and that many would have
received the vaccine recently. The
observation that some children with autism
recently received MMR is, therefore, expected.
However, determination of whether MMR causes
autism is best made by studying the incidence of
autism in both vaccinated and unvaccinated
children. This wasn't done.
- Although the authors claim that autism is a consequence
of gastrointestinal inflammation,
gastrointestinal symptoms were observed after, not
before, symptoms of autism in all 8 cases.
- Children with autism were claimed to have low levels of
circulating immunoglobulin A (IgA). However,
levels reported were within the normal
range for that age group.
- Intestinal nodular hyperplasia (like enlarged tonsils in
young children) is considered to be a variant of
normal.
The second Wakefield paper
In 2002, Wakefield and coworkers published a second paper
examining the relationship between measles virus and autism.(2)
The authors tested intestinal biopsy samples for the
presence of measles virus genome from children
with and without autism. Measles virus
genome was detected by reverse-transcriptase polymerase chain
reaction (RT-PCR) and in situ
hybridization. 75 of 90 children with autism were found
to have measles virus genome in intestinal
biopsy tissue as compared with only 5 of 70
control patients.
Critical flaws
- Measles vaccine virus is live and attenuated. After
inoculation, the vaccine virus probably replicates
15-20 times. Measles vaccine virus is
likely to be taken up by specific cells
responsible for virus uptake and
presentation to the immune system (termed antigen-presenting cells or
APCs). Macrophages, B cells, and
dendritic cells (DC) are different types of APCs. Because
all APCs are mobile, and can travel
throughout the body (including the intestine), it
is plausible that a child immunized with MMR would
have measles virus genome
detected in intestinal tissues using a very sensitive
assay (such as RT-PCR). To determine if MMR
is associated with autism one must determine if
the finding is specific for children
with autism. Therefore, children with or
without autism must be identical in two ways. First,
children with or without autism must be
matched for immunization status (i.e., receipt of
the MMR vaccine). Second,
children must be matched for the length of
time between receipt of MMR vaccine and collection of
the biopsy specimen. Although this
information was clearly available to the
investigators and critical to their hypothesis, it
was specifically omitted from the paper.
- Because natural measles virus is still circulating in
England, it would have been important to determine
whether the measles virus genome detected
in these samples was natural measles virus or
vaccine virus. Although primers
are available to distinguish these two types of virus,
the authors chose not to use them.
- RT-PCR is a very sensitive assay. Laboratories that work
with natural measles virus (such as the lab
where these studies were performed) are at high
risk of getting false positive results. No mention
is made in the paper as to
how this problem was avoided.
- As is true for all laboratory studies, the person who is
performing the test should not know whether the
sample is obtained from a case or a control
(blinding). Because no statement is made in the
method section, it is unclear
that blinding of samples occurred.
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STUDIES SHOWING THAT MMR VACCINE DOES NOT CAUSE AUTISM
Four studies have been performed to refute a causal
association between receipt of MMR and autism.
The first Taylor paper
In 1999, Brent Taylor and coworkers examined the relationship
between receipt of MMR and development of
autism in an excellent, well-controlled study.(3)
Taylor examined the records of 498 children with
autism or autism-like disorder. Cases were identified
by registers from the North Thames region
of England before and after the MMR vaccine was
introduced into the United Kingdom in 1988.
Taylor then examined the incidence and age at diagnosis
of autism in vaccinated and unvaccinated
children. He found the following: 1) the
percentage of children vaccinated was the same in
children with autism as in other children in the
North Thames region; 2) no difference in the age
of diagnosis of autism was
found in vaccinated and unvaccinated children; and 3) the onset
of "regressive" symptoms of autism did not
occur within 2, 4, or 6 months of receiving the
MMR vaccine.
The JAMA paper
In 2001, Natalie Smith and coworkers examined the
relationship between the increase in the number of
cases of autism in California and receipt of the
MMR vaccine.(4) The percentage of children
immunized with MMR vaccine between 1980 and 1994
was compared with the incidence of autism during
the same period. Although a dramatic
increase in the incidence of children with autism was
reported, the percentage of children that
received MMR vaccine remained the same.
The British Medical Journal paper
In a study that supported the findings in the JAMA paper,
Hershel Jick and coworkers examined the
incidence of autism in England between 1988 and
1993 and compared this with MMR immunization
rates.(5) Although the incidence of autism
increased, MMR immunization rates remained the
same.
The second Taylor paper
A second study by Brent Taylor and coworkers examined the
relationship between MMR vaccine and "new
variant autism" (Wakefield's claim that autism is
associated with inflammation of the small
intestine).(6) Children with autism
diagnosed between 1979 and 1998 were examined. The
authors compared the number of children with
autism and intestinal symptoms before 1988 and
after 1988 (MMR was
introduced into England in 1988). There was no
difference. They concluded that there was,
therefore, no evidence for "new variant autism"
and provided further evidence that MMR vaccine was
not associated with autism.
---------------------------------------------------
STUDIES ON THE ETIOLOGY OF AUTISM
Studies have focused on the genetics of autism and the
timing of the first symptoms of autism.
Genetics of autism
One of the best ways to determine whether a particular
disease or syndrome is genetic is to examine
the incidence in identical (monozygotic)
and fraternal (dizygotic) twins. Using a strict
definition of autism, when one twin
has autism, 60% of monozygotic and 0% of dizygotic twins
have autism. Using a broader definition of
autism (i.e. autistic spectrum disorder), when one
twin has autism, approximately
92% of monozygotic and 10% of dizygotic
twins have autism. (7,8)
Therefore, autism clearly has a genetic basis.
Timing of development of autism
- Autism symptoms are present before 1 year of age
Perhaps the best data examining when symptoms of autism
are first evident are the "home-movie
studies." These studies took advantage of the fact
that many parents take movies of their children
during their first birthday
(before they have received the MMR vaccine). Home
movies from children who were eventually
diagnosed with autism and those who were not
diagnosed with autism were shown to blinded
neurodevelopmental specialists.
Investigators were, with a very high degree of
accuracy, able to separate autistic from
non-autistic children at 1 year of age.(9-13)
These studies found that subtle symptoms of autism are
present earlier than some parents had
suspected, and that receipt of the MMR vaccine did
not precede the first symptoms of autism.
-Autism symptoms are present before 4 months of age
Other investigators extended the home-movie studies of
one-year-old children to include videotapes of
children taken at 2-3 months of age. Using
a sophisticated movement analysis, videos from
children eventually diagnosed with
autism or not diagnosed with autism were coded and
evaluated for their capacity to predict
autism. Children who were eventually diagnosed
with autism were predicted from
movies taken in early infancy.(14)
This study supported the hypothesis that very subtle
symptoms of autism are present in early infancy
and argue strongly against vaccines as a
cause of autism.
- Evidence that autism occurs in utero
Toxic or viral insults in utero as well as certain central
nervous system disorders are associated with an
increase in the incidence of autism.
For example, children exposed to thalidomide during the
first or early second trimester were found to
have an increased incidence of autism.(15)
However, autism occurred in children with ear, but
not arm or leg,
abnormalities. Because arms and legs develop after 24
weeks gestation, the risk period for autism
following receipt of thalidomide must be before 24
weeks gestation. In support of this finding,
Rodier and colleagues(16) found evidence
for structural brainstem abnormalities in children
with autism. These abnormalities could only
have occurred during brainstem development in utero.
Similarly, children with congenital rubella syndrome are
at increased risk for development of autism.(17-
3) Risk is associated with exposure to
rubella prenatally, but not postnatally.
Finally, children with fragile X syndrome or tuberous
sclerosis are also at increased risk of developing
autism.
Taken together, these findings indicate that autism is
likely due to abnormalities of the central nervous
system that occur in utero.
----------------------------------------------------
SUMMING UP
Studies of 1) the genetics of autism, 2) the timing of the
first symptoms of autism (home-movie studies),
3) the relationship between autism and the
receipt of the MMR vaccine, 4) the histopathology
of the central nervous
system of children with autism, and 5) thalidomide, natural
rubella infection, fragile X syndrome, and
tuberous sclerosis all support the fact that
autism occurs during development of the
central nervous system early in utero.
Unfortunately, for parents who will someday bear children
diagnosed with autism, the controversy
surrounding vaccines has diverted attention and
resources away from a number of promising leads.
-----------------------------------------------------
REFERENCES
1. Wakefield, A.J., et al.Ileal-lymphoid-nodular
hyperplasia, non-specific colitis, and pervasive
developmental disorder in children
Lancet 351: 637-641,1998.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9500320&dopt=Abstract
2. Uhlmann, V., et al. Potential viral pathogenic
mechanism for new variant inflammatory bowel disease.
Journal of Clinical Pathology: Molecular
Pathology 55:1-6, 2002.
http://mp.bmjjournals.com/cgi/content/full/54/6/DC1?eaf
3. Taylor, B., et al. Autism and measles, mumps, and
rubella vaccine: no epidemiological evidence for a causal
association. Lancet 353:2026-2029, 1999.
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4. Dales, L., et al. Time trends in autism and in MMR
immunization coverage in California. JAMA 285:1183-1185,
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Can language disorder not due to peripheral deafness be an
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Pediatrics 52:296-299, 1973.
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Please forward Dr. Offit's article to interested parties. For
a PDF version of the article to print and
distribute, go to:
http://www.immunize.org/autism/offit_article.pdf
For more information on the MMR-vaccine-and-autism theory,
go to CDC's MMR and autism web page at:
http://www.cdc.gov/nip/vacsafe/concerns/autism/default.htm
For additional links and references to studies on the safety
of MMR vaccine with respect to autism, go
to:
http://www.immunize.org/autism/
To learn more about the Vaccine Education Center at the Children's
Hospital of Philadelphia, go to:
http://www.vaccine.chop.edu/
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