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COMMENTARY |
Division of Pediatric Infectious Disease, Duke University Medical Center, Durham, North Carolina
Abbreviations: MMR, measles-mumps-rubella • ASD, autism spectrum disorder
Initiated by a report in 1998 by Wakefield et al1 that the onset of a syndrome of ileal-lymphoid-nodular hyperplasia and nonspecific colitis accompanied by pervasive developmental disorder had appeared shortly after receipt of measles-mumps-rubella (MMR) vaccine by 8 children, the vaccine was soon indicted as the etiology of autism spectrum disorders (ASDs). Subsequent reports elaborated on this theory, and several laboratories claimed to have detected measles virus or its genome in intestinal biopsies as well as peripheral blood mononuclear cells from such autistic children.2–4 Other reports described elevated levels of measles antibodies in children with autism.5 In this issue of Pediatrics, D’Souza et al6 present their detailed, careful laboratory studies that refute these claims and explain the errors that led to them.
Within a short time after the initial report by Wakefield et al, many parents in the United Kingdom and the United States opted to refuse the MMR vaccine for their infants and children. One explanation offered by the original reporters was that simultaneous MMR vaccination might lead to an aberrant immune response resulting in persistent infection and increased permeability of an inflamed gastrointestinal tract. Such conditions permitted the transport of opiate-like peptides to the central nervous system resulting in the autism syndromes.7 These claims occurred at a time of recognition that reports of children with ASDs were steadily increasing throughout the United States. Because onset often occurred contemporaneously with the immunization schedule at 12 to 18 months of age, this association led to the conviction that there was a causative relationship, not merely a temporal one. Despite the many subsequent epidemiologic studies demonstrating the fallacies of this hypothesis, with the MMR vaccine having been widely available and administered since 1971, these concerns persisted in the United States until late 1999 to early 2000 when the American Academy of Pediatrics and the US Public Health Service recommended the discontinuation of the use of thimerosal as a preservative in multidose pediatric vaccines. Very quickly in the United States the accusations moved from MMR vaccination to mercury, one of the major ingredients in thimerosal (actually ethyl mercury, not methyl mercury, to which central nervous system toxicity had been attributed). Nevertheless, in the United Kingdom, MMR vaccination has continued to remain the culprit despite the shift of blame in the United States. Although endemic measles has been eliminated from the United States as a result of widespread acceptance of the 2-dose MMR vaccine schedule,8 a recent outbreak in Indiana demonstrated the vulnerability of unimmunized youngsters when the virus is introduced by importation from an endemic country.9
In attempts to probe these challenges, and in hopes of restoring public confidence in immunization programs, the American Academy of Pediatrics10 and the Institute of Medicine of the National Academy of Sciences11 conducted independent reviews of the available information regarding MMR vaccine and autism. It was concluded in the Pediatric Academy’s review conference that "the available evidence does not support the hypothesis that MMR vaccine causes autism or associated disorders or inflammatory bowel disease." The Institute of Medicine concluded that "the body of epidemiologic evidence favors rejection of a causal relationship between the MMR vaccine and autism."
Because these 2 major assessments focused on epidemiology, the lingering issue remained that of the alleged laboratory evidence of a relationship between persisting measles virus and ASDs. Wakefield et al had suggested that in contrast to the trivalent MMR vaccine, monovalent measles vaccine would be safe and acceptable. As a result, many parents in the United Kingdom clamored for the availability of monovalent vaccine and, when unable to obtain it, refused immunization for their youngsters. MMR coverage diminished from >90% before the 1998 article to <80% 6 years thereafter.
In the absence of laboratory refutation of the publications claiming detection of measles virus components in peripheral blood mononuclear cells and in intestinal wall biopsies, the MMR-ASD etiology retained credibility among its proponents. Therefore, the studies conducted by D’Souza et al are of major significance. Essentially what they have demonstrated is that the laboratories reporting the measles component findings were in error. The D’Souza et al studies were exquisitely conducted, repeated, and documented to demonstrate the fallacies of these earlier reports as well as the reasons for them. With the techniques available to them and enhanced tests developed in their laboratories, they highlighted the false-positive reactions in both the ASD specimens and the control samples used previously. By laboratory refinement they were able to eliminate these false-positive results and demonstrated that "no sample from either autism spectrum disorder or control groups was found to contain nucleic acids from any measles virus gene."6 As an additional feature of their investigations, they assayed measles antibodies in their own Montreal ASD and control groups (54 and 34 patients, respectively) with no difference in titers measured between the groups. Almost simultaneously, one other group of investigators published similar studies again demonstrating the absence of any measles virus genome sequences in blood of children with ASDs who had received MMR vaccine.12 Hopefully the reliable results from these 2 laboratories will suffice to convince those who retain the belief that MMR vaccination causes ASDs and/or inflammatory bowel disease that this hypothesis is no longer tenable. Actually, in a third, but unpublished, laboratory demonstration, the errors in studies claiming to have detected measles virus products were presented to the US Congress Committee on Government Reform in 200113 when coded samples containing measles RNA from cultured cells and transgenic mice were sent to the offending laboratories and were incorrectly identified by them on 2 separate submissions. The source of these coded samples, Dr Michael Oldstone14 of the Scripps Institute in La Jolla, California, stated that on the basis of these results, their "record of performance would not be acceptable for certifying a clinical laboratory."
What remains now, of course, is to devote similar skilled laboratory investigation to explore the possible role of ethyl mercury from thimerosal in the etiology of ASDs. Despite the removal 4 to 5 years ago of all but traces of thimerosal in every pediatric vaccine, with the exception of influenza virus, ASD case numbers have continued to rise. The challenge to the National Institutes of Health, the Centers for Disease Control, the Food and Drug Administration, and nongovernment laboratories is to solve this problem with augmented investment of funds, personnel, and time.
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FOOTNOTES |
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Address correspondence to Samuel L. Katz, MD, Duke University Medical Center, Division of Pediatric Infectious Disease, Box 2925, Durham NC 27710. E-mail: katz0004{at}mc.duke.edu
Financial Disclosure: Dr Katz is a member of the Merck Vaccine Advisory Board; Merck is the producer of the measles-mumps-rubella vaccine.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
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This article has been cited by other articles:
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  C. P. Johnson, S. M. Myers, and and the Council on Children With Disabilities Identification and Evaluation of Children With Autism Spectrum Disorders Pediatrics, November 1, 2007; 120(5): 1183 - 1215. [Abstract] [Full Text] [PDF]
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