MMR vaccine controversy

The MMR vaccine controversy is over the safety of the MMR vaccine. Critics of the vaccine say that the incidence of autism has greatly increased and that the vaccine is a primary cause of this increase. They posit that the vaccine can overwhelm the young immune system, which they assert is often already struggling from the effects of other environmental insults such as exposure to heavy metals. Critics also say that the live measles virus in the formulation of the MMR harms susceptible individuals in a way that wild measles does not.^[1]

The consensus of the medical and scientific community is that the benefits of the vaccine greatly outweigh the risks, and that there is no scientific evidence to support the critics' claims. The Centers for Disease Control,^[2] the Institute of Medicine of the National Academy of Sciences,^[3] and the UK National Health Service^[4] have all concluded that there is no evidence of a link between the MMR vaccine and autism. A systematic review by the Cochrane Library concluded that there is no credible link between the MMR vaccine and autism, that MMR has prevented diseases that still carry a heavy burden of death and complications, and that the lack of confidence in MMR has damaged public health.^[5]

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Wakefield et al. report

1998 Lancet paper

In February 1998, a group led by Andrew Wakefield published a controversial paper in the respected British medical journal The Lancet that reported on the cases of twelve children with developmental disorders referred to the Royal Free Hospital in London. The paper described a collection of bowel symptoms said to be evidence of a possible novel syndrome that Wakefield would later call autistic enterocolitis, and recommended further study into the possible link between the condition and environmental triggers, such as the MMR vaccine. The paper suggested that the connection between autism and the gastrointestinal pathologies was real, but said that it did not prove an association between the MMR vaccine and autism.^[6]

At a press conference before the paper's publication, Wakefield said that he thought it prudent to use single vaccines instead of the MMR triple vaccine until this could be ruled out as an environmental trigger, given that parents of eight of the twelve children studied were said to have blamed the MMR vaccine, saying that symptoms of autism had set in within days of vaccination at approximately 14 months. He declared, "I can't support the continued use of these three vaccines given in combination until this issue has been resolved."^[7] In a video news release issued by the hospital to broadcasters in advance of the press conference, he called for MMR to be "suspended in favour of the single vaccines."^[8] In a BBC interview Wakefield's mentor Roy Pounder, who was not a coauthor, admitted the study was controversial, and added: "In hindsight it may be a better solution to give the vaccinations separately, although administratively it is a wonderful idea. When the vaccinations were given individually there was no problem."^[9] These suggestions were not supported by Wakefield's coauthors nor by any scientific evidence.^[10]

Controversy following publication of report

The paper, press conference and video sparked a major health scare in the United Kingdom. As a result of the scare, full confidence in MMR fell from 59 to 41 per cent after publication of the Wakefield research. In 2001, 26 per cent of family doctors felt the government had failed to prove there was no link between MMR and autism and bowel disease.^[11] After it became clearer that Wakefield's claims were not supported by scientific evidence, confidence in the MMR vaccine increased. A 2003 survey of 366 family doctors in the UK reported that 77% of them would advise giving the MMR vaccine to a child with a close family history of autism, and that 3% of them thought that autism could sometimes be caused by the MMR vaccine.^[12] A similar survey in 2004 found that these percentages changed to 82% and at most 2%, respectively, and that confidence in MMR had been increasing over the previous two years.^[13]

A factor in the controversy is that through most of the UK National Health Service doctors, only the combined vaccine is available; those who do not wish to have it given to their children must either have the separate vaccines given privately, or not vaccinate their children at all. The former Prime Minister, Tony Blair, strongly supported the vaccine in public and hinted that his son Leo had received the MMR vaccine, stating that "the vaccine was safe enough for [his] young son, Leo".[2] ". However, some see this statement as evasive and thus as evidence of the former Prime Minister's own concern about the vaccine. The current Prime Minister, Gordon Brown, has explicitly confirmed his son has been immunized.^[14]

The great majority of doctors prefer to administer the combined vaccine rather than the separate ones, as it is less distressing to the child, and parents are more likely to attend for one vaccination than for three. Using separate, single vaccines in place of MMR puts children at increased risk since the combined vaccine reduces the risk of them catching the diseases while they are waiting for full immunisation cover.^[15][16] Wakefield has been heavily criticized on scientific grounds and for triggering a decline in vaccination rates,^[17] There is no scientific basis for preferring separate vaccines, or for using any particular interval between separate vaccines.^[18]

John Walker-Smith, a coauthor of Wakefield's report and a supporter of the MMR vaccine, wrote in 2002 that epidemiology has shown that MMR is safe in most children, but observed that epidemiology is a blunt tool and studies can miss at-risk groups that have a real link between MMR and autism.^[19] However, if a rare subtype of autism were reliably identified by clinical or pathological characteristics, epidemiological research could address the question whether MMR causes that autism subtype.^[20] As yet there is no scientific evidence that MMR causes damage to the infant immune system, and there is much evidence to the contrary.^[18]

Wakefield has been heavily criticized, both on scientific grounds and for triggering a decline in vaccination rates.^[21] In 2001, Berelowitz, one of the co-authors of the paper, said "I am certainly not aware of any convincing evidence for the hypothesis of a link between MMR and autism".^[15] The Centers for Disease Control,^[22] the Institute of Medicine of the National Academy of Sciences,^[23] and the UK National Health Service^[4] have all concluded that there is no evidence of a link between the MMR vaccine and autism.

Conflict of interest allegations

In February 2004, investigative reporter Brian Deer wrote in The Sunday Times of London that Wakefield had received £55,000 funding from Legal Aid Board solicitors seeking evidence to use against vaccine manufacturers, that several of the parents quoted as saying that MMR had damaged their children were also litigants, and that Wakefield did not inform colleagues or medical authorities of the conflict of interest.^[24] Although Wakefield maintained that the legal aid funding was for a separate, unpublished study,^[25] the editors of The Lancet judged that the funding source should have been disclosed to them.^[26] Richard Horton, the editor-in-chief, wrote, "It seems obvious now that had we appreciated the full context in which the work reported in the 1998 Lancet paper by Wakefield and colleagues was done, publication would not have taken place in the way that it did."^[27] Several of Dr. Wakefield's co-researchers also strongly criticized the lack of disclosure.^[24]

Deer continued his reporting in a BBC television documentary, "MMR: What They Didn't Tell You", broadcast on November 18 2004, which alleged that Wakefield had applied for patents on a vaccine that was a rival of the MMR vaccine, and that he knew of test results from his own laboratory at the Royal Free Hospital that contradicted his claims.^[28]

In 2006, Deer reported in The Sunday Times that Wakefield had been paid more than £400,000 by British trial lawyers attempting to prove that the vaccine was dangerous, with the undisclosed payments beginning two years before the Lancet paper's publication.^[29]

Retraction of an interpretation

The Lancet, and many medical journals, requires papers to include the authors' conclusions about their research, known as the "interpretation". The summary of the 1998 Lancet paper ended as follows:

Interpretation We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.^[6]

In March 2004, immediately following the news of the conflict of interest allegations, ten of Wakefield's twelve coauthors retracted this interpretation.^[30]

General Medical Council investigation

The General Medical Council, which is responsible for licensing doctors and supervising medical ethics in the UK, is investigating the affair [3]. Wakefield's colleagues Professor John Walker-Smith and Professor Simon Murch also face charges of serious professional misconduct over their roles in the affair. The General Medical Council alleges that the trio acted unethically and dishonestly in preparing the research into the MMR vaccine. They deny the allegations.^[31] The case is proceeding in front of a fitness to practice panel, of three medical and two lay members, at the GMC.^[32] Due to scheduling issues for the large number of lawyers and doctors involved in the proceedings, after the prosecution presented its case, between August and October 2007, they were agreed by the parties to be postponed until January 2008.

Urabe mumps strain

Further information: MMR vaccine safety

A late-1980s trial in Britain of a form of the MMR vaccine containing the Urabe mumps strain produced three cases of probably-associated febrile convulsions per 1,000 vaccinations, and concerns about adverse reactions to the this vaccine were raised by American and Canadian authorities and were based on reports from Japan linking Urabe MMR with high levels of meningoencephalitis. Despite these concerns, the British government went ahead with mass vaccinations in October 1988.^[33] The National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead.^[34]

Recent studies

The number of reported cases of autism increased dramatically in the 1990s and early 2000s. This increase is largely attributable to changes in diagnostic practices; it is not known how much, if any, growth came from real changes in autism's prevalence, and no causal connection has been demonstrated to the MMR vaccine.^[35] The following studies were published after the 1998 Wakefield et al. paper.

• A 1998 population study of Swedish children found no difference in the prevalence of autistic children born before and after the 1982 introduction of the MMR vaccine in Sweden.^[36]

• A retrospective cohort study of all 537,303 children born in Denmark from January 1991 through December 1998 found no statistically significant difference in risk of autism among the 440,655 who were vaccinated with MMR. This study provided strong evidence against the hypothesis that MMR vaccination causes autism.^[37]

• In February 2004, a population-based case-control study of 624 cases and 1,824 matched controls, conducted by the Centers for Disease Control, found no evidence to support an association between MMR and autism.^[38]

• In September 2004, a case–control study of 1,294 cases of pervasive developmental disorder and 4,469 controls from the UK General Practice Research Database found a relative risk of 0.86 for MMR vaccine, which suggest that MMR is not associated with an increased risk of pervasive development disorders such as autism.^[39]

• In fall 2004, a linear regression analysis of Danish data, which attempted to adjust for ascertainment bias, reported that the relative risk for autism increased fourfold between the 1980s and the early 2000s.[4] This analysis was published in the Journal of American Physicians and Surgeons, a non-MEDLINE-indexed publication of a group that opposes mandatory vaccination on political grounds.

• In October 2004, a review, financed by the European Union, was published in the October 2004 edition of Vaccine^[40] that assessed the evidence given in 120 other studies and considered unintended effects of the MMR vaccine. The authors concluded that
  • the vaccine is associated with some positive and negative side effects,
  • it was "unlikely" that there was a connection between MMR and autism, and
  • "The design and reporting of safety outcomes in MMR vaccine studies ... are largely inadequate".

• In January 2005, a study of all younger residents of Olmsted County, Minnesota reported an eightfold increase in the age-adjusted incidence of research-identified autism over a period beginning in the early eighties and ending in the late nineties, but found no evidence of a link with MMR. The study's authors said that the timing of the increase suggested that it may have been due to improved awareness of the disorder, a growth in services, and changing definitions.^[41]

• From January 2005 through July 2007, Dan Olmsted, a senior editor for UPI, conducted a journalistic investigation reported in his "Age of Autism" column^[42] and found no unvaccinated children with autism. Olmsted looked for autistic children among unvaccinated Amish; in a subset of homeschooled children who are not vaccinated for religious reasons; and in a pediatric practice in Chicago with several thousand never-vaccinated children. However, in a critical 2005 assessment Olmsted's reporting was characterized as "misguided" by two anonymous reporters. Both sources "believed that Olmsted has made up his mind on the question and is reporting the facts that support his conclusions".^[43] A 2006 study contradicted Olmsted by demonstrating a genetically determined syndrome of autism and mental retardation prevalent in the Old Older Amish population.^[44]

• Japan provided a natural experiment on the subject: combined MMR vaccine was introduced in 1989, but the programme was terminated in 1993 and only single vaccines used thereafter. In March 2005 a study of over 30,000 children (278 cases) born in one district of Yokohama concluded "The incidence of all autistic spectrum disorders (ASD), and of autism, continued to rise after MMR vaccine was discontinued. The incidence of autism was higher in children born after 1992 who were not vaccinated with MMR than in children born before 1992 who were vaccinated. The incidence of autism associated with regression was the same during the use of MMR and after it was discontinued." The authors concluded: "The significance of this finding is that MMR vaccination is most unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD, and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD."^[45]

• In October 2005, the Cochrane Library published a review of 31 scientific studies, which found no credible evidence of an involvement of MMR with either autism or Crohn's disease. The review also stated "Measles, mumps and rubella are three very dangerous infectious diseases which cause a heavy disease, disability and death burden in the developing world.… [T]he impact of mass immunisation on the elimination of the diseases has been demonstrated worldwide." However the authors of the report also stated that "the design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate."^[5] Vaccination critics say that the review's evidence contradict its conclusions and that the British government unduly influenced the review.^[46]

• In July 2006, a study of 27,749 Canadian children ruled out an association between pervasive developmental disorder and MMR vaccinations.^[47]

• A review published in September 2006 found no scientific evidence that the MMR vaccine plays any part in the causes or triggering of autism, even in a subgroup of children with the condition.^[48]

• A 2006 study found no evidence of measles virus genome sequences persisting in the blood of autistic children vaccinated with MMR.^[49]

• A 2006 multi-site study of 351 children with ASD found no evidence that onset of autistic symptoms or of regression was related to MMR vaccination.^[50]

• A 2007 study found that there was no change in the rates of regressive autism after MMR was withdrawn from Japan.^[51]

• A 2007 case study used the figure in Wakefield's 1999 letter to The Lancet alleging a temporal association between MMR vaccination and autism^[52] to illustrate how a graph can misrepresent its data, and gave advice to authors and publishers to avoid similar misrepresentations in the future.^[53]

• A 2007 review of independent studies performed after the publication of Wakefield et al.'s original report found that these studies provide compelling evidence against the hypothesis that MMR is associated with autism.^[54]

Litigation

During the 1980s and 1990s, a number of lawsuits were brought in the United States against manufacturers of vaccines, alleging the vaccines had caused a variety of physical and mental disorders in children. While these lawsuits were inconclusive,^{[citation needed]} they did lead to a massive jump in the costs of the MMR vaccine, as pharmaceutical companies sought to cover potential liabilities by lobbying for legislative protection.^{[citation needed]} By 1993, Merck KGaA had become the only company willing to sell MMR vaccines in the United States and the United Kingdom. Two other MMR vaccines were withdrawn in the UK in 1992 on safety grounds arising from the strain of mumps component.^{[citation needed]}

In September 1995, the Legal Aid Board in the UK granted a number of families financial assistance to pursue legal claims against the state health authorities and the vaccine's manufacturers, claiming that their children were killed or seriously injured by the MMR vaccine.^{[citation needed]} A pressure group called JABS (Justice, Awareness, Basic Support) was established to represent families with children who, their parents said, were "vaccine-damaged." This litigation is now discontinued [5].

Disease outbreaks

After the controversy began, the takeup of MMR dropped sharply in the United Kingdom, from 92% in 1996 to 84% in 2002. In some parts of London, it was said to be as low as 60%, far below the rate thought to be needed to avoid an epidemic of measles.

After vaccination rates dropped, the incidence of two of the three diseases increased greatly in the UK. 449 measles cases were confirmed in the first five months of 2006, with the first death since 1992; cases occurred in inadequately vaccinated children.^[55] Mumps cases began rising in 1999 after years of very few cases, and by 2005 the United Kingdom was in a mumps epidemic with almost 5000 notifications in the first month of 2005 alone.^[56] Measles and mumps cases continued in 2006, at incidence rates 13 and 37 times greater than respective 1998 levels.^[57]

References