MMR vaccine and autism

The MMR vaccine controversy refers to claims that autism spectrum disorders can be caused by the MMR vaccine. The scientific consensus is that no credible evidence links the vaccine to autism, and that the vaccine's benefits greatly outweigh its risks.

Claims of a connection between the vaccine and autism were raised in a 1998 paper in The Lancet, a respected British medical journal.. Later investigation (particularly by Sunday Times journalist Brian Deer) discovered that the lead author of the article, Andrew Wakefield, had multiple undeclared conflicts of interest, had manipulated evidence, and had broken other ethical codes. The Lancet paper was retracted, and Wakefield was found guilty of serious professional misconduct in May 2010.

The claims in the Lancet article were widely reported; vaccination rates in the UK and Ireland dropped sharply, which in turn led to greatly increased incidence of measles and mumps, resulting in a few deaths and some severe and permanent injuries. Following the initial claims in 1998, multiple large epidemiologic studies were undertaken. Reviews of the evidence by the Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, the UK National Health Service, and the Cochrane Library all found no link between the vaccine and autism. The Cochrane review also concluded that the vaccine has prevented diseases that still carry a heavy burden of death and complications, and that the lack of confidence in the vaccine has damaged public health. A special court convened in the United States to review claims under the National Vaccine Injury Compensation Program rejected compensation claims from parents of autistic children.

Background of the controversy

Further information: [[:MMR vaccine safety]]

Concerns about the Urabe strain

Before the autism-related controversy started in 1998, some concern had already arisen about the safety of the MMR vaccine due to side effects associated with the Urabe mumps strain including rare adverse events of aseptic meningitis, a transient mild form of viral meningitis. 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 vaccine were raised by American and Canadian authorities and were based on reports from Japan linking Urabe MMR with high levels of meningoencephalitis.In early 1988, Canadian authorities suspended distribution of the Urabe-based MMR and eventually recalled the product. Despite these concerns, the junior Health Minister Edwina Currie[3] first granted a license for a Urabe-based MMR vaccine in July 1988 and then proceeded with mass vaccinations in October of that year.

The UK National Health Service stopped using MMR vaccines with the Urabe mumps strain in September 1992 following the identification of an unacceptable risk of aseptic meningitis 15–35 days after vaccination. Decisions taken by British authorities at this time were to be criticized later following documents delivered by FOIA [4]. With no such risk seen in vaccines using the Jeryl Lynn mumps strain, the UK NHS withdrew two of the three MMR vaccine then available (Immravax, made by Merieux UK, and Pluserix, made by SmithKline Beecham) in favor of Merck Sharp and Dohme's MMR II brand, based on the Jeryl Lynn strain. Although MMR administration did continue with MMR II, the MMR vaccination rate began to fall in 1995.

The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain, and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events.

Revaccination campaign

In the wake of measles outbreaks which occurred in England in 1992, and on the basis of analyses of seroepidemiological data combined with mathematical modelling, British Health authorities predicted a major resurgence of measles in school age children . Two strategies were then examined : either to target vaccination at all children without a history of prior measles vaccination or to immunize all children irrespective of vaccination history [5].In November 1994,a national measles and rubella campaign depicted as"one of the most ambitious vaccination initiatives that Britain has undertaken" choose the second solution [6]:within one month 92% of the 7.1 million schoolchildren in England aged 5–16 years received measles and rubella (MR) vaccine [7].

The MMR/MR Litigation starts

In April 1994, Richard Barr [8], a solicitor, succeeded in winning legal aid for the pursuit of a class action against the manufacturers of MMR under the Consumer Protection Act 1987. The class action case was aimed at Aventis Pasteur, SmithKlineBeecham, and Merck, manufacturers respectively of Immravax, Pluserix-MMR and MMR II [9]. This suit, based on a claim that MMR is a defective product and should not have been used, was the first big class action lawsuit funded by the Legal Aid Board - now the Legal Services Commission - after its formation in 1988. Owing to 10 year limit on the period in which an action can be brought under the Consumer Protection Act, court proceedings were started before the medical research had concluded [10]. Noticing two publications from Andrew Wakefield - “Evidence of Persistent Measles Virus in Crohn’s Disease,”published in Journal of Medical Virology 39 (1993),345-53 and “Is Measles Vaccine a Risk for Inflammatory Bowel Disease?” published in The Lancet 345 (1995), 1071-74., Barr decided to contact Dr Wakefield for expertise. They first met on 6 January 1996.[11]

Wakefield et al. report

Starting in 1998, the controversy was kept alive by periodic articles published on the case by Brian Deer that entailed other publications and subsequent declarations of various persons; be they scientists, "lay persons", parents of autistic children, even politicians. Legal actions took place and notably a disciplinary case brought by the General Medical Council which, initially scheduled for 64 days would last more than three years, making it the longest and most complex case of the organisation's 148-year history.

1998 Lancet paper

In February 1998, a group led by Andrew Wakefield published a controversial paper in the respected British medical journal The Lancet. Announced one day before by a brief press release of the Royal Free Hospital [12], this paper reported on twelve children with developmental disorders referred to the Royal Free Hospital in London. The parents or physicians of eight of these children had linked the start of behavioral symptoms to MMR vaccination. The paper described a collection of bowel symptoms, endoscopy findings and biopsy findings that were 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 the MMR vaccine. The paper suggested that the connection between autism and the gastrointestinal pathologies was real, but said it did not prove an association between the MMR vaccine and autism.

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 said, "I can't support the continued use of these three vaccines given in combination until this issue has been resolved." 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." 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." These suggestions were not supported by Wakefield's coauthors nor by any scientific evidence.

The initial press coverage of the story was reasonable for a small and not very significant study. The Guardian and the Independent reported it on their front pages, while the Daily Mail only gave the story a minor mention in the middle of the paper, and the Sun didn't cover it. In the entire year of 1998 across all publications there were only 122 articles that mentioned the subject.

Controversy following publication of the Lancet paper

The controversy began to gain momentum in 2001 and 2002, after Wakefield published papers which suggested that the immunisation programme was not safe. These were a review paper with no new evidence, published in an minor journal, and two papers on laboratory work which he claimed showed that measles virus had been found in tissue samples taken from children who had autism and bowel problems. There was wide media coverage including distressing anecdotal evidence from parents, and political coverage attacking the health service and government peaked with unmet demands that Prime minister Tony Blair reveal whether his infant son Leo had been given the vaccine. It was the biggest science story of 2002, with 1257 articles mostly written by non-expert commentators. In the period January to September 2002, 32% of the stories written about MMR mentioned Leo Blair, as opposed to only 25% which mentioned Wakefield. Less than a third of the stories mentioned the overwhelming evidence that MMR is safe. 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% after publication of the Wakefield research. In 2001, 26% of family doctors felt the government had failed to prove there was no link between MMR and autism and bowel disease.

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. 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.

A factor in the controversy is that through most of the UK National Health Service doctors, only the combined vaccine is available; the importation license for the single measles vaccine was withdrawn in 1988. Prime minister Tony Blair gave support to the programme, and said that "the vaccine was safe enough for his young son, Leo", but refused on privacy grounds to state whether Leo had received the vaccine; in contrast, the subsequent Prime Minister, Gordon Brown, explicitly confirmed that his son has been immunised. The privacy concerns of the Blairs were later undermined when Cherie Blair mentioned Leo's vaccination history when promoting her autobiography.

Administration of the combined vaccine instead of separate vaccines decreases the risk of children catching the disease while waiting for full immunisation coverage. The combined vaccine's two injections results in less pain and distress to the child than the six injections required by separate vaccines, and the extra clinic visits required by separate vaccinations increases the likelihood of some being delayed or missed altogether; vaccination uptake significantly increased in the UK when MMR was introduced in 1988. Health professionals have heavily criticized media coverage of the controversy for triggering a decline in vaccination rates. There is no scientific basis for preferring separate vaccines, or for using any particular interval between separate vaccines.

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. 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. There is no scientific evidence that MMR causes damage to the infant immune system, and there is much evidence to the contrary.

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". The Canadian Paediatric Society, the Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the UK National Health Service 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. Although Wakefield maintained that the legal aid funding was for a separate, unpublished study, the editors of The Lancet judged that the funding source should have been disclosed to them. 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." Several of Dr. Wakefield's co-researchers also strongly criticized the lack of disclosure.

Deer continued his reporting in a BBC television documentary, MMR: What They Didn't Tell You, broadcast on November 18, 2004. This documentary alleges 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. Wakefield's patent application was also noted in the 2008 book Autism's False Prophets by Paul Offit.

In November 2004, Dr Wakefield sued Channel 4, 20/20 Productions, and the investigative reporter Brian Deer, who presented the Dispatches programme MMR: What They Didn't Tell You in front of the Press Complaints Commission [13]. It should be recalled that the PCC received five other complaints connected to the article published by Deer on 22 February 2004 [14].

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. This funding came from the UK legal aid fund, a fund intended to provide legal services to the poor.

Retraction of an interpretation

The Lancet and many other medical journals require 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.

In March 2004, immediately following the news of the conflict of interest allegations, ten of Wakefield's twelve coauthors retracted this interpretation. while insisting that the possibility of a distinctive gastrointestinal condition in children with autism merited further investigation.MMR and autism: what parents need to know , Michael Fitzpatrick , p. xii However, a separate study of children with gastrointestinal disturbances found no difference between those with ASD and those without, with respect to the presence of measles virus RNA in the bowel; it also found that gastrointestinal symptoms and the onset of autism were unrelated in time to the administration of MMR vaccine.

Manipulation of data

On 8 February 2009, Brian Deer reported in The Sunday Times that Wakefield had manipulated patient data and misreported results in his 1998 paper, creating the appearance of a link with autism. Wakefield denied these allegations, and even filed a complaint with the Press Complaints Commission (PCC) over this article on 13 March 2009. The complaint was expanded by a 20 March 2009 addendum. In July 2009, the PCC stated that it was staying an investigation initiated by Wakefield's complaint regarding the Times article, pending the conclusion of the GMC investigation.

General Medical Council investigation

The General Medical Council (GMC), which is responsible for licensing doctors and supervising medical ethics in the UK, investigated the affair. The GMC had brought the case itself claiming that it was in the public interest. The then-secretary of state for health, John Reid MP, called for a GMC investigation, an investigation Wakefield seems himself to have wished [15]. During a debate in the House of Commons, on 15 Mar 2004, Dr Evan Harris [16], a Liberal Democrat MP, called for a judicial inquiry into the ethical aspects of the case, even suggesting it might be conducted by the CPS.[17] In June 2006 the GMC confirmed that they would hold a disciplinary hearing of Wakefield.

The GMC's Fitness to Practise Panel first met on 16 July 2007 [18] to consider the cases of Dr Wakefield, Professor John Angus Walker-Smith, and Professor Simon Harry Murch [19]. All faced charges of serious professional misconduct. The GMC examined, among other ethical points, whether Wakefield and his colleagues obtained the required approvals for the tests they performed on the children; the data-manipulation charges reported in the Times were not at question in the hearings. The GMC stressed that it would not be assessing the validity of competing scientific theories on MMR and autism. The General Medical Council alleged that the trio acted unethically and dishonestly in preparing the research into the MMR vaccine. They denied the allegations. The case proceeded in front of a GMC fitness to practice panel of three medical and two lay members.

On 28 January 2010, the GMC gave a preliminary verdict: Wakefield was found to have acted "dishonestly and irresponsibly" and to have acted with "callous disregard" for the children involved in his study, conducting unnecessary and invasive tests. The trial involved procedures with medical risks but was not approved by an Independent Ethics Committee and Wakefield was shown to have multiple conflicts of interest in the conduct of the study. These breached basic requirements for medical research ethics laid out in the Declaration of Helsinki, a widely recognized standard for research bioethics.

Full retraction

In response to the GMC investigation and findings, the editors of The Lancet announced on 2 February 2010 that they "fully retract this paper from the published record."

Latest developments

In an April 2010 report in the BMJ, Deer expanded on laboratory aspects of his findings recounting how normal clinical histopathology results generated by the Royal Free Hospital were later changed in the medical school to abnormal results, published in The Lancet. A. Wakefield answered these accusations in a press release [20].

On 15 April 2010, Deer wrote an article in the BMJ casting doubt on the "autistic enterocolitis" which Dr Wakefield claimed to have discovered [21]. In the same edition, Deirdre Kelly, President of the European Society of Pediatric Gastroenterology and Nutrition and the Editor of the Journal of Pediatric Gastroenterology and Nutrition expressed some concern about the BMJ publishing this article while the GMC proceedings were underway.[22]

On 24 May 2010, the GMC published its verdict: Dr Wakefield was found guilty of serious professional misconduct over unethical research, and struck off the medical register. John Walker-Smith was also found guilty of serious professional misconduct and struck off the medical register. Simon Murch was found not guilty, despite having previously been found to not have ethical approvals for the study.[23]

Litigation

Litigations are parts of the controversy in different ways. 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 unsuccessful they did lead to a large jump in the costs of the MMR vaccine, and pharmaceutical companies sought legislative protections. In 1993, Merck KGaA became the only company willing to sell MMR vaccines in the United States and the United Kingdom.

In UK

Commenced before the Civil Procedure Rules were promulgated, The MMR Litigation had its status as group litigation achieved by the then Lord Chief Justice’s practice direction of 8 July 1999. On 8 June 2007, the High Court judge, Justice Keith, put an end to the group litigation because the withdrawal of legal aid by the legal services commission had made the pursuit of most of the claimants impossible. He ruled that all but two claims against various pharmaceutical companies must be discontinued [24]. The judge stressed that his ruling did not amount to a rejection of any of the claims that MMR had seriously damaged the children concerned [25].

A pressure group called JABS (Justice, Awareness, Basic Support) was established to represent families with children who, their parents said, were "vaccine-damaged". £15 million in public legal aid funding was spent on the litigation, of which £9.7 million went to solicitors and barristers, and £4.3 million to expert witnesses.

Several British cases where parents claimed that their children had died as a result of Urabe MMR had received compensation under the “vaccine damage payment” scheme [26].

In the USA

The Omnibus Autism Proceeding (OAP)[27] is a coordinated proceeding before the Office of Special Masters of the U.S Court of Federal Claims - commonly called the vaccine court. It is structured to facilitate the handling of nearly 5000 vaccine petitions involving claims that children who have received certain vaccinations have developed autism. The Petitioners' Steering Committee have claimed that MMR vaccines can cause autism, possibly in combination with thiomersal-containing vaccines. In 2007 three individual test cases were presented to test the theory about the combination; these test cases failed. The vaccine court ruled against the plaintiffs in all three cases, stating that the evidence presented did not validate their claims that vaccinations caused autism in these specific patients, or in general.

In some cases, the plaintiffs' attorneys decided to opt out of the highly charged Omnibus Autism Proceedings and argue their autism cases in the regular vaccine court:

On 30 July 2007, the family of Bailey Banks, a child with pervasive developmental delay, won their case versus the Dept. of Health and Human Services [28]. Special Master Richard Abell ruled that the Banks had successfully demonstrated that "the MMR vaccine at issue actually caused the conditions from which Bailey suffered and continues to suffer" In his conclusion, he ruled that Petitioners had proven that the MMR had directly caused a brain inflammation illness called acute disseminated encephalomyelitis (ADEM).

In other cases, attorneys elected not to claim overtly for vaccine induced autism but seek recovery instead for encephalopathy/encephalitis or seizure disorders [29].

Elsewhere

The Osaka district court in Japan ruled on March 13, 2003 that the death of two children (among numerous other serious conditions) were caused by Urabe MMR.[30]

Recent research

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 to the MMR vaccine has been demonstrated. The following were published after the 1998 Wakefield et al. paper:

• In October 2004, a meta review, financed by the European Union, was published in the October 2004 edition of Vaccine that assessed the evidence given in 120 other studies and considered unintended effects of the MMR vaccine. The authors concluded that although the vaccine is associated with positive and negative side effects, a connection between MMR and autism was "unlikely".

• 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."

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

• 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.

• A review of the work conducted in 2004 for UK court proceedings but not revealed until 2007 found that the polymerase chain reaction analysis essential to the Wakefield et al. results was fatally flawed due to contamination, and that it could not have possibly detected the measles that it was supposed to have detected.

• A 2009 review of studies on links between vaccines and autism discusses the MMR vaccine controversy as one of three main hypotheses which epidemiological and biological studies fail to support.

Disease outbreaks

Further information: [[:Measles outbreaks in the 2000s and Mumps outbreaks in the 2000s]]

After the controversy began, the MMR vaccination compliance dropped sharply in the United Kingdom, from 92% in 1996 to 84% in 2002. In some parts of London, it was as low as 61% in 2003, far below the rate needed to avoid an epidemic of measles. By 2006 coverage for MMR in the UK at 24 months was 85%, lower than the about 94% coverage for other vaccines.

After vaccination rates dropped, the incidence of two of the three diseases increased greatly in the UK. In 1998 there were 56 confirmed cases of measles in the UK; in 2006 there were 449 in the first five months of the year, with the first death since 1992; cases occurred in inadequately vaccinated children. 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. The age group affected was too old to have received the routine MMR immunisations around the time the paper by Wakefield et al. was published, and too young to have contracted natural mumps as a child, and thus to achieve a herd immunity effect. With the decline in mumps that followed the introduction of the MMR vaccine, these individuals had not been exposed to the disease, but still had no immunity, either natural or vaccine induced. Therefore, as immunisation rates declined following the controversy and the disease re-emerged, they were susceptible to infection. Measles and mumps cases continued in 2006, at incidence rates 13 and 37 times greater than respective 1998 levels. Two children were severely and permanently injured by measles encephalitis despite undergoing kidney transplantation in London.

Disease outbreaks also caused casualties in nearby countries. 1,500 cases and three deaths were reported in the Irish outbreak of 2000, which occurred as a direct result of decreased vaccination rates following the MMR scare.

In 2008, for the first time in 14 years, measles was declared endemic in the UK, meaning that the disease was sustained within the population; this was caused by the preceding decade's low MMR vaccination rates, which created a population of susceptible children who could spread the disease. MMR vaccination rates for English children were unchanged in 2007–08 from the year before, at too low a level to prevent serious measles outbreaks. In May 2008, a British 17-year-old with an underlying immunodeficiency died of measles. In 2008 Europe also faced a measles epidemic, including large outbreaks in Austria, Italy, and Switzerland.

See also

• Vaccine controversy

Further reading

• "The Vaccine War", PBS FRONTLINE documentary, April 27, 2010