LONDON The UK government earlier this week announced a major publicity campaign to reassure parents about the safety of the MMR (measles, mumps and rubella) vaccine, after a unique high-level summit was held to work out how to regain public confidence. The vaccine has become controversial because of claims — based on studies lead by one researcher, Andrew Wakefield, a consultant gastroenterologist at the Royal Free Hospital, London — that it might be linked to autism and bowel disease.

The MMR controversy was triggered initially by a study published in 1998, which claimed to show that MMR is linked to autism and intestinal abnormalities (Lancet 1998, 351:637–641). The study assessed 12 children who were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. The researchers reported that the parents associated the onset of behavioural symptoms with MMR vaccination in 8 of the 12 children, with measles infection in one child and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Nine of the children were judged to have autism.

The researchers concluded that they had identified associated gastrointestinal disease and development regression in a group of previously normal children, which was generally associated in time with possible environmental triggers. They noted: "We did not prove an association between measles, mumps and rubella vaccine and the syndrome described." But, Wakefield, who was a member of the research team, went out on a limb by suggesting that there might be a link and that parents should consider single vaccinations for measles, mumps and rubella rather than the combined triple vaccine.

The hypothesis was based on the 'opioid excess' theory of autism, suggesting that autistic disorders result from the incomplete breakdown and excessive absorption of gut-derived peptides from foods. These peptides may exert central opioid effects, leading to disruption of normal neuroregulation and brain development. The Royal Free group suggested that impaired intestinal function could permit increased permeability to exogenous peptides.

Paul Shattock, Director of the Autism Research Unit at the University of Sunderland, explained why the triple vaccine was considered to be more risky than the single vaccines. "Research has suggested that having wild-type measles and mumps close together in time increases the risk of Crohn's disease in later life." From this, he extrapolated that giving the vaccines together might cause problems.

The Wakefield study and the hypothesis were widely criticised, because of the small numbers involved and the lack of any causal association between MMR and autism or bowel disorders. David Elliman, consultant in community child health at St George's Hospital, London, and district immunisation co-ordinator for Merton, Sutton and Wandsworth Health Authority, pointed out: "The Royal Free group was known to have an interest in children who might have developed bowel problems due to measles, so they were biased referrals." He noted that the number of studies showing no link between MMR and bowel disease or autism — including some published by Wakefield — far outweighs the few that have alleged an association.

A different research group from the Royal Free published a large epidemiological study contradicting the alleged link (Lancet 1999, 353:2026-2029). This study identified children with autism born since 1979 in eight North Thames health districts. Information from clinical records was linked to immunisation data held on the child health computing system. The research team looked for evidence of a change in the incidence or age at diagnosis associated with the introduction of MMR vaccination to the UK in 1988.

Results showed no sudden 'step up' or change in the trend of autism prevalence after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated.

One of the study authors, Brent Taylor, from the department of community child health, Royal Free and University College Medical School, commented: "Our analyses do not support a causal association between MMR vaccine and autism. If such an association occurs, it is so rare that it could not be identified in this large, regional sample." He argued that Wakefield's claims were based on a reported close temporal association between these two events. "Since MMR vaccine is given at around 12–15 months of age, and the mean age at which parents of children with autism first report concern about their child's development is 18–19 months, a close temporal association in some autistic children would be expected by chance."

Soon after, the Committee on the Safety of Medicines examined medical records of 92 children with autism and 15 with Crohn's disease, which had been passed to the committee by a firm of solicitors. Evidence of autism before vaccination was found in 36 cases, and a further 28 showed a family history of the condition. Eight autistic children and four with Crohn's disease seemed to have developed symptoms after MMR vaccination, but the committee said that the small numbers and the fact that the onset of autism often occurs around the age of 18 months meant that this was not enough to suggest causation.

Wakefield's next shot was the publication of a study of 25 children with autism showing that 24 had traces of the measles virus in their gut. Co-researcher John O'Leary, director of pathology at Coombe Women's Hospital, Dublin, argued there was now "compelling evidence" of a link between autism and MMR. The Department of Health argued that the research "did not prove anything and there remains no evidence to suggest there is any link between the MMR jab and autism." In an unusual move, the Royal Free hospital published a statement pointing out weaknesses in the research.

The matter seemed to be largely settled — in favour of the vaccine's safety — with the publication earlier this month of a large, prospective follow-up of the MMR vaccination programme in Finland. Results demonstrated that serious adverse events were rare and greatly outweighed the risks of disease (Pediatric Infectious Disease Journal 2000, 19:1127–1134). The study followed 1.8 million individuals for 14 years from the start of the MMR vaccination programme in 1982. By the end of 1996, almost three million doses of the vaccine had been given, and 173 potentially serious reactions had been recorded as having possibly been caused by the vaccine. The most common event was febrile seizure.

The study's authors, from the Hospital for Children and Adolescents in Helsinki, reported that 45% of these adverse events proved to have probably been caused by some other factor, giving an incidence of serious adverse events of 3.2 per 100 000 vaccine doses. No cases of inflammatory bowel disease or autism were detected. The study was criticised by groups concerned about MMR who argued that it did not look specifically for these conditions. The researchers noted, however, "The study was not designed to look for any specific adverse events, but to record any problems reported, of any kind."

In the latest twist of the saga, Wakefield — refusing to throw in the towel — published a study the week before the government MMR summit alleging that the vaccine had been inadequately tested prior to its introduction (Journal of Adverse Drug Reactions and Toxicology Review 2000, 19(4)). The department of health rejected this, saying that the paper contained no new data and was "highly selective." The department pointed out that the paper included incorrect dates for when vaccines were licensed, misled readers as to how long follow-up studies lasted and used wrong statistical analyses.

Wakefield acknowledged earlier this week: "We have established a link between autism and bowel disease and the bowel disease is consistent with a viral pathology. Other scientific data suggest the measles virus has been identified in these children. The crucial question is whether it is a causal relationship and to establish that we have to go to another level."

David Salisbury, head of the government's immunisation programme, commented: "Dr Wakefield is on a crusade. In the past, he has asserted that the measles vaccine causes bowel disease and linked MMR to autism, and now that MMR was licensed without proper safety studies." He continued "His views have no support from experts in vaccines. We also need to recognise that this is not a problem faced by the UK alone. MMR is used all over the world, and it is unlikely that the US, Canada, Australia and other countries made their decisions on the same data. So were they all wrong, or is Dr Wakefield wrong? The evidence points to MMR having an excellent safety and efficacy record in use, with hundreds of millions of doses used."

So what is the solution to the apparent stalemate? Some parents' groups have called for the option of having their children vaccinated separately against each of the three diseases. Wakefield said "We have the means to artificially dissociate [the three vaccines] to prevent this potentially disastrous consequence. Please provide parents with the choice until this is resolved scientifically."

Salisbury warned, however, that the gap required between giving each vaccine would leave children at risk for a longer time. Japan is the only country in the world that recommends single measles and rubella vaccines, whereas the US, Canada and more than 35 European countries use the combined MMR vaccine. The danger that use of single vaccines may bring is illustrated by the fact that 79 deaths from measles occurred in Japan between 1992 and 1997, whereas no deaths due to the disease have occurred in the UK over the past decade.

The National Autistic Society wants even more research into the safety of MMR. Paul Shattock noted "In the vast majority of cases of autism, MMR is not the causative factor. But there are sufficient cases claiming a link to take the issue seriously. We want MMR to be investigated adequately." He suggested that all children who develop autism should be studied carefully including a thorough review of their symptoms, medical history (including vaccination) and testing for the presence of measles virus in the gut. "The Department of Health hasn't looked at this issue properly. They have just looked for ways to get the vaccine proved to be safe."

This assertion — that there needs to be more research on possible links between MMR and autism — has most vaccination specialists wringing their hands with despair. They think that the enormous body of information suggesting no association is enough to end the argument. Salisbury said "Every single one of the concerns has been looked at in great detail over and over again. All of these concerns are groundless."

The next step in the MMR saga may well be an outbreak of measles. Even though the allegations of problems with MMR have been refuted repeatedly, public confidence in the vaccine has fallen. Immunisation levels have fallen from 93% to 88% nationally, with rates dropping to below 75% in some parts of the UK. And it is not just the public who have had their confidence shaken. A recent study showed that 48% of health professionals had reservations about the second dose of the MMR vaccine and 3% disagreed with the policy of giving it (BMJ 2001, 322:82-85). The drop in vaccine coverage increases the risk of an outbreak of measles.

During the last outbreak of measles in the late 1980s — before MMR vaccination was introduced —17 children died, even though the outbreak was relatively minor. This hints at the potential mortality that could result from what might just be poor science given a lot of media coverage.