Dr. Andrew Wakefield is one among a growing number of scientists who links the combined measles, mumps and rubbella (MMR) vaccine to autism. He was asked to leave his job. Dr. Mae-Wan Ho reviews the scientific findings and raises key questions.
In August, general practitioner Peter Mansfield was summoned to appear before the General Medical Council (GMC). He had been giving single measles and rubella vaccines to more than 700 families at private clinics in several counties in Britain . The families had demanded single vaccines because of fears that the combined measles mumps and rubella (MMR) vaccine could cause autism and bowel disease, although the government and the medical establishment had categorically denied such risks. The newspaper for GPs, Doctor, noted that the attacks on the MMR vaccine had been "widely discredited". The government does not allow separate vaccines on the National Health Service, maintaining that the combined MMR is safe, and that giving separate vaccines will only endanger the community on account of the delays in immunisations involved.
The debate over the safety of the combined MMR vaccine has surfaced periodically since its introduction in 1988 in the UK and 10 years before that in the United States. The Independent is practically the only broad sheet newsprint in the UK that does not take the establishment line. It sees Dr. Mansfield as "a test case for parents freedom to choose how to vaccinate their children". While the Doctor sees it as "a test case for GPs clinical freedom" to give what they regard as the most effective treatment. A recent survey found that one in four GPs wants single vaccines to be licensed. Not only are the professionals divided over MMR vaccine, there is divergent opinions on the efficacy of vaccinations in general, divergent practices in different countries  and a mass of conflicting findings.
Dr. Mansfield was eventually allowed to continue giving single jabs three months after he was summoned by the GMC. But the researcher at the centre of the controversy was forced to quit his job in December . "I have been asked to go because my research results are unpopular," said Dr. Andrew Wakefield of the Royal Free Hospital and School of Medicine, and added, "I have no intention of stopping my investigations."
For Wakefield, it all began in a paper published in 1998 , which suggested a link between MMR and regressive autism in 12 children who also had an unusual chronic bowel disease (see Box 1).
What did Wakefields team find?
Dr. Andrew Wakefield and his team at the Royal Free Hospital and School of Medicine in London examined twelve children with intestinal symptoms and autism - pervasive developmental disorder with loss of acquired skills. These children had all been normal before their illnesses developed. All twelve had been vaccinated with MMR.
In 8 of the children, the parents noticed that they started behaving abnormally when given MMR vaccination, one child was infected with measles, another with mumps. All twelve had intestinal abnormalities ranging from enlarged lymph nodes to ulcers. Patchy chronic inflammation was present in the colon in 11 children and reactive overgrowth of the ileum in 7 of them. Nine of the children were diagnosed with autism, one with disintegrative psychosis, and two with possible post-viral or vaccination encephalitis (inflammation of the brain). There were no specific neurological abnormalities, and Magnetic Resonance Imaging and EEG tests were normal.
However, abnormally high levels of methyl-malonic acid were found in the childrens urine compared with age-matched controls. Urinary methylmalonic acid is increased in bowel disorders such as Crohns disease in which cobalamin excreted in bile is not reabsorbed.
Wakefield and his colleagues suggested that the intestinal disorders and autism formed one disease entity, and both might be linked to MMR vaccination. Abnormal intestinal permeability was previously identified in 43% of a group of autistic children with no gastrointestinal symptoms by other researchers . The intestinal disorders could, therefore, play a part in the behavioural changes in some children.
One theory of how autism arises blames the incomplete breakdown of proteins from foods such as barley, rye, oats and dairy products, resulting in peptides that affect brain activity being absorbed in excessive amounts. These food-derived peptides then interfere with the bodys own neuro-peptides, thereby disrupting normal neuro-regulation and brain development.
The report was widely condemned. There were seven letters published in the next issue of The Lancet, all critical. The research was faulted on methodology and sample size. Mostly, it was attacked for bringing vaccination into disrepute, thereby decreasing vaccination coverage and jeopardising public health. That argument cuts both ways. If the MMR vaccine offered 100% protection, those who failed to take it up would only be jeopardising their own health. Unfortunately, vaccines are seldom 100% effective in offering protection against disease.
The strongest evidence against autism being linked to MMR vaccination came from Finland. A long-term vaccination project aimed at eliminating measles, mumps and rubella was launched by the National Board of Health and National Public Health Institute in 1982. All children were vaccinated twice, at age 14-18 months and 6 years. Adverse events were reported prospectively to the Institute. Those who developed gastrointestinal symptoms or signs lasting 24h or more at any time after MMR were traced. By the end of 1996, about 3 million vaccine doses had been delivered, only 31 children developed gastrointestinal symptoms after vaccination, all except one after the first vaccine dose, none went on to develop inflammatory bowel disease and no case of autism was reported .
But Richard Halvorsen, a London GP who offers single jabs, was not impressed. He says he began to worry precisely when he started to read the scientific papers cited as proof of safety . The Finnish study relied on passive surveillance by GPs, which, in Britain, is notorious for under-reporting. Furthermore, Halvorsen points out that the study was not designed to look for autism in the first place. If medical staff were not asked to look for autism as a possible side-effect, then there was no reason to report it as reaction to MMR. Consultant neuropsychologist Ken Aitken concurred. Other research suggests autism cases quadrupled in Finland over this period, and if the researchers had acknowledged autism as a possible reaction to MMR, they might have picked up at least some of the cases. The other problem is that most children with regressive autism and bowel disorder suffer a slow degeneration into autism. The average delay between vaccination and diagnosis of autism was two and a half years.
Another paper published in 1999 was deemed to demolish Wakefields hypothesis once and for all. Taylor and colleagues  identified all 498 known patients with autism spectrum disorders (ASD) in North East London who had been born in 1979 or later. They failed to show any sudden increase in cases of autism with the introduction of MMR vaccine in Britain in 1988.
Wakefield  pointed out that although the MMR vaccine was introduced in 1988, there was simultaneously a catch-up campaign, targeted at all children, whatever their age, who presumably had not received either monovalent mumps or rubella vaccine. This would have smoothed out the jump in incidence associated with the first introduction of the vaccine that was expected. Another factor that would smooth out the jump is the variable delay between vaccination and the development of autism mentioned earlier.
Can the dramatic increase in autism be attributed to a change in diagnostic practice, Wakefield asked? Data from California Office of Developmental Services show a dramatic parallel to data from north-east London. Identical temporal trends are shown, with the rise in autism from a steady baseline value, coinciding with the introduction of MMR vaccine in both countries.
"In 1998 the expected numbers of newly diagnosed autistic children in California should have been 105-263 cases,...the actual figure was 1685 new cases. The temporal trend in north-west London is almost identical, although the rise is delayed by about 10 years. The two countries use the same diagnostic criteria. The sequential trends are consistent with the timing of introdution of MMR to both regions."
One obvious weakness in the analysis of Taylor and coworkers that no one has commented on, is in fitting exponential trends to the data, which is notoriously unreliable. And separating the data into three groups, core autism, atypical autism and Aspergers syndrome as Taylor and coworkers did, makes it even worse. It is virtually impossible to distinguish between an exponential increase that began in 1979 or in the year of vaccine introduction, 1988.
The time-trend in the increase in autism was confirmed by researchers in the Boston collaborative Drug Surveillance Program, Boston University School of Medicine, based on GP records in the United Kingdom . They found the incidence of newly diagnosed autism increased sevenfold, from 0.3 per 10 000 in 1988 to 2.1 per 10 000 in 1999. (Actually, the peak value of 2.2 was reached in 1997). In 114 boys born in 1988-1993, the risk of autism in 2-5 year old boys increased nearly fourfold, from 8 per 10 000 in 1988 to 29 per 10 000 in 1993.
But this too, was construed as evidence against MMR being linked to autism, because in the same period, the vaccination rate was said to be constant at 95%. This paper was criticised, rightly, to be too simplistic. The vaccination rate was almost certainly not constant, as in the early years of introduction, the coverage could fall well short of 95%. Furthermore, there was delayed diagnosis in 40% of the early cases, and increasing awareness of the condition among pediatricians in later years. Another factor that may have contributed to further increases in autism cases was a trend towards earlier vaccinations that could have given rise to more cases .
In a paper published last year, Wakefield and Montgomery  reviewed the early studies that gave approval to the MMR vaccine. They pointed out that the original safety studies on the MMR vaccine consisted of observation lasting at most 28 days, and often considerably less. But measles virus, and to a lesser extent, measles vaccines are associated with both acute and delayed encephalopathic events. In addition, as measles was also known to cause acute gastroenteritis and other gut illnesses, the gasterointestinal tract was a likely site for delayed pathology. This was borne out by demonstration of persistent measles virus infection of the diseased appendix. All that was known in 1968 or earlier.
In the year prior to its general introduction in the UK, a surveillance of adverse reactions to MMR was conducted on 10 000 children. The trial was not controlled and followed up was 3 weeks only.
Meanwhile, possible delayed gastrointestinal complications from measles vaccines were detected in a series of studies on the monovalent measles vaccines in Senegal, The Gambia, Guinea Bissau Haiti and Peru. High titer vaccines were given to overcome the effects of maternal antibodies. There was delayed excess mortality from diarrhoea, wasting and growth disorder in females. In Peru, researchers identified subtle but consistent aberrations in cellular immunity in both sexes, more in females than males, consistent with more female deaths than males.
Hilleman of Merck reviewed these studies and highlighted both the diarrhoea-associated deaths and persistent immunodeficiency, "The process bears resemblance to AIDS" .
The potential for interference between the components in multivalent vaccines was never properly addressed. Vaccine manufacturers are aware of this interference. Douglas of Merck stated, "The complexity of vaccine delivery today in clinical practice with 15-17 injections in the first two years of life emphasizes the need for development of combination pediatric vaccines, .. This has proved to be far more difficult than previously believed due to unpredicted immune interference and incompatibilties on mixing of different components, demonstrating again the inadequacy of our understanding of how vaccines work and the empiric nature of the science."
One major complication is over-stimulation of the immune system in having to cope with three vaccines at the same time. Another complication that does not seem to have been raised is the possibility of complementation and recombination between the viral genes and genomes in the multivalent vaccines.
In April 2001, the US Institute of Medicine (IOM) rejected claims of a causal relation between the MMR vaccine and autism in a review of current evidence. However, the 15 independent scientific experts that comprised the IOMs immunisation Safety Review Committee warned that they could not rule out that MMR may contribute to autistic spectrum disorders (ASD) because epidemiological evidence lacked the precision to assess rare occurrences of a response to MMR leading to ASD. Studies are hampered by poor understanding of the risk factors, failure to use a standard case definition, and the difficulty in assessing the exact onset of the condition. There is also no animal model linking MMR vaccine and ASD.
The IOM Committee recommended continued scientific attention and investigations on whether the measles vaccine is present in the intestines of ASD children.
In my view, the molecular characterisation of different MMR vaccines should also be done, and effort directed towards identifying recombinant viruses in ASD children, and their immune status ascertained.
The Scottish Parliament expert advisory group is due next February. Meanwhile, around 1000 children in the UK are using legal aid to pursue a joint action in the courts against the three MMR manufacturers Merck, SmithKline Beecham and Aventis Pasteur. These are among the 3000 children whose parents have contacted lawyers.
Article first published 12/12/01
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