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Another Independent Scientist
Falls Victim over Findings Against MMR Vaccine
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 [1]. 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 [2] 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 [3]. "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 [4], which
suggested a link between MMR and regressive autism in 12 children who also
had an unusual chronic bowel disease (see Box 1).
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Box 1
What did Wakefield’s 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
children’s urine compared with age-matched controls. Urinary methylmalonic
acid is increased in bowel disorders such as Crohn’s 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 [5]. 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 body’s own
neuro-peptides, thereby disrupting normal neuro-regulation and brain
development.
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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 [6].
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 [7]. 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 Wakefield’s
hypothesis once and for all. Taylor and colleagues [8] 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 [9] 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 Asperger’s 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 [10]. 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 [11].
In a paper published last year, Wakefield and Montgomery [12] 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" [13].
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
IOM’s 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.
- "Single-jab row heats
up" The editor, August 11, 2001, p.6.
- Howard J. Divergent
thinking about self-defence. Science 2001, 219-20.
- "Doctor who linked jab
to autism quits" by James Meikle, The Guardian 3 December
2001.
- Wakefield AJ, Murch SH,
Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP,
Thompson MA, Harvey P. Valentine A, Davies SE and Walker-Smith JA.
Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive
developmental disorder in children. The Lancet 1998, 351, 637-41.
- D’Eufemia P, Celli M,
Finocchiaro R, et al. Abnormal intestinal permeability in children with
autism. Acta Paediatrica 1996, 85, 1076-9.
- Peltola H, Patja A,
Leinikki P, Valle M, Davidkin I and Paunio M. No evidence for measles,
mumps, and rubella vaccine-associated inflammatory bowel disease or
autism in a 14-year prospective study. The Lancet 1998, 351,
1327-8.
- "‘It’s not about the
science. It’s about belief’" by Linda Steele, The Guardian
G2, 5 December 2001.
- Taylor B. Miller E,
Farrington CP, Petropoulous M-C, Favot-Mayaud E. Li J and Waight PA.
Autism and measles mumps and rubella vaccine: no epidemiological evidence
for a causal association. The Lancet 1999, 353, 2026-9.
- Wakefield A. MMR
vaccination and autism. The Lancet 1999, 354, 949-50.
- Kaye JA, del Mar
Melero-Montes M and Hershel J. Mumps, measles and rubella vaccine and
the incidence of autism recorded by general practitioners: a time trend
analysis. BMJ 2001, 322, 460-3.
- Edwards M and Baltzan M.
Measles, mumps and rubella (MMR) vaccine and autism. BMJ 2001, 323, 163.
- Wakefield A. and Montgomery
SM, Measles, mumps rubella vaccine: through a glass, darkly. Adverse
Drug React. Toxicol Rev. 2000, 19, 265-83.
- Hilleman MR. The dilemma of
AIDS vaccine and therapy. Possible clues from comparative pathogenesis
with measles. AIDS Research and Human Retroviruses 1992, 8, 1743-7.
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