PART F - EVIDENCE TO SUGGEST THAT THERE IS A LINK
24. Paper By Weibel, Caserta, Benor and Evans, "Acute Encephalopathy
Followed By Permanent Brain Injury Or Death Associated With Further Attenuated Measles
Vaccines: A Review of Claims Submitted to the National Vaccine Injury Compensation Program",
Pediatrics, Vol 101 No. 3 March 1998.
The purpose of this study was to determine any causal relationship between acute
encephalopathy and subsequent permanent brain injury or death, following measles vaccine,
mumps vaccine, rubella vaccine, MR or MMR. The conclusion was that a causal relationship
may exist as a rare complication.
The study looked at children who received the first dose of these vaccines 1970-93
and who then developed an encephalopathy with no determined cause within 15 days
A total of 48 children (out of 403 claims submitted) aged 10-49 months met the
criteria. Eight had died, the remainder had mental regression and retardation, chronic
seizures, motor and sensory deficits and movement disorders. Symptoms were clustered on
days 8 and 9 after vaccination. The clustering was accepted as suggesting a rare
complication of measles immunisation.
Of the 48, 1 child had MR, 30 had MMR, 2 had MMR plus DTP, 2 had MMR plus
haemophilus influenzae type b (Hib), 4 had MMR plus DTP plus oral polio vaccine (OPV), 1
had MMR plus DTP plus OPV plus Hib
Two of the deaths were in previously apparently normal healthy children, who then
received MMR. Three deaths occurred 3 months to 4 years later. One non-fatal case reviewed
had eventual hyperactivity and aggressive behaviour at age 5 years.
The authors thought that (1) the 48 cases represented under-reporting from a passive
system, but (2) most serious cases had been captured by the system - a self-comforting
point?
25. US paper, by Drs. Delgiudice-Asch (clinical
instructor in psychiatry, Mount Sinai School of Medicine) and Hollander
(Seaver Autism Research Centre)
This includes:
- the noting of the potential relevance of antimyelin autoantibodies
- reference to the work of Stubbs in the USA and the suggestion that an inflammatory
reaction in the brain may contribute to the development of autism
- references to indirect evidence of immune activation in autism
- the reference to Singhs finding, also in the USA, that identified serum antibodies
to myelin basic protein in 19 out of 33 autistic children, compared with only 9% in a
control group
- reference to Todd and Ciaranellos detection of circulating antibodies in seven out
of thirteen children with autism
26. Paper, Dialysable Lymphocyte Extract In Infantile Onset Autism: A Pilot Study,
has been published (journal not identified) by Dr. H. H. Fudenburg of the
NeuroImmuno-Therapeutics Research Foundation, Spartanburg, South Carolina.
This studied 40 infantile autistic patients ranging from 6-15 years, of which 22 were
classical infantile autism ("true autism", or TA) and 18 lacking one or more
defects associated with infantile autism and were therefore termed "pseudo-autism
syndrome" (PAS). Medical histories focused on possible viral infection in the mother,
especially during second trimester, whether the child had multiple infections, especially
otitis media, in the first to fifteenth month of life, and the relation of onset of
symptoms to immunisation. Results were:
- antibodies to myelin basic protein were present in 20 out of 22 TA and 4 out of 18 PAS
children
- 12/22 TA and 6/18 PAS children had a decreased response to ConA and negative LIF
response to PHA and a decrease in suppressor functional assay (later studies showed a good
correlation of the above with low levels of CD8/CD28 and CD8/CD38 T-cells)
- 6/22 TA and 12/18 PAS children had increased toxic metal levels, usually aluminium) and
decreased levels of trace minerals necessary for a normal immune response
- 10/22 TA and 6/18 PAS children had elevated thyroid stimulating immunoglobin values
- titers to rubella were ten times normal in 11/22 TA and 5/18 PAS children
- several of the children had elevated IgM levels to measles, indicating a defect in
immune regulation
Fudenberg states that:
- the very low IL-2 receptor/positive lymphocytes and the decrease in DR+, but not IL-2
receptor+ lymphocytes, suggests incomplete activation in the TA children, a finding seen
in other autoimmune diseases; this suggests that TA may be an autoimmune disease
- it is possible that "auto-antibodies" are directed against various viruses and
that the reaction to myelin basic protein, neuron axone filaments, one or other receptors
for neurotransmitters, represent molecular mimicry
- TA is probably due to adverse reactions to live virus or live virus vaccine in a
genetically-predisposed individual, one whose cell-mediated arm of his/her immune system
is not yet mature, or, in a very young infant, by transplacental IgG antibodies from a
mother with high titers of antibodies to one of the vaccine constituents, e.g. diptheria
toxin
27. Unpublished paper by Dr. Vijendra Singh at the College of
Pharmacy, University of Michigan, Ann Arbor, jointly with the late Professor Reed
Warren, Professor of Biology at the Centre for Persons with Disabilities, Utah
State University in Logan and Adjunct Professor of Psychiatry at the University of Utah,
and also Dennis Odell
This studied the immune responses to myelin basic protein, which is a protein component
of myelin. Defects in myelin would dramatically affect brain activity. The study of 33
autistic children at or over ten years old was compared with eighteen age-matched normal
children. twenty children with unknown-cause mental retardation and twelve children with
Down syndrome were also studied as controls, and testing for serum antibodies to MBP
undertaken:
- antibodies were found in nineteen of the 33 (58%) of autistic children
- the corresponding level for controls was 7%, or over eight times higher
- testing of the autistic children showed features also found in patients with autoimmune
diseases such as rheumatoid arthritis, insulin-dependent diabetes and multiple sclerosis
The features above included genetic predisposition, gender imbalance (four or five
times higher frequency in boys than girls), major histocompatibility association, and
immune activation.
- The authors suggest that autoimmunity may be a critical factor in the cause of autism.
- They note that an essential part of the autoimmune mechanism should involve
antibody-mediated immune responses or antibodies against the brain, and that other recent
studies have found evidence of antibodies to brain tissue antigens, such as myelin basic
protein, neurofilament proteins and serotonin receptor.
- They also note that antibodies to MBP may have some pathological relevance since
abnormal cell-mediated immune response involving a soluble factor but not antibodies to
this protein has been detected by other researchers, suggesting that autistic children
develop inappropriate immune responses to this brain protein.
- They conclude that at present (1992) the relationship between antibodies to MBP and
autism was not understood, but they hypothesised that the development of the immune
response could be the basis of autoimmune pathogenesis in some cases of autism. It was
conceivable that if an immunological assault was to occur before birth or during infancy
or early childhood, it could lead to poor myelin development or abnormal function of the
nerve fibre myelin.
28. Further unpublished US paper, from Dr. Vijendra Singh
This suggests that:
- a significant number of autistic children have positive titers of measles and/or MMR
autoantibody which is associated with the presence of myelin basic protein autoantibody
- a measles-related triggered autoimmune response to myelin may play a pathogenesis role
in the cause of autism in at least a subset of cases
29. Paper by Singh, Warren, Odell, Warren and Cole, published in Brain
Behaviour 1993 March 7(1) 97-103
This investigated the possible pathological relationship between autoimmunity and
autism, reported that:
- antibodies reactive with myelin basic protein (anti-MBP) had been investigated in the
sera of autistic children
- nineteen out of 33 (58%) of sera of autistic children under or equal to age ten were
found to be positive for anti-MBP
- in controls, only eight out of 88 (9%) were positive; controls were age-matched and
included normal children and children with mental retardation or Downs Syndrome, as well
as normal adults aged 20-40.
30. Paper by Weizman, Weizman, Szekely, Livni and Wijsenbeek,
published in the American Journal of Psychiatry 1982 Nov 139 (11) 1462-5
This reported a study by macrophage migration inhibition factor test, in seventeen
autistic patients and a control group of eleven patients suffering from other mental
diseases, of cell mediated immune response to human myelin basic protein. It found:
- of the seventeen autistic patients, thirteen demonstrated inhibition of macrophage
migration
- none of the non-autistic patients showed such a response
- the results therefore indicate the existence of a cell-mediated immune response to brain
tissues in autism
31. Paper by Drs. Gupta, Aggarwal and Heads, titled Dysregulated
Immune System in Children with Autism - Beneficial Effects of Intravenous Immune Globulin
on Autistic Characteristics, published in the Journal of Autism and Developmental
Disorders, vol. 26 no. 4 1996
This suggested a theory that high titers of rubella antibody present in mothers of
children with autism could be transplacentally transferred and could persist in the child,
and that when the child received MMR, rubella antigen may complex with pre-existing
antibodies, thereby possibly playing a role in the pathogenesis of autistic features
32. Unpublished US paper, by Dr. Oleske and Assistant Professor Zecca,
New Jersey Medical School
This found that:
- among 16 children diagnosed with autism, there was a threefold increase in their serum
rubeola titers over the expected normal range
- the unusually high and persistent titers of anti-measles antibodies in autistic children
was statistically significant when compared with a similar group of non-autistic subjects
- it is suggested in the paper that MMR may play a role in the pathogenesis of autism
because elevated titers of anti-measles antibodies may signify a chronic over-activation
of the immune system
33. US paper by Teresa
Binstock, Researcher in Developmental
and Behavioural Neuroanatomy, IMI, Denver
This found that
- brain regions whose pre-vaccination neuronal damage had been relatively insignificant
may, via vaccine-induced clonal expansions, suffer additional damage.......resulting in
vaccination-enhanced neuropathy presenting clinically as autism
- recent research findings are instructive regarding autistic children for
whom.......medical records show a history of infections, antibiotic treatments,
vaccinations and temporally-associated onset of autistic traits.........
- nearly any vaccine may have the potential for inducing neuronal damage in persons with
NdEs." (Source: Hypothesis: Infection, Antibiotics, Vaccination-Induced
Neuropathies; Mechanism Of Pathogenesis In Some Cases Of Autism, ADHD, Tourettes, by
Theresa C. Binstock, bit.listserv.autism 3rd January 1997)
- although presented as a hypothesis, a route is offered that demonstrates how a small
subset of susceptible infants could be affected, that a variety of vaccines could be
involved for this subset of cases, and that prior treatment with antibiotics may play a
critical role
34. Paper by Diane E. Griffin, D. E. Hussy et al, John Hopkins University,
US, has established (source: Journal of Infectious Diseases, 173 (6), 1320-26, June
1996)
This found that:
- measles virus and measles vaccinations impair cell-mediated immunity
- they also increase the likelihood of other viral infections
These researchers found that:
- of 88 children immunised at six or nine moths with Edmonston-Zagreb or Schwarz SW6 or
SW9 strain of measles vaccine, mitogen-induced lymphoproliferation was decreased at 2
weeks in the SW9 group and at 3 months in all groups
- this was negatively correlated with measles antibody level at 3 months
- CD8 T-cells, soluble CD8, neopterin and beta2-microglobulin were increased at 2 weeks in
the SW9 group
- soluble CD8 and beta2-microglobulin remained elevated at three months
- therefore measles immunisation resulted in suppression of lymphoproliferation, which was
most evident in infants with the highest antibody responses and most immune activation
35. Paper by P. G. Auwaerter and Diane Griffin, (source: Clinical Immunolgy
and Immunopathology, 79(2): 163-70, May 1996):
This found that:
- measles produces immune suppression which contributes to an increased susceptibility to
other infections
- high-titred measles vaccines have been linked to increased long-term mortality among
some female recipients
- vaccines can impair cell-mediated immunity by shifting cytokines release into a Th2
pattern, thereby allowing intracellular pathogens (e.g. many viruses) to be more
successful
36. Paper by Martinez et al, (source: Proceedings of the National Academy of
Sciences, 94.8726-31 1997):
This found that:
- relative deficiency of T-helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) responses
in early life is associated with an increased susceptibility to infections by
intracellular microorganisms
- this is likely to reflect a preferential polarisation of immature CD4 T-cells towards a
Th2 rather than a Th1 pattern upon immunisation with conventional vaccines
37. Early Report by Dr. Andrew Wakefield and team, Inflammatory Bowel Disease
Study Group at the Royal Free Hospital, London
Dr. Wakefield suggested in early 1998 that there could be the possibility of a linkage
between vaccination and autism and other disorders. Although he was not in a position at
that time to present the published evidence of comprehensive studies, his initial findings
suggested that his hypothesis was plausible. The Royal Free Hospital study found:
- that there was patchy inflammation of the colon and swelling of the lymph glands in the
last part of the small intestine in 39 out of 40 children studied that had developmental
disorders. All the children had previously gone through periods of normal development, ad
most had acquired words and social skills which were subsequently lost
- most children had suffered either diarrhoea or alternating periods of diarrhoea or
constipation, frequently associated with bloating, abdominal pain and poor appetite, and
occasionally the passing of blood
- parents reported in some cases that certain foods made their childs symptoms
worse, and witholding those foods improved behaviour
- this implied that there could be a syndrome that linked intestinal inflammation with
developmental disorders of the autistic spectrum, and could offer a vital clue in
understanding the origins of some forms of childhood autism
Dr. Wakefield also speculated that if the bowel was damaged during a critical period of
brain growth, an excess of peptides could gain access to the developing brain, where these
peptides may not only influence behaviour but also brain growth and development. The
disease pathway was described as "speculative but biologically plausible".
No evidence to contradict this hypothesis has been offered to date by the UK Department
of Health, and the Department has yet to offer evidence of its own that degeneration into
autism or the onset of inflammatory bowel disease following vaccination is caused by some
other source.
38. Letter published in The Lancet, Vol. 352, July 18th 1998, from Drs. Sabra,
Bellanti and Colon of the International Centre for Interdisciplinary Studies of
Immunology and the Department of Paediatrics, Georgetown University Medical Centre,
Washington DC
This stated that:
- in support of the findings of Dr. Andrew Wakefield are several behavioural and clinical
features known to be related to the central nervous system, such as infantile colic and
attention-deficit hyperactivity disorder, which have been related to food allergy
- the US researchers had noted a striking appearance of ileal-lymphoid nodular hyperplasia
in patients with non-IgE-mediated food allergy who had presented a range of conditions
including asthma and attention-deficit-hyperactivity disorder
- examination of two cases with hyperactive disorders who were intolerant to various
foods, by colonoscopy of their terminal ileum, had produced findings match those of
Wakefield et al
- ileal-lymphoid nodular hyperplasia lesions of the gastrointestinal tract allowed the
entry of antigens across the inflamed mucosa of the bowel as a result of the reactive
inflammatory response in the adjacent lymphoid tissue of Peyers patches in patients
with non-IgE-mediated food allergies
- the researchers proposed that similar mechanism(s) may be involved in the pathogenesis
of the central nervous system dysfunction in the patients described by Wakefield et al
39. Dr. Edwin Cook, Director of the Laboratory of Developmental Neuroscience,
university of Chicago, in a joint paper with Courchesne, Lord, Cox, Yan, Lincoln Haas,
Courchesne and Leventhal, published in the May 1996 edition of Molecular Psychiatry
This noted that:
- it was a well-established finding that a significant number of people with autism have
elevated levels of blood serotonin, and the successful use of medications (potent
serotonin transporter inhibitors, or PSTIs) suggest the possibility that serotonin plays a
role in autism
- the authors studied 86 people with autism and their parents to examine whether the gene
for the serotonin transporter may contribute to the risk of autism. They found evidence of
a significant relationship
- it was possible that the serotonin transporter gene HTT was serving as a marker in
linkage disequilibrium with a genomic variant which was contributing to susceptibility to
autistic disorder
- several lines of evidence suggested the serotonin transporter as the most logical
candidate gene, based on existing evidence, but many other candidates could be considered
on only slightly weaker evidence
- the short variant at the serotonin transporter locus was found to be preferentially
transmitted from parents to children with autistic disorder, and this provides preliminary
evidence that the serotonin transporter may serve as a susceptibility locus in autistic
disorder. This finding may contribute to identification of other factors which add
additively or in a multiplicative manner
40. The late Dr. Reed Warren, formerly Professor of Biology at Utah State
University in Logan, set out a pathogen-autoimmune hypothesis for autism:
- some children are susceptible to an environmental pathogen, probably a virus or
bacterium, resulting from an inherited deficiency of their immune system
- unable to clear the pathogen, the child is at higher risk for the pathogen to damage the
developing brain or trigger an autoimmune response
- the pathogen would not necessarily create gross neuronal damage, but have more subtle
effects on portions of the brain controlling behaviour
- although not a requirement, the pathogen might persist and replicate slowly or be
maintained in homeostasis by the immune system
Dr. Warren outlined the possibility of several key factors, which included:
- exposure to a certain pathogen at a vulnerable time, i.e. at the time the central
nervous system is undergoing rapid development
- the existence of an immune susceptibility or deficiency that would allow a pathogen to
persist
- a genetic constitution that allowed certain T cells to react to the pathogen in such a
way as to cause reactivity against the central nervous system or products of the central
nervous system such as neurotransmitters
- in some cases an immune susceptibility or deficiency in the immune system of the mother
that may permit a pathogen to be present in utero or allow an immune response within the
foetus
- in some cases, a purported immune mechanism may have not caused irreversible damage to
the central nervous system but is only interfering with brain function such as by binding
to various neurotransmitters or their receptors
41. Warren and Singh studies
In his own studies, jointly with Singh et al, published in the journal Immunogenetics
36:203-207 of 1992, he noted that:
- of the 46 chromosones of 23 patients, 27 chromosones (58.7%) had an extended haplotype
as compared to an unrelated control group in which 33/128 (only 25.8%) of chromosones
carried an extended haplotype
- the frequency of extended haplotypes on chromosones of autistic children was much
greater than that on family-parent normal chromosones, the latter being only 30.7%
- in the initial and later studies, only eight out of 45 autistic subjects did not have an
extended haplotype, and fifteen autistic subjects carried an extended haplotype on each of
their chromosones
- also, the mothers but not the fathers of the autistic children had an increased
representation of extended haplotypes
- an additional control group of subjects with general severe learning difficulties had a
haplotype frequency of 26%, similar to that of the earlier-mentioned unrelated controls
He noted that many normal individuals possess one or more of the above factors, but it
would only be those children that possessed all of these, plus probably others,
simultaneously, where autism would occur. He also noted that four season-of-birth studies
had found an excess of births in the month of March, and that, if a pathogen was involved
in autism, it was conceivable that it was more prevalent during early winter so as to
affect March babies. He also noted that four to five times more boys than girls were
affected by autism, but that autoimmune diseases were often more common in one sex, with
the influence of sex hormones on immune functions well-established. He further noted the
link between genetic background and frequency of infections:
- the products of the C4A and C4B genes are crucial to the activation of the other vital
components of complement involved in protection against viruses, bacteria and other
infectious agents
- C4A proteins bind avidly to amino-rich surfaces and C4B proteins form linkages with
hydroxyl-containing carbohydrate surfaces
- deficiency in the C4 proteins especially C4B has been associated with increased viral
and bacterial infection
- inherited abnormalities of the complement C4 proteins are linked to certain autoimmune
diseases
42. Paper by Kulman, Neri, Rovelli, Roselli, Lissoni and Bertolini, Divisione di
Neuropsichiatria Infantile, Ospedale S. Gerardo, Monza, Italy
This examined the role of the pineal hormone melatonin (MLT) in the pathogenesis of
autism. The study included 14 children affected by autism, median age seven years, mostly
suffering sleep disorders, and found that:
- no patients exhibited physiological MLT increase during the night
- mean serum levels of MLT observed during the night were significantly lower in patients
than controls
- there was therefore an indication of severe pineal function damage
- the absolute lack of MLT increase during the night would justify exogenous
administration of MLT as replacement hormonal therapy
43. A USA parents group, the Developmental Delay Registry, has reported that of
nearly 700 children aged between one and twelve that had been surveyed in 1994:
- those that had taken more than 20 cycles of antibiotics in their lifetime were more than
50% more likely to suffer developmental delays
- nearly 75% of the developmentally-delayed children had been reported as developing
normally in their first year of life
- developmentally-delayed children were 37% more likely to have had three or more ear
infections than non-developmentally delayed children
- developmentally-affected children were nearly four times as likely to have had adverse
reactions to immunisations
44. Other Researchers Who Believe Link Possible
- Published evidence by Stratton et al ("Adverse Events Associated With Childhood
Vaccines", National Academy Press 1994, 64-65) states "In the course of
its review the committee encountered many gaps and limitations in
knowledge.......(including) inadequate understanding of biological mechanisms underlying
adverse events, insufficient information from case reports and case series, inadequate
size or length of follow-up of many population-based epidemiologic studies".
- A paper published by Bitnun et al, Clinical Infectious Diseases Journal, October 1999,
confirmed the presence of measles virus in the brain tissue of a previously-healthy
21-month-old boy, 8.5 months after he received MMR. The child had no history of exposure
to measles or if immune deficiency. The nucleotide sequence in the nucleoprotein and
fusion gene regions was identical to that of the Moraten and Schwartz vaccine strains. The
fusion gene differed from known genotype A wild-type viruses.
45. Statement by Professor Walter O. Spitzer
Although not a study, the statement by Professor Spitzer deserves a high profile.
Professor Walter O. Spitzer, Emeritus Professor of Epidemiology, McGill University,
Montreal, stated on December 6th 2000:
- "The safety of MMR has been brought into question, both in the United Kingdom
and in California. It is not possible to rule out the possibility that excessive rates of
autism occur among children immunised with MMR"
- "The early epidemiological findings are worrisome. The clinical and laboratory
data strongly suggest the biological plausibility of a link between MMR and autistic
disorders"
- He "......strongly endorses immunisation as a pillar of public health strategy
for most diseases. But one should never surrender caution".
46. Wakefield & Montgomery "Through A Glass Darkly" Paper (Look
Back At MMR Safety Trials), Journal of Adverse Drug Reactions, 2000 19(4), 265-283)
Wakefield & Montgomery reviewed following safety studies: Buynak et al 1969, Stokes
et al 1971, Minekawa et al 1974, Schwartz et al 1975, Crawford and Gremillion 1981, Miller
et al 1987.
- Buynak study identified viral "interference". Follow-up only 12 days
- Stokes study revealed persistent gastrointestinal problems in US trial children.
Follow-up only 28 days. Stokes compared 228 MMR children with 106 unvaccinated controls.
Data, from Philadelphia and Costa Rica and San Salvador, was combined - serious
methodological error.
- Gastroenteritis significantly more common in Philadelphia vaccinees (24%) compared with
unvaccinated Philadelphia controls (5.6%). No significant difference between vaccinated
and unvaccinated in Costa Rica and San Salvador because of high levels of gastroenteritis anyway
(50% in vaccinees, 44% in controls). Combining all the data masked these instructive
differences.
- Also significant "unrelated" illness in 39% of Philadelphia vaccinees (otitis,
allergy, viral infection, abdominal pain), compared with 12.2% controls. Relevance not
seen at time.
- Minekawa study confirmed viral interference. Follow-up only 15 days.
- Schwartz study also merged its data, so provided insufficient insight. Follow-up only 21
days. Looked at two different populations, 282 children in Ohio and 926 children in Santo
Domingo, Dominican Republic. Merging of data from different countries again a serious
error. No data provided to permit analysis of adverse events.
- Crawford and Gremillion study of USAF recruits confirmed viral interference. Follow-up
only 19 days. Some 512 vaccinees were compared with 835 unvaccinated controls. Study noted
increased fever and diarrhoea in those that received measles and rubella vaccines
simultaneously. Effect not ADDITIVE but SYNERGISTIC - key point.
- Eddes study (small UK study) 1991 compared reactions to MMR with monovalent measles
vaccine. High rates of gastrointestinal disorders (41.9% and 37.8%). Authors dismissed
these as normal background illness.
- Miller study noted diarrhoea common (26% of vaccinees). Follow-up only 21 days. Major
missed opportunity of following up large cohort. (NB Dr. Elizabeth Miller, who has been so
vociferous in criticising the Wakefield findings and in defending MMR, including
presentations to MP groups, was co-author, and designed the poor 1999 Taylor, Miller North
London study)
- Stokes, Schwartz, Miller and Eddes studies were all too small or too superficial to pick
up uncommon adverse events.
- Plesner et al study of gait disturbance following MMR (Acta Paediatrica, 2000, 89,
58-63) confirmed association and indicated more severe cerebellar ataxias following MMR
may be associated with residual cognitive deficits.
Peer review comments on Wakefield & Montgomery paper very powerful. Peer reviewers
included Dr Peter Fletcher, former Principal Medical Officer in Medicines Division (now
MCA), who was medical assessor to Committee on Safety of Medicines. His comments:
- "Evidence on safety very thin", and "Too few followed for
sufficient time"
- "Big numbers were necessary, and computerised databases already in place to
permit this, but was not done"
- "Caution should have ruled the day", and "Should have been
strong encouragement to conduct 12-month observational study on 10,000-15,000
children" (not done)
- "Granting of product licence was premature"
Wakefield paper is actually argument for vaccination - but not using
triple measles-containing vaccines. Wakefield not anti vaccination per se. Duty is
to patient. He is investigating children brought to him, not campaigning against DoH for
its own sake. He is simply relating what he is finding.
Other background points relevant to paper:
- Is already accepted by Medical Research Council that concurrent exposure to natural (or
vaccine) measles and natural mumps is a risk-factor for inflammatory bowel disease
- Also is legal precedent for triple vaccine causing autism (Lassiter case, US, 1996).
This was a DPT vaccine, but established important ruling on probability of causation.
- MCA has left itself an escape route for later: "The numbers included in the
trials, even if they were all followed up long term, would not be sufficient to detect
rare problems.....". But what is "rare"?
47. The Wakefield/Watson/Shattock Rebuttals - "Anything You Can Rebut, I Can Rebut
Better"
Through A Glass Darkly safety paper by Wakefield and Montgomery has been criticised
by Mike Watson, Medical Director of Aventis Pasteur MSD, the manufacturers of MMR.
But Watsons criticisms do not themselves stand up to scrutiny, as demonstrated
below by Paul Shattock of Sunderland University Autism Research Unit (tel 0191 515 2000).
The only aspects that cannot be bottomed-out by Shattock are where the studies themselves
have not been published.
- Watson maintains that observation period in trials (as reported in paper by Stokes et
al, 1971) was up to 63 days, not up to 28 as reported by Wakefield. However, Shattock
quotes Stokes study as saying "Joint involvement was noticeably absent during six
to nine week follow-up....Present studies with queries at six to nine weeks following
vaccination did not reveal any occurrence of arthritis or arthralgia beyond the 28-day
period for close observation". Trial therefore was 28 days, with only queries for
arthritis etc beyond this. Wakefield version therefore correct.
- Watson maintains that "MMR I" safety was investigated in four studies prior to
licensing in US 1971 and UK 1972. Also, "MMR II" investigated by seven studies,
two of which published. Immruvax also tested in seven studies. But Shattock: unclear
whether studies are published or secret. (Please publish?) Wakefield can only comment on
what is published.
- Watson states that virologists generally accept wild measles virus only causes
persistent disease in central nervous system, as subacute sclerosing panencephalitis
(SSPE) or measles inclusion body encephalitis (MIBE). Wakefield maintains potential for
delayed intestinal pathology has been borne out by Fournier et al, 1968. Shattock:
technology has failed to isolate measles virus RNA in affected children, but further
progress expected.
- Watson states that mutant measles virus genetic material can persist in tissues of
apparently healthy people without causing disease (Katayama et al, 1998). Shattock: so
mutant measles can persist but vaccine strains cannot? - challenge for evidence to
substantiate this claim.
- Shattock also makes points that (a) MMR test group in Stokes 1971 paper had way more GI
problems than controls, (b) that in Schwartz et al paper 1975 the results of 282 children
from Daytona Ohio and the 1192 from Santo Domingo and Panama were pooled (unscientific),
and (c) why was gastroenteritis completely omitted from list of side effects when
difference of incidence between groups so blatant?
- Watson: "gold standard" in safety studies was placebo-controlled crossover
study of 1162 twins in Finland 1982. More detail published by Virtanen, Peltola et al
2000. Shattock: was 1982 study published?/where? The 2000 paper was actually only
published after Wakefield & Montgomery paper submitted.
- Wakefield: follow-up interval reduced from 4 weeks in initial controlled trial to 3
weeks in subsequent trials. Watson: insists follow-up was up to 63 days. Shattock:
observations were for 28 days. At up to 63 days, parents asked about any significant
illness - side effects listed in paper apparently excluded. No doubt Wakefields 28
days is right.
- Watson: later MMR II studies had observation period of 42 days. Priorix studies had
periods of 42-60 days. Shattock: where are publication details?
- Watson: numerous post-marketing studies of MMR have been conducted and published.
Shattock: references please? Why havent they been quoted by DoH, why cant
anyone find them?
Other "facts" quoted by Watson in "Aventis Pasteur MSD - Vaccines For
Life" paper:
- Watson: "national safety regulators require all side effects to be reported".
But this doesnt mean they actually are, especially novel syndrome with (up till
1998) no publicity, delayed onset, and official refusal to count as "adverse
reaction"
- Watson: "there have been over 500m doses given worldwide". But there
are also many hundreds of thousands of cases of autism worldwide, and none of these has
been admitted by authorities to be consequence of MMR, keeping its safety record
clean.......
- Watson: "As anyone in clinical trials knows, all participants or their parents
are very carefully informed and consented". Yes, but this wouldnt have
covered a warning to watch out for subsequent delayed degeneration into autism!
- Watson: "Any unusual event that occurs in that child at any time after trial
should be reported to MCA". But this would almost certainly never have
included autism pre-1997, when very first publicity was given in Pulse magazine and BBC
Newsnight. (In Oliver Thrower case, Newsnight report 8/97 was first clue, nine years
after vaccination. In his case, vaccination never previously mentioned or considered as
possibility by health professionals. He was added to MCA database 11 years after
vaccination. So much for the value of even a 63-day trial follow-up!)
- Watson: "An unimmunised child is the infectious equivalent of a drunk driver".
This comment is a revealing insight.
- Watson: "Giving vaccines separately would be more expensive". More
expensive than all the extra health costs, care costs, special education costs, special
needs transport costs, lost earnings of victim, lost tax revenues, parents lost
earnings and taxes?
- Quote from MSD product insert on MMR: "Clinical studies of 279 triple
seronegative children, 11 mths to 7 years of age, demonstrate that MMR is highly
immunogenic and generally well tolerated." (So is just 279 the number?)
48. UK Department of Health Repudiation of Wakefield & Montgomery "Through A
Glass Darkly" Paper
The UK DoHs response was summarised in its press release of 21st January 2001.
The main points are set out below, with the DoH in italics, and with my own responses
following.
- The claim by Wakefield & Montgomery that there was insufficient research "is
factually incorrect, as many studies recorded safety data up to six weeks, which is
standard for vaccines, and some studies recorded data for longer - up to a year in some
cases". Yes, but autism did not form part of this surveillance, the importance of
gastrointestinal problems was not appreciated, the reference to six weeks being
"standard for vaccines" doesnt address the autism/gut syndrome, and very
few cases indeed, in very few studies indeed, followed up for longer than a few weeks. The
syndrome was missed.
- "Combined MMR vaccines had been extensively tried and tested in Scandinavia and
the USA before they were introduced in the UK in 1988". As a statement, this
proves nothing. The new syndrome of autistic enterocolitis was not suspected in
these countries, either, and again was missed.
- "Now MMR is successfully used in over 30 European countries as well as the USA,
Canada, Australia and New Zealand". Same comments apply. Presumably, these
other Governments are claiming that "its safe because its used in the
UK"?
- "A publication in 1988 lists 30 published studies where combined MMR vaccines
were studied and follow-up extended up to ten years". Same comments again apply.
(See also the Wakefield/Watson/Shattock rebuttals section)
- "The safety of combined MMR vaccines has been reviewed repeatedly by the
Governments independent expert scientific advisory committees including the
Committee on Safety of Medicines and the Joint Committee on Vaccination and Immunisation".
This is true in a literal sense, but the reviews have been mis-designed and halfhearted or
inconclusive ("It was impossible to prove or refute the suggested
association between MMR vaccine and autism/pervasive development disorder or inflammatory
bowel disease because of the nature of the information, the self-selection of cases and
the lack of comparators" - Committee on Safety of Medicines Report of the Working
Party on MMR Vaccine, page 12, paragraph 5.5).
- One can also argue that the Committees quoted are neither independent (see other
references) nor expert in the field of gastroenterology, as opposed to immunology. They
stand to lose a great deal by a link being exposed, both corporately and individually, and
possibly financially.
- "The use of MMR vaccine is also endorsed by the World Health Organisation, the
British Medical Association, the Royal College of General Practitioners and the Royal
College of Nursing." This in itself proves little in the context of an intense
scientific debate about a new discovery in gastroenterology. The latter institutions may
come to regret their endorsement in the fullness of time. Have their advisers read all the
evidence, on both sides, first-hand?
- "By 2000, several hundred million doses will have been given wordwide".
Yes, and there will also be several tens, or hundreds, of thousands of cases of autism
worldwide, some of which may have been precipitated by MMR.
In short, the DoHs rebuttal was a "non-denial denial". It sought to
refute the Wakefield/Montgomery paper, but was almost entirely couched in generalities.
The devil is in the detail of the Wakefield/Montgomery paper. And the DoH was unable to
refute this detail - indeed, it largely avoided addressing it at all.
49. Department of Health Re-Launch of MMR, 22/1/01
On 22/1/01, DoH launched £3m publicity campaign for MMR and rejected Wakefield
"Through A Glass Darkly" MMR safety-test paper, without:
- Announcing any investigation into affected children
- Any additional funding for research into causes of autism (however, see later DoH/MRC
announcement of 5th March 2001)
- Any explanation as to why autism is rising so steeply in UK and around the developed
world (again, see DoH/MRC announcement of 5th March)
- DoH also released 15-page paper, "Combined MMR Vaccines: Response of the Medicines
Control Agency and DoH" to attempt to refute Wakefield paper. However, paper merely
re-assembles previous studies quoted by DoH, and adds nothing new of note.
- The Chairman of the Committee on Safety of Medicines, Professor Alasdair Breckenridge,
said "MMR vaccination is very safe. There is no question-mark whatever over its
licensing". (Breckenridge is one of the 10 - out of 37 - members of the CSM to
have no declared interests whatever).
- Professor Michael Langman, chairman of the JCVI, said "My Committee has
independently (sic) considered all the issues and reached the same position as the
Committee on Safety of Medicines". Langman has non-current non-personal declared
links with Merck Sharpe Dohme.
- The Chief Medical Officer, Professor Liam Donaldson, said "We are very pleased
to have this further confirmation from the two independent expert committees".
- Some parents feel that, in the absence of conclusive evidence, either way, and taking
all the surrounding factors into account, the re-launch of MMR was a serious error,
leaving the authorities no escape should the test cases win in the High Court. The
Department of Healths high-risk strategy would, if this was the outcome, severely
damage public confidence, probably in all forms of immunisation. The repercussions for the
Department, and for child health generally, would be significant. The Departments
actions seem to have not countenanced this potential scenario.
Part G - Flawed UK Regulatory
and Monitoring Systems
MMR and Late-Onset Autism -(Autistic Enterocolitis) - A
Briefing Note by David Thrower