• 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 Singh’s 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 Ciaranello’s detection of circulating antibodies in seven out of thirteen children with autism

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

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, Tourette’s, 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 child’s 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 Peyer’s 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 Watson’s 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 Wakefield’s 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 haven’t they been quoted by DoH, why can’t 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 doesn’t 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 wouldn’t 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 DoH’s 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" doesn’t 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 "it’s safe because it’s 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 Government’s 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 DoH’s 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 Health’s 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 Department’s actions seem to have not countenanced this potential scenario.