MMR and Acquired Autism (Autistic Enterocolitis)

A Briefing Note by David Thrower April 2002

Executive Summary

Part A: A Novel Syndrome
1. What Is Acquired Autism/Autistic Enterocolitis
2. The New Syndrome
3. Recognised Adverse Reactions to MMR
4. Contraindications To Receiving MMR
5. Families Taking Legal Action
6. The UK Department of Health’s Position
7. The Parents Have Seen What They’ve Seen.....

Part B: The Costs of Autism
8. The Financial Costs - Autism Is Costing Billions
9. Estimates
10. Failure to Monitor Increases In UK Autism Numbers
11. "Now Almost Everyone Knows Someone Who’s Autistic"
12. University of Cambridge Research
13. University of Sunderland Research
14. National Autistic Society Estimates
15. Report by Fiona Loynes for UK All Party Parliamentary Group, Dec. 2001
16. Is Autism Increasing? - Some Recent Official UK Pronouncements
17. Autism In The USA
18. California
19. New Jersey

Part C: Studies That Have Been Used To Disprove An MMR/Autism Link
20. Stokes et al paper, Journal of American Medical Association (JAMA), Oct. 1971
21. Study by Peltola and Heinonen, Lancet, April 1986
22. Paper by Miller, Miller et al, The Practitioner, January 1989
23. Gillberg Study, Sweden, British Journal of Psychiatry, 1991
24. Commentary by Gillberg and Heijbel, Autism, 1998
25. Letter by Fombonne, Pediatrics, March 1998
26. UK Committee on Safety of Medicines Study, June 1999
27. Paper By Taylor, Miller and Farrington, Lancet, June 1999
28. Paper by Miller & Farrington to US Government Reform Committee, April 2000
29. Patja, Peltola et al Study, Finland, Pediatric Infectious Disease Journal Dec. 2000
30. Kaye, Melero-Montez and Jick Study, British Medical Journal, 2000
31. Fombonne Paper, Pediatrics, January 2001
32. Dales, Hammer and Smith Study, JAMA, March 2001
33. De Wilde, Carey & Richards Study, Br. Journal of General Practice, March 2001
34. Davis et al study, Archive Pediatrics Adolescent Medicine, 2001
35. Further Paper by Farrington, Miller and Taylor, Vaccine Journal, 2001
36. Fombonne & Chakrabarti Study, Pediatrics, October 2001
37. Further Paper by Taylor, Miller et al, BMJ.com, February 2002

Part D: Reviews That Conclude There Is No Evidence Of A Link
38. Medical Research Council Ad-Hoc Review, March 1998
39. Presentation by Miller to UK All Party Parl. Group on Primary Health Care, 2000
40. Medical Research Council Sub-Committee Report, March 2000
41. Review by US Institute of Medicine, 2001
42. Elliman, Bedford and Miller Review, Arch. of Diseases in Childhood, Oct. 2001
43. Medical Research Council Review, July-December 2001
44. Further Review by US Institute of Medicine, February 2002

Part E: The MMR Original Safety Trials Debate
45. Wakefield & Montgomery "Through A Glass Darkly" MMR safety-studies paper
46. Dr. Peter Fletcher Commentary, Journal of Adverse Drug Reactions, 2001
47. Dr. Stephen Dealler Commentary, Journal of Adverse Drug Reactions, 2001
48. Dr. F. Edward Yazbak Commentary, Journal of Adverse Drug Reaction, 2001
49. The Wakefield/Watson/Shattock Rebuttals
50. The UK Department of Health’s Repudiation of "Through A Glass Darkly".

Part F: Studies/Papers That Point Towards An MMR Link
51. Paper by Eggers, Klinical Paediatrics, March 1976
52. Weizman, Weizmann, Szekely et al Study, Am. Journal of Psychiatry, Nov. 1982
53. Delgiudice-Asch and Hollander Study
54. Fudenberg paper
55. Paper by Dr. Reed Warren
56. Warren and Singh Study, Immunogenetics, 1992
57. Singh, Warren, Odell, Warren and Cole Paper, March 1993
58. Singh, Warren, Odell et al Study, Brain Behaviour, March 1993
59. Oleske and Zecca paper
60. Binstock paper
61. Anne-Marie Plesner Letter, Lancet, February 1995
62. Gupta, Aggarwal and Heads Study, Journal of Autism and Dev. Disorders, 1996
63. Montinari, Favoino and Roberto paper, Naples conference May 1996
64. Auwaerter and Griffin paper, Clinical Immunology and Immunopath., May 1996
65. Cook, Courchesne et al Paper, Molecular Psychiatry, May 1996
66. Griffin and Hussy Study, Journal of Infectious Diseases, June 1996
67. Martinez et al Study, Proceedings of National Academy of Sciences, 1997
68. Paper by Zecca, Graffino et al, Meeting of National Inst. of Health, Sept. 1997
69. Weibel, Caserta and Evans Study, March 1998
70. Wakefield et al "Early Report", Lancet, February 1998
71. Paper by Montgomery, Morris et al (publication date/details not yet known)
72. Sabra, Bellanti and Colon letter, Lancet, July 1998
73. Further Unpublished Paper by Singh and Yang, October 1998
74. Uhlmann, Sheils et al Paper
75. Bitnun et al Study, Clinical Infectious Diseases Journal, October 1999
76. Paper by Dr. Singh to the US Committee on Government Reform, April 2000
77. O’Leary Paper Presented to US Congressional Oversight Committee, April 2000
78. Kawashima, Takayuki et al Study, Digestive Diseases and Sciences, April 2000
79. Hagenbuch, Kullak-Ublick et al Study, Journal of Pharm. Exp. Ther., July 2000
80. Wakefield et al Paper, American Journal of Gastroenterology, September 2000
81. Statement by Professor Walter O. Spitzer, December 2000
82. Furlano, Anthony et al Study, Journal of Pediatrics, 2001
83. Study by Jyonouchi, Sun and Le, J. Allergy & Clinical Immunology, Feb. 2001
84. Study by Jyonouchi, Sun and Le, J of Neuroimmunology, 2001
85. Paper by Spitzer, Aitken et al, Journal of Adverse Drug Reactions & Tox., 2001
86. Paper by Dr. Ken Aitken to the Scottish Society for Autism, 2001
87. Paper by Imani and Kehoe, Clinical Immunology, September 2001
88. Paper by Dr. Timothy Buie, Oasis 2001 Conference for Autism, Portland, US
89. Paper by Uhlmann, Wakefield, O’Leary et al, J. of Clinical Pathology, Feb. 2002
90. Paper by Singh and Nelson, February 2002

Part G: Other Potentially Relevant Papers
91. US Developmental Delay Registry Report, 1994
92. Stratton et al Study, National Academy Press, 1994
93. Paper by Carbone.
94. Iizuka, Saito et al Study, Gut, May 2001 (Mumps Study)
95. Statement by Spitzer, US House of Repres. Govt Reform Committee, April 2001

Part H: Future Papers Investigating A Link
96. Fombonne et al Study, London
97. Charman et al Study, London
98. Study by Professor Andrew Hall, London
99. Study by Takahashi et al, Tokyo
100. Study by Byrd et al, M.I.N.D. Institute, University of California at Davis

Part J: The Thiomersal Issue
101. Thiomersal’s Possible Role
102. Thiomersal In Vaccines: Statement of US AAP/Public Health Service, July 1999
103. UK Vaccines With Thiomersal
104. Scientific Review by US Centre for Disease Control, Simpsonwood, June 2000
105. Press Release by Waters and Kraus, March 2002
106. UK Medicines Control Agency Position

Part K: Flawed UK Regulatory and Monitoring Systems
107. Fighting Measles, Missing Autism, Overlooking Damage?
108. Has the Medicines Control Agency Missed the Syndrome?
109. UK Department of Health Re-Launch of MMR, January 2001

Part L: UK and US Political Initiatives
110. UK House of Commons Health Committee, Westminster
111 UK All Party Parliamentary Group on Autism, Westminster
112. Scottish Parliament, Edinburgh
113. UK Liberal Democrats
114. UK Conservatives
115. US House of Representatives Government Reform Committee

Part M: Some Conclusions and Some Unanswered Questions
116. Some Broad Conclusions
117. Some Unanswered Questions

EXECUTIVE SUMMARY

This note - which has been put together by the parent of a child who became autistic after immunisation - sets out the concerns of parents whose children have degenerated into an acquired-autistic state after MMR or measles vaccines.

It does not attempt to cover every single piece of the available scientific literature for or against an MMR/autism link, but it reviews about 70 of the most recent, most pivotal, or most frequently-quoted studies and papers.

Its key finding is that there has not been a single credible study that can robustly refute the claims of the parents that their children’s acquired autism has been caused by MMR or related vaccines. Each of the studies that seeks to "disprove" an MMR/autism link can be argued to be flawed in design or ambiguous in results. These flaws are discussed in detail in the text.

It also notes that all but one of the studies that seek to disprove an MMR/autism link did not look at the actual children themselves, but rather were based upon statistical analyses of the medical records of the wider population. Such epidemiological studies are not appropriate to the identification of relatively-rare adverse outcomes.

Such studies also fail to address the problem - what was it that damaged the specific children whose parents are now taking action through the UK High Court?

The one study that has both claimed there is no MMR/autism link and also actually looked at a sub-set of the damaged children was unable to prove or refute the suggested association with MMR on the basis of the information available - although it went on, despite this, to insist that MMR was safe.

Parents who have scrutinised the studies quoted by the Department of Health as "proof" of there being no link have found that such studies crumble easily when pressed. To give just one example, the Finnish study by Patja, Peltola et al was very loudly heralded at the start of 2001 by the Department of Health as convincing and conclusive proof that MMR was safe. After intense critical scrutiny by parents and media, by the end of 2001 the Medical Research Council was forced to admit that Patja, Peltola et al’s original 1998 paper "did not examine the relationship of MMR and autistic spectrum disorders.....and does not therefore provide useful evidence on this point." Of the later 2000 paper by Patja, Peltola et al, the MRC admitted: "The findings need to be interpreted with some caution, as cases of autistic spectrum disorder or bowel disorders not considered at the time attributable to MMR would not necessarily have been reported". Quite a retreat.

In contrast, the parents find that there are a number of studies that suggest that MMR could be causing acquired autism (or "autistic enterocolitis") in significant numbers of children.

Not all of these studies originate from only one group of researchers, as has sometimes been asserted by those who defend MMR. The studies that point to a link have involved a growing number of research teams, in several countries. Other studies, whilst not specifically targeting MMR, offer further clues as to what may be happening, and are consistent with an MMR involvement.

Furthermore, many of the studies that suggest that there is an MMR/autism link are based upon the scientific analysis of data gathered from detailed individual medical examination, and upon medical samples taken from the children concerned. These are the studies that actually seek to address the two key questions, "what is the damage sustained by this specific child, and what exactly precipitated the damage to this specific child?".

A "house of cards" has thus been constructed by the UK Department of Health over the past five years, with repeated assurances being given to the public, but with these being based upon a lop-sided, partisan and selective gathering and interpretation of the available evidence.

This briefing note also finds that there are other related concerns - from the regulatory bodies themselves - about the risk of permanent developmental damage from thiomersal-containing vaccines, though it is not yet clear whether these problems are directly interlinked biologically to the MMR/autism problems (MMR does not contain thiomersal). Class-action lawsuits are now under way in the US over thiomersal and autism, just as they are in the UK over MMR and autism.

Although complete and precise scientific proof of how the children have been damaged by vaccines and become autistic is still emerging, there have been numerous vital clues over the past five years or more - clues that all too often have been ignored, or, worse still, rejected out of hand, by the authorities.

The medical establishment has repeatedly asked itself the wrong question. It has asked itself "Is MMR safe?", hoping for an affirmative answer. In contrast, researchers and parents have asked two very different questions: "What is wrong with this child?", and "Why did this child change from being healthy to being autistic?". It is answering these latter two questions that should be the key issue.

The children that have been damaged have had their lives ruined. They were previously healthy. They now have seventy or eighty years of mental handicap ahead. Whether their sacrifice is justified in the interests of wider public health is not the point at issue.

Finally, this briefing note poses a number of unanswered questions about MMR, and about the UK children that are believed to have been severely damaged by its administration

PART A

A NOVEL SYNDROME

1: What Is Acquired Autism/Autistic Enterocolitis?

Autism is not an illness in itself, so much as a manifestation of a dysfunction in certain parts of the central nervous system, particularly affecting language, cognitive and intellectual development and the ability to relate to others.

The "classic" form of autism was first described by Dr. Leo Kanner. These children were different from normally-developing children from birth.

However, a very different form of autism has now begun to predominate. In this, children develop normally, passing all their developmental milestones, and then later acquire an autistic-like condition. They lose their previously-demonstrated speech, learned behaviour and social skills. In effect, they dissolve into a state of mental impairment, of varying severity. Often the damage is severe or very severe, and usually the damage is permanent.

This late onset of autism typically follows the receipt of MMR vaccination. It does not necessarily occur immediately afterwards - onset of autism is not in any case an "acute" reaction - and there are now grounds for believing that onset following vaccination may be very gradual indeed, spread over at least many weeks, more probably several or many months, or even in some cases several years.

Crucially, the onset of this acquired form of autism is accompanied by other visible manifestations of problems. These include bright red ears and dark rings under the eyes after certain foods, gluten and casein intolerances, hyperactivity, night sweating and loss of temperature control, and chronically poor sleep patterns.

The arrival of these problems and the degeneration of the child into autism as a "package" strongly suggests that they are interconnected

The timing of onset following vaccination is described by the UK Department of Health as a coincidence. Their argument is that it is "noticed" around this time, because this is a time when child development is most rapid, and any failure most noticeable.

However, very significantly, much older children have also degenerated into autism after MMR. If degeneration in affected children always follows immunisation with MMR or measles-containing vaccine, regardless of the age of the child, then it implies that the link is not coincidental.

Also, no cases are known, at least to campaigning parents, of any children who have become autistic just before MMR.

Also, it is not simply a failure to develop. The children have developed normally, then inexplicably acquired their autistic state. This protracted event has been directly observed by parents and relatives, and in many cases recorded on photographs and video footage.

No credible alternative explanation for why a previously-healthy child should become severely autistic has been put forward. The unheralded acquisition of a state of severe disability, in a substantial number of hitherto-healthy children, has to have a significant causal trigger.

Undoubtedly there are other factors involved, pointing to a predisposition of certain children to be vulnerable to damage, of varying severity. Research should be trying to pinpoint those factors, but is not. It is being held up by the refusal of the medical establishment in the UK to recognise the problem, or even to recognise the increase in autism.

Also coinciding with the late onset of autism in many of the children (or other damage - autism is not the only manifestation of there being a problem), has come gastrointestinal problems such as alternating bouts of diarrhoea and constipation, chronic abdominal pains and bloating.

Examination of children has identified a novel form of inflammatory bowel disease, ileal-lymphoid nodular hyperplasia. This has emerged after ileocolonoscopy of affected children and analysis of samples. This research has not only come from the Royal Free Hospital, London, but also from other centres in the US.

The simultaneous onset of these problems after a normal early development suggests that it is highly likely that these other elements are linked into the biological explanatory sequence of autism, notably through the pathway of gut damage and either the penetration of the blood-brain barrier or the triggering of some other process, such as serious myelin damage (in basic terms, the myelin sheath is the "insulation" around the neurons or "wires" of the brain).

2: The New Syndrome

This is a summary of the new syndrome of autistic enterocolitis:

In a 200-strong cohort of children examined through ileocolonoscopy at the Royal Free Hospital, London, an almost 100% incidence of ileal-lymphoid nodular hyperplasia has been found. This condition manifests itself as swollen lumps throughout the intestinal tissue of autistic children. The condition is very rare in non-autistic children.

The condition is believed to have developed in each case in the period following MMR immunisation

Because of its swollen and hyperplasic condition, undigested toxins , having not been stopped by either the intestine or the liver (which can also be damaged) may then be able to attack the central nervous system. The evidence for the complete pathway of damage is uncertain at present, due to lack of research.

An alternative pathway of damage may be that the virus(es) in the vaccine, or other constituents of the vaccine, may be inflicting the actual damage, or interfering with the brain’s further development by damaging myelinisation. Comprehensive studies to determine this have also yet to be undertaken.

It is also possible that thiomersal, a mercury-based preservative that has been routinely used in a number of vaccines, may have played a role. Again, adequate research has not yet been done.

Damage may in the event be via a combination of these pathways.

3. Recognised Adverse Reactions to MMR

As a background to the controversy about MMR’s safety, it is important to make clear that there is already a range of adverse reactions to the vaccine that are recognised by the manufacturers themselves, if not by the UK Department of Health. The latter insists that the vaccine is safe and has a good safety record worldwide. However, the February 2000 edition of the manufacturer’s notes, issued by Merck & Co., lists the following possible adverse reactions reported during clinical trials:

(body as a whole) panniculitis, atypical measles, fever, syncope, headache, dizziness, malaise, irritability

(cardiovascular system) vasculitis

(digestive system) pancreatitis, diarrhoea, vomiting, parotitis, nausea

(endocrine system) diabetes mellitus

(hemic and lymphatic system) thromobocytopenia, purpura, regional lymphadenopathy, leukocytosis

(immune system) anaphylaxis and anaphylactoid reactions, angioneurotic edema, bronchial spasm

(musculoskeletal system) arthritis, arthralgia, myalgia

(nervous system) encephalitis, encephalopathy, measles inclusion body encephalitis (MIBE), subacute sclerosing panencephalitis (SSPE), Guillain-Barre Syndrome, febrile convulsions, afebrile convulsions or seizures, ataxia, polyneuritis, polyneuropathy, ocular palsies, paresthesia. On encephalitis, the Merck notes state that "the data suggest the possibility that some of these (reported) cases may have been caused by measles vaccines."

(respiratory system) pneumonitis, sore throat, cough, rhinitis

(skin) Stevens-Johnson syndrome, erythema multiforme, urticaria, rash, burning/stinging at injection site, wheal and flare, redness, swelling, induration, tenderness, vesiculation at injection site

(special senses - ear) nerve deafness, otitis media

(special senses - eye) retinitis, optic neuritis, papillitis, retrobulbar neuritis, conjunctivitis

(urogenital system) orchitis

(other) "death from various and in some cases unknown causes has been reported rarely following vaccination with MMR; however, a causal relationship has not been established"

The above, although qualified in Merck’s preamble as being "without regard to causality", does suggest that rare or relatively rare serious adverse events are not unknown and are already recognised by the manufacturers of MMR. In this context, the possibility of an unrecognised adverse event such as autism - particularly if its onset is insidious - becomes rather more credible.

4. Contraindications to Receiving MMR

This list of potential contrainications to receiving MMR, contained in the Merck manufacturer’s information sheets, is also lengthy. It is very questionable as to whether all parents of UK recipients of MMR during the late 1980s and the 1990s were questioned in detail on these aspects before their child received MMR: Contraindications include:

Hypersensitivity to any component of MMR, including gelatine

Anaphylactic or anaphylactoid reactions to neomycin

Febrile respiratoty illness or other active febrile infection

Patients receiving immunosuppressive therapy

Individuals with blood dyscrasias, leukemia, lymphomas of any type or other malignant neoplasms affecting the bone marrow or lymphatic system

Primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manifestations of infection with human immunodeficiency virues

Patients with cellular immune deficiencies or hypogammaglobulinemic and dysgammaglobulinemic states. The Merck information sheets note that "Measles inclusion body encephalitis (MIBE), pneumonitis and death as a direct consequence of disseminated measles vaccine virus infection has been reported in immunocompromised individuals inadvertently vaccinated with measles-containing vaccine"

Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated

Some of the above contraindications could be partly relevant to the MMR/autism issue. And clearly, if a hitherto-unrecognised syndrome such as the insidious onset of autism, should exist but go unreported, then the list of contraindications would remain too narrowly defined until the syndrome became recognised. Much therefore depends on the effectiveness of reporting systems and length of follow-up. These issues will be covered later.

5. Families Taking Legal Action

Between 2,000 and 3,000 families whose children became autistic or had other serious adverse events after MMR are believed to be now taking legal action, or actively seeking to take legal action, in the UK, against MMR manufacturers Aventis Pasteur MSD Ltd, Merck and Company Inc, SmithKline Beecham & French Laboratories Ltd and SmithKline Beecham Plc. The trial date is currently fixed for October 2003 in the High Court of Justice in London.

Leading UK legal firms involved are Alexander Harris, Freeth Cartwright Hunt, and Hodge Jones & Allen. The action is being brought under the European Union’s Product Liability Directive, the Consumer Protection Act.

Cases include children who received Aventis Pasteur MSD’s Immravax and Glaxo SmithKline’s Pluserix brands of MMR vaccine. These brands were withdrawn by the UK Department of Health in 1992, two years after a similar vaccine containing the Urabe strain of mumps virus was withdrawn in Canada, following reports of meningitis.

The UK lawyers Alexander Harris have stated that a clear pattern of events began to emerge when they were contacted by families, with children who had been developing well, both physically and intellectually, before the MMR vaccine, then acquired their autistic state after the vaccine. This condition was often accompanied by other symptoms, with sometimes only a gradual decline into autism. Many of these children are now chronically ill and mentally or physically disabled.

By 2002, the number of UK cases of alleged damage by MMR was growing rapidly, with an increase of well over a hundred cases in the space of a few weeks.

A class action over autism is now also under way in the US, led by a large consortium of specialist lawyers. This action is based upon autism and other damage being caused by thiomersal, a mercury-based preservative. This is used in some vaccines, but reportedly not MMR. However, as noted, it is possible that damage caused by MMR and damage caused by thiomersal may be interlinked biologically.

The initial US lawsuit was filed by Walters & Krauss (Long Beach, California). Other law firms taking action are Anderson & Krieger (Temecula, California), Dogan & Wilson ((Pascagoula, Mississippi), Doran & Murphy (Buffalo, New York), Evert & Weathersby (Atlanta, Georgia), Hendrickson & Long (Charleston, West Virginia), Jones, Martin, Parris & Tessener (Raleigh, North Carolina), Leach, Schwarz & Strassberg (Bala Cynwyd, Pennsylvania), Martzell & Bickford (New Orleans, Louisianna), and Wise & Julian (Alton, Illinois). More firms are expected to become involved.

The US defendants are Aventis Pasteur Inc., Pfizer Inc., Glaxo SmithKline, Merck and Co., Abbott Laboratories, American Home Products, Baxter International Inc., Eli Lilly & Co., Sigma Chemical Co. and Aldrich Chemical Co.

It is also noteworthy that there is a legal precedent for autism being triggered by multiple vaccination, even if not by measles-containing vaccine. In the United States Court of Federal Claims, in the case of Eric Lassiter v. Secretary of the Department of Health and Human Services, in a judgement filed on December 17th 1996, a case of autism was successfully brought by the parents of Eric Lassiter. The decision of entitlement was as follows:

"This case arises under the National Vaccine Injury Compensation Program. Petitioner’s mother, Mrs. Mary Lassiter, filed this claim on behalf of her son on September 26th 1990, alleging that as a result of the administration of a diptheria-pertusis-tetanus (DPT) shot on April 19th 1972, the petitioner sustained an injury set forth on the Vaccine Injury Table (s14 of the Act), namely an encepalopathy, with permanent neurological damage. Respondent defends by arguing that because no contemporaneous medical records exist that document conclusively that the onset of the injury occurred within the requisite time frame, petitioner has not established a Table injury. Respondent argues further that petitioner’s condition, more likely than not, is due to autism and is unrelated to the DPT vaccine. Following a careful review of the record in its entirety, the Court concludes that Eric Lassiter is entitled to compensation."

The judgement also included the following paragraph:

"A careful interpretation of the literature indicates that autism can be mirrored by a condition that includes "autistic-like" signs or symptoms. Eric’s condition has never been diagnosed conclusively as autism according to the medical records. The predominating diagnosis refers instead to "static encepalopathy with autistic tendencies in addition to delayed development"".

The judgement concluded:

"In summary, respondent’s (Department of Health & Human Services) evidence and proffered explanations are weak, unconvincing and insufficient to support a finding of an underlying metabolic or genetic disorder as the cause of Eric’s affliction. Petitioner (Lassiter) has presented a better case in support of a Table injury. The Court concludes that a preponderance of the evidence requires a finding for the petitioner."

6. The UK Department of Health’s Position On MMR

Despite research pointing to an original failure to properly conduct safety tests with adequate follow-up of MMR (see later), and emerging research linking MMR with autism (autistic enterocolitis syndrome) and/or inflammatory bowel disease, the UK Department of Health and other medical institutions continue to insist that MMR is safe

This claim is based upon advice of the UK Committee on Safety of Medicines and Joint Committee on Vaccination and Immunisation - both of which would suffer a catastrophic loss of public confidence, should such a link emerge - and a number of studies, all of which arguably have severe methodological weaknesses or inconclusive outcomes. Details follow later in the text.

Much of the support for MMR, and denial of a link with autism, is based around a very small number of these studies, which the various sectors of the medical establishment have then endorsed.

There have also been general reviews of the MMR/autism issue by the Medical Research Council, most recently in late 2001, and by other bodies. These reviews have failed to find a link between MMR & autism. The parents believe this failure was inevitable, given the past lack of funded research into causes, and the superficial nature of these reviews, which have accepted "absence of evidence" as "evidence of absence" of a link.

The outcome of these reviews, and other published papers, has then been misrepresented or misinterpreted by the Department of Health as hard evidence that there is not a link.

The DoH-sponsored impression of "a growing body of evidence" that there is no MMR/autism link is therefore illusory - the "house of cards".

The Department of Health’s position on MMR has been endorsed by many of the major medical institutions, though it is questionable whether these institutions have themselves fully considered, in adequate detail, all the evidence on both sides of the argument.

It is also unlikely that any of these bodies has met with parents or listened sufficiently attentively to their accounts of how their children degenerated. It is likely that some of the bodies, and spokespersons, backing MMR and refuting a link with autism are entirely basing their confidence upon a few selected studies, and that their knowledge of the actual children believed to have been damaged is very poor. Their detailed knowledge of the studies that point towards there being a problem may be weak and incomplete.

The starting point should be to listen to the patient. Most of those giving reassurance have never even met the patient, nor the patient’s parents, nor examined the affected child, nor reviewed their medical case-notes.

Despite the DoH’s position of "MMR or nothing" (and increasing numbers of parents seem to be choosing the latter), when MMR was introduced in 1988, the UK National Health Service advice to doctors was that single vaccines should be made available for any parents not wishing their child to have MMR.

In the pamphlet, Immunisation Against Infectious Disease", which accompanied the introduction of MMR to the UK, it stated: "For children whose parents refuse MMR vaccine, single antigen measles vaccine will be available" (source: Joint Committee on Vaccination and Immunisation, 1988). It is unclear when, or why, this advice was withdrawn by the DoH, but it may have followed discontinuation of the single vaccines as an economy measure.

During the years 1998-2002, a one-sided view of the MMR/autism issue has thus been adopted by the Department of Health and its satellite organisations, much of it aimed at restoring public confidence in immunisation, to fight communicable diseases, rather than rigorously searching-out the cause of the damage to the actual children. Fresh publicity issued during early 2002 took a one-sided view of the debate, and ignored some key scientific evidence such as the January 2002 research by Dr. Vijendra Singh (see later), despite the latter being widely available in advance of the date of the Department’s publicity.

A similar denial process has occurred in the US, but its main roots lie in the UK, and based on (mainly statistical) advice stemming from only a very small number of sources.

At the end of 2001, the UK Department of Health released a "Top 10 Truths/Top 10 Myths" leaflet about MMR, and this is summarised below, with a critique alongside:

(UK Department of Health’s "Top 10 Truths")

The Department of Health’s "Top 10 Truths" leaflet ends with the reassuring statement, "All of the above are correct"! The above critique suggests that the "truth" is nowhere near clear-cut, and the Department’s position is thus exposed as artificial and one-sided.

(UK Department of Health’s "Top 10 Myths")

The Department of Health’s leaflet ends, "All of the above are wrong". In the view of the parents, of the "Top 10 Myths", four are irrelevant to the debate about an MMR/autism link, one statement about a "Myth" is factually incorrect, and the remainder can readily be disputed because the research has not been completed, or in some cases even commissioned, to decide the issue either way.

7: The Parents Have Seen What They’ve Seen.......

It is not in dispute that vaccines have saved millions of lives. The MMR/autism parents are not anti-vaccination in principle. These parents all took children to be vaccinated. We all recognise the need to protect children from diseases.

But saving lives from diseases doesn’t justify ruining significant numbers of lives from unrecognised and unmonitored vaccine damage.

It is also felt by many parents that the mantra "the benefits of vaccination outweigh the risks" has become increasingly skewed by

(a) occasionally overstating the dangers of diseases, citing experience of diseases from poor and underdeveloped countries, or UK experiences from half a century ago, or pointing to recent deaths (e.g. Ireland) where other factors played a major part, or

(b) grossly underplaying or dismissing outright any risks from vaccination. This latter has been aided by the extremely poor monitoring of adverse outcomes, and by the authorities strenuously refusing to accept that an adverse outcome was the result of a vaccine.

All affected parents are in the privileged position of having watched their child degenerate. It is a powerful first-hand experience. Comparing notes results in finding that other parents have undergone extremely similar experiences. Unfortunately, such experiences are not part of a scientifically-controlled study, so are routinely dismissed by the Department of Health as anecdotal.

Usually there appears to be a very gradual degeneration over many weeks and months, not an acute event, more akin to (eg) the onset of cancer than the rare acute reactions to vaccines seen in the past.

But all the attention of the past upon possible adverse reactions to vaccines has focussed upon acute near-immediate events.

The onset of gut/bowel problems and hyperactivity have accompanied the onset of autism. Some link between them is therefore likely, even without detailed research.

An anecdote is an anecdote. A consistent pattern of anecdotes is much more powerful. What we have is a consistent detailed pattern of reports from parents. The importance of this pattern has been ignored by the Department of Health.

PART B

THE COSTS OF AUTISM

8: The Financial Costs - Autism Is Costing £$Billions

Quite apart from the immense social costs of autism, there are the huge financial costs. Autism effects every UK and US taxpayer. In the UK, the costs comprise:

Health costs - specialist hospital visits, GP visits, prescriptions, exclusion diet costs

Education costs - special schools, extra teachers, extra teaching assistants, extra training

Transport costs - taxis plus drivers and escorts, plus local authority management costs, plus environmental/congestion costs of extra traffic

Social Services costs - respite care costs, transport, management, inspection, reviews

Loss of earnings of parents acting as carers

Social Security costs - carers allowances, disability living allowances

Inland Revenue costs - loss of earnings of parent, loss of revenues from child when he/she reaches earning age

Wider economic costs - loss of gross domestic product to the national economy

It would be interesting to know if the UK Treasury had a view on these costs, and whether sufficient resources were being devoted to investigating acquired autism and other forms of autism, as they represent a significant loss to the wider national economy. Is autism too important to be left to the Department of Health?

9: Estimates

In June 2000 a study for the Mental Health Foundation found that

the annual costs of autistic disorder in the UK were at least £1 billion

individual lifetime costs per child affected could run to £2.94 million each.

The full costs, taking into account wider economic costs, are probably considerably higher still.

10. Failure To Monitor Increases In UK Autism Numbers

There has been a consistent argument on the part of the authorities, and those seeking to defend MMR, that the apparent rise in autism may be largely a matter of better recognition. This has received some backing from autism researchers. But where hard UK or US data is available, increases are far too steep, and in far too short a timescale, to be credibly ascribed to better recognition alone..

For this to be "better recognition" or "improved diagnosis", this would have required these children to have been missed, simultaneously, by their parents, their relatives, their doctors and their teachers in the past This is simply not credible. For example, the increase in autism 1992-99 in Wakefield, West Yorkshire, local education authority was from 5 cases to 111 cases. If increased autism is down to better recognition, it would mean that, back in 1992, there really were 111 cases, but only 5 were recognised, and the remaining 106 were missed, and by all the parties - parents, doctors, health visitors, teachers - concerned. This is completely implausible.

Undoubtedly there has been some degree of better recognition and reclassification, following introduction of ICD-10 (international classification of diseases/disorders) criteria in 1992, and DSM-IV (diagnostic statistics manual) criteria in 1995. But this will account for only a minority of the growth.

The UK DoH has failed to monitor autism, and is still failing to (despite a specific 1997 recommendation of the House of Commons Health Committee to do so). Is it now afraid of what it might find? If it does decide to monitor autism, will it find that numbers are high and then claim it has always been so?

UK Health Boards/Authorities are also failing to monitor autism locally. Health Boards/Authorities have little data and no consistent approach. At the health authority level, official figures vary wildly, by factor of 300-fold, i.e. 300-times (not 300%). The data is an extraordinary mess.

In the year 2000, only 1 in 6 UK Boards/Authorities had any credible figures at all. Most used estimates from textbooks.

The Scottish schools census now includes autism. The census commenced in 1998. The 1999 census showed 18% increase over the 1998 census. The 2000 census showed a 31% increase over the 1999 census. The 2001 census will report during mid-2002.

There are other indications of the level of increases: Kaye et al paper (see later) found a sevenfold increase 1988-99 in UK. An unpublished 1999 paper by Dr. Fiona Scott, Autism Research Unit, Cambridge, indicated autism at eleven times the expected level (1 in 174) - see later.

The 2001 Medical Research Council review found autism to be at 1 in 166, many times higher than hitherto thought. Sixteen studies published between 1966 and 1991 found rates of between 1 in 3030 and 1 in 625. A rate of 1 in 166 is nearly four times higher than 1 in 625, itself the highest of these sixteen, and from a relatively-recent study in 1983.

Urging that the apparent increase is down to better recognition may therefore be little more than a counsel of complacency.

11. "Now Almost Everyone Knows Someone Who’s Autistic"

Autism was a very rare condition, but is now almost regarded as commonplace. Very many cases are now of late-onset autism, whereas almost all used to be cases from birth. We have to ask why this is.

Some UK research noted the sharp increases in autism in the 1990s. A paper by Powell et al, Department of Public Health and Epidemiology, University of Birmingham, UK, Changes in the Incidence of Childhood Autism and Other Autistic Spectrum Disorders in Pre-School Children from Two Areas of the West Midlands, UK, was published in Developments in Medicine and Child Neurology, September 2000. This looked at the incidence of childhood autism and ASD in pre-school children between 1991 and 1996.

The study found that there were year-on-year increases in classical autism during this period of 18%, but for "other ASDs" the annual increase was no less than 55%. But the study then concluded that this was due to clinicians being increasingly able or willing to make a diagnosis. The possibility of an underlying genuine increase, and any follow-on question as to causes, does not appear to have occurred to the study team.

But parents of children believe to have been damaged by MMR strongly believe that part of the increase is down to a new phenomena, autistic enterocolitis.

It is not the autism of the past. Such a severe acquired regressive syndrome after a normal early childhood would have been noticed in the past by parents, and recognised medically, and also reflected in much higher historic rates of prevalence/incidence.

In the parents’ view, there is clear evidence of recent dramatic rates/increases:

examples - an East Surrey 1/69 rate amongst three year old boys, 1/139 rate amongst three year old boys+girls combined (source: personal communication of 10/6/99 from Caroline Clark, Commissioning Manager, Learning Disability Services, East Surrey Health Authority). The letter from East Surrey stated: "In the remaining half of the District, it is estimated that there are at least 50 children on the autistic spectrum under the age of five. A special needs audit has been undertaken of children aged three by the community paediatrician. This is the age where the paediatrician expects to identify children at the more severe end of the autistic spectrum. Thirty-six children have been identified during the last two years as presenting with autism, of which twenty-nine were between the ages of two and three, with seven children slightly older. The general population is around 2,500 children (born) per year in this part of the District. The prevalence of autism indicated by the audit is 0.72% (1 in 139) but with 1.44% (1 in 69) for young boys."

Bromley Autistic Trust figures show a 1990-94 increase of 280% over 1980-84 figures (source: personal communication of 16/9/99 from Miss C. M. Povey, Services Director, Bromley Autistic Trust)

Wakefield LEA autism pupils up from 5 to 111 in seven years (source: survey by David Brown, a specially-seconded headmaster from the Park School, Wakefield, on behalf of Wakefield Local Education Authority, 1999)

Telford health data up from 4 new cases per year in 1990 to 17 per year 1998 and again 1999 (source: personal communication of 20/11/00 by Dr F. R. J. Hinde, Consultant Paediatrician, Princess Royal Hospital, Telford)

As noted, Scottish schools census up 18% in one year (1999 vs. 1998), and then a further 31% in the next year (2000 vs. 1999); (source: Scottish Annual School Censuses, available from Scottish Education Office, tel 0131 556 8400)

12. University of Cambridge Research

On 18/2/01, the UK Sunday Telegraph reported on research undertaken by Dr. Fiona Scott at the Autism Research Centre at the UK University of Cambridge. The research, Prevalence of Autism Spectrum Conditions in Children Aged 5-11 Years in Cambridgeshire UK, by Scott, Baron-Cohen et al, which is due to be published shortly, was undertaken across schools in Cambridgeshire. It found that:

One in 175 (58/10,000) children was autistic, whereas previous studies had pointed to a rate of 1 in 2000 (5/10,000)

Extrapolated across the UK, that would imply 30,000 primary school (age 5-11) children with autism

Linking these rates to estimated costs of education and care for sufferers would give a figure of as high as £5 billion per year, year after year. The Cambridge autism figures were described as "if anything an under-estimate". They included only children with a definite clinical diagnosis. Any child who had only been "statemented" (= educational needs-assessed) as autistic, but not yet clinically diagnosed, was not counted

One in eight children with special educational needs was suffering from some form of autistic spectrum disorder. The increase of actual numbers over previously-assumed numbers would have enormous cost implications for central and local Government

A year-2000 report for the UK Mental Health Foundation by Professor Martin Knapp for the UK Institute of Psychiatry used the earlier "textbook" rate of autism of 5/10,000 to put the total UK economic cost of autism at £1bn. The Knapp report estimated the lifetime cost of a severely-affected child at £3m, for a high-functioning autism child at £0.8m, and for an Asperger’s syndrome child at £0.5m. The revised £5bn per year estimate is based upon these costs.

13. University of Sunderland Research

An unpublished study by the UK University of Sunderland found a tenfold increase in diagnosis of autism, during the years 1989-93.

14. UK National Autistic Society Estimates

The NAS issued a factsheet in early 1997 which gave the following prevalence rates:

People with Kanner syndrome (IQ less than 70) 5/10,000, or 1 in 2,000

Other spectrum disorders (IQ less than 70) 15/10,000, or 1 in 666

Asperger’s (IQ 70 or above) 36/10,000, or 1 in 278

Other spectrum disorders (IQ 70 or above) 35/10,000, or 1 in 286

Combined total of above four groups 91/10,000, or 1 in 110

The above implies a very high level of autism in the UK, and the previously-described studies seem to bear this out.

The NAS reach its 91 in 10,000 or 1 in 110 rate by taking the Wing & Gould study (Camberwell, London) of 1979, which looked at children with an IQ of under 70 and found a rate of 20 per 10,000, and adding this to the study by Ehlers & Gillberg (Sweden) of 1993 which looked at autistic children with an IQ of over 70 and found a rate of 71 per 10,000 (1 in 141).

The 91/10,000 rate is thus "merged data", collected in two different countries and some years apart, and thus needs to be treated with caution, particularly if rates have since been rising further. The Wing & Gould study is now over two decades out of date, and also pre-dates MMR introduction into the UK.

15. Report by Fiona Loynes, UK All-Party Parliamentary Group on Autism, Dec. 2001

The purposes of this report included:

To establish numbers of children with autistic spectrum disorders

To learn whether UK local education authorities believed there had been a recent increase in the last five years

To ascertain whether LEAs routinely collected data

The findings included the following:

100 out of 115 LEAs reported an increase in autism in the past five years. Some reported small increases, others reported far higher increases, in one case by 77%.

The study compared the expected prevalence rate of all autistic spectrum disorders in each LEA (91 in 10,000 or 1 in 110) with the actual recorded number of children with ASD and a Statement of Educational Needs (21 in 10,000 or 1 in 476). If the estimated numbers are correct, then the implication is that 75% of children with autism do not become included in the Statement data, because they have no Statement.

Only 44 out of the 100 LEAs reporting an increase had actual data. Some of these reported dramatic increases, up to 400% in four years.

16. Is Autism Increasing? - Some Recent Official UK Pronouncements

These are some recent, and sometimes self-contradicting, statements:

"There is no good evidence that the frequency of autism has increased since the introduction of MMR" - Tessa Jowell, then Minister for Public Health, October 1997 (personal communication to David Thrower)

"The true incidence of autism is uncertain" - Sir Kenneth Calman, then Chief Medical Officer, March 1998

The apparent rise in autism in the UK began more than ten years before the introduction of MMR" - Tessa Jowell, in June 1998

"Rates of autism are rising, but not because of MMR" (Committee on Safety of Medicines, June 1999)

"There is no robust data on the prevalence of autism before and after MMR’s introduction" - Brent Taylor, in a June 1999 study heavily quoted by the Department of Health

"Numbers of cases of autism are rising, but the reason for this is unclear" - John Hutton, Minister for Public Health, December 2000

17. Autism In The USA

The UK DoH is fond of saying how MMR is safely used in 32 countries, including the USA, as though its use elsewhere is proof in itself that it is safe. But the USA, at least, has clear evidence of an autism epidemic. Other countries may also be becoming aware of increases, for example Finland, where a 400% increase in cases has been alleged since was MMR introduced.

The US has IDEA (Individuals with Disabilities Education Act). This picks up numbers of schoolchildren with developmental problems. Autistic pupils are up from 12,222 to 65,396 between 1992-1993 and 1999-2000 (Source: US IDEA State data). So for every 2 cases there were in 1993, by 2000 there were nearly 11. Numbers will have risen even further since.

To the above total also has to be added a further 15,581 cases of autism amongst children aged 3-5 years, as at year 2000.

There have been huge increases in some States between 1992-1993 and 1999-2000 - up 885% in Alabama, 529% in Connecticut, 435% in Florida, 513% in Idaho, 636% in Kansas, 561% in Minnesota, all in just seven years (Source: US State data, Individuals with Disabilities Education Act)

It is also interesting that individual towns such as Round Rock, Texas, are reported to be up from 6 cases to 115 cases in eight years - very much like Wakefield Local Education Authority in the UK (up from 5 to 111 in seven years). On the face of it, this suggests that UK increases may very closely match those in the USA.

The latest California increases (the State with the best database) showed autism up 19% in 1999 and up again nearly 16% in 2000.

It has been alleged that Brick Township (New Jersey) has manifested an "autism cluster". Some 40 of Brick Township’s 6,000 3-10 year olds have autistic spectrum disorder. It has made Brick Township the "autism capital of the USA" (but note, East Surrey rates in the UK are higher still). In Brick Township, Federal investigators collected data on surface and ground water, sites of industrial spillages and waste dumping, and also ensured that there had been correct diagnosis of the actual children. They have found nothing untoward. Their findings were reported in April 2000.

The latest statistics produced by the Department of Education in the United States, for numbers of children aged 6-21 served by IDEA (Individuals With Disabilities Discrimination Act) who have autism are as follows:.

The following is taken from the statistics produced by the Department of Education in the United States, for numbers of children aged 6-21 served by IDEA (Individuals With Disabilities Discrimination Act) who have autism. It compares the increase over the eight years between 1992-93 and 2000-01:

(Source: Individuals With Disabilities Education Act data, US Department of Education. Note: Where increases are from a very low base figure, these have been expressed as "almost infinite".)

For every two cases there were in 1993, there are now thirteen. And the latest 2000-2001 figures represent a single-year increase of 20% over 1999-2000

The current estimate for the year-end of 2002 is 94,000-95,000.

It seems obvious that the US has an autism epidemic. The UK is a similar health environment to the US, so it also seems reasonable to conclude that the UK probably has an autism epidemic, too, but just hasn’t yet realised it.

Dr Bernard Rimland of the US Autism Research Institute, San Diego: "Some supposed experts will tell you that the (US) increase reflects only greater awareness. That is nonsense. Any paediatrician, teacher or school official with 20 years experience will confirm there is a real increase, and the numbers are huge and growing".

18. California

California has probably the most useful autism data in the world, going back to 1970. Trends monitored there have a potential worldwide significance.

The rise in autism was first highlighted by a report Changes in the Population of Persons With Autism and Pervasive Developmental Disorders in California’s Developmental Services System, 1987 through 1998 - A Report to the Legislature, tabled on March 1st 1998 by the Department of Developmental Services, Sacramento, California Health and Human Services Agency.

The latest Department of Developmental Services data, released at the start of 2002, shows that a record number of professionally-diagnosed DSM-IV criteria autism cases, 2,725 cases, entered the State system during 2001.

This year-2001 number represents a 20% increase over the year 2000, itself a record.

In 2001, there were more cases of level-one autism in California than in 1994, 1995 and 1996 combined.

Historically, autism made up 3% of childhood disability in the State Developmental Services system. It now comprises 35% of the total.

Two out of three persons with autism in California’s child-developmental system are now young children between the ages of 3 and 13. Eight out of ten persons with autism have been born since 1980 (1980 was the year that California mandated the full complement of childhood vaccines as a condition of school entry. MMR was also introduced in California 1979-80).

California now has 16,802 persons with level-one autism in its Developmental Services system.

The total intake for the three years 1999-2001 was 6,596. This compares with a total intake for the twenty-five years 1970-1995 of 6,527 cases.

This does not include children with persistent developmental disorder, non-specific (NOS) developmental delays, Asperger’s or and other autistic spectrum disorder - it is therefore the tightest definition of the severe-case numbers.

19. New Jersey

Data on autism in New Jersey, recorded by the IDEA system for individuals with disabilities who require special education, suggest that there is a vast preponderance of cases amongst children/young people ages 6-21 amongst the youngest ages. The following figures relate to the position as at 1st January 2002:

The total number of cases is 3,501. This equates to an average of 219 for each age-year. For ages 11 and under, the number exceeds this average, and for ages 12 and over, it is less than this average.

The youngest three years average out at 495 cases. The oldest three years average out at 36 cases. The average of the youngest years is about 14 times that of the oldest three years.

PART C

STUDIES THAT HAVE BEEN USED TO DENY AN MMR/AUTISM LINK

This section deals with the numerous recent official studies and reviews, many in the UK but some in the US or elsewhere, that "prove" there is no connection between autism and vaccination.

As will be seen, all when scrutinised critically are actually either irrelevant, inconclusive, or are seriously methodologically questionable.

The UK Government’s advice on MMR and autism comes from the DoH, the Medicines Control Agency (MCA), the Committee on Safety of Medicines (CSM) and the Joint Committee on Vaccination and Immunisation (JCVI). These bodies are closely intertwined, and have based their position on a barely more than a handful of studies. Further advice has come from the Medical Research Council.

Much of the focus has been upon the need maintain public confidence in MMR to prevent communicable diseases, rather than the need to investigate specific cases of alleged damage.

The studies are also of random groups of children, but not of the actual children reported by parents as damaged by MMR.

Finally, the Department of Health has implied in the past that the evidence for a link between MMR and regressive autism has come from only one team of researchers, which is not factually correct. However, the very same criticism can be levelled at the "anti-link" camp. A significant proportion of the studies below only comes from a very small number of sources, some very close to the Department of Health itself.

20. Stokes et al Paper, Trivalent Combined Measles Mumps Rubella Vaccine, Journal of the American Medical Association, 4th October 1971

This paper, by Stokes, Weibel, Villarejos, Jorge, Arguedas, Buynak and Hilleman, has assumed more importance recently (see later Wakefield/Watson/Shattock debate section).

The paper stated that triple vaccines were desirable to simplify administration, reduce costs and minimise visits (my emphasis). There was no mention of greater effectiveness, or inherent drawbacks with single vaccines.

There were three trials, firstly of 30 children in Philadelphia, then of 214 children in Philadelphia, then of 440 children in rural Costa Rica and San Salvador, total 684 but (note) of very different economic and geographical backgrounds.

The mean ages of children in the three trials was 1.1, 1.5 and 3.0 years. Note that the present age of receiving MMR is about 14 months, and therefore the vast majority of the trial children were significantly older than today’s UK MMR recipients. Some 64% were also not from Western social/health backgrounds.

The 30 children’s parents were given report cards for recording temperatures for 28 days, and queried at six to nine weeks. For the 214 child-cohort and the 440 child-cohort trials, follow-up was 28 days. The parents were instructed to notify any significant illnesses during the 28-day period, and were queried at the second bleeding, six to nine weeks after vaccination - but the implication is that this query may have covered the 28-day interval, not longer.

The study noted that "the fifth to twelfth day after vaccination is the critical time period for occurrence of the expected low incidence of febrile reaction", also that the significance of the difference between vaccinees and controls in terms of miscellaneous subsequent complaints (gastroenteritis included) was "doubtful" (though it was actually very marked in the study tables, up to 18/228 of vaccinees with gastroenteritis, compared with at most 3/106 of controls)

At no point in the study was autism mentioned as a risk-factor or an actual outcome. Clearly, the possibility was not even considered. The study noted the lack of arthritis and arthralgia.

Overall verdict: this study is not relevant to disproving an MMR/autism link

21: Study of Twins By Peltola and Heinonen, Frequency of True Adverse Reactions to MMR Vaccine; A Double-Blind Placebo-Controlled Trial in Twins, National Public Health Institute and Children’s Hospital, University of Helsinki, Finland, published Lancet, April 26th 1986

This study sought to check levels of adverse reactions following MMR. MMR was introduced into Finland in 1982, being administered at 14-18 months and at 6 years, using Merck Sharp Dohme Viravac.

The study was a double-blind crossover study involving 581 twins. The vaccines were administered blind, but one twin of each pair first received active MMR, then three weeks later, received a placebo. The other twin was given the placebo first, then three weeks later received MMR.

Each twin was given a colour coded questionnaire to be completed daily by parents, for 21 days after the injections.

In theory, this should have provided a foolproof test of how reactive MMR was. However, the study completely founders on:

the issue of the potential time-delay between receipt of MMR and any possible gradual degeneration into autism. If such a delay could exceed 21 days, then the study would have missed it as an adverse reaction

Secondly, the linking of autism/developmental delays with MMR, or indeed any other vaccine. Parents in 1982, or indeed until about mid-1997, were not linking MMR with autism. It is extremely unlikely that regressive autism would have been connected, in the minds of either parents or the study authors, with MMR back in 1982. Virtually no literature or press reports had appeared on the issue.

As with the original safety trials of MMR (see later papers), this study was not designed to verify whether rare and complex adverse events might follow months or years after MMR.

The study only looked at one brand of MMR. As subsequently transpired, some brands of MMR used in the UK and elsewhere had a less satisfactory safety record than others, and (in the UK) were withdrawn at very short notice in 1992. A study with Viravac cannot be used to give safety clearance to other brands if the brands are found to have been variable.

A further criticism is that the study is still quite small in relation to rare events. It involved 581 twins. All other things being equal, if a rare adverse outcome occurred at a rate of 1 in 2 x 582, or less frequently, this study would not have found it.

The authors did actually acknowledge this, stating:

"The study was designed to explore relatively common symptoms and signs occurring after the vaccination" (they mean, "within 21 days of"), and

"Rare reactions due to the MMR vaccine cannot be studied with this small sample".

It is therefore suggested that this study, regarded as the "gold standard" by the exponents of MMR, offers no evidence for or against an MMR/autism link; it is clearly irrelevant. Overall verdict: this study is not relevant to disproving an MMR/autism link

22: Study by Miller, Miller, Rowe et al, Surveillance of Symptoms Following MMR Vaccine in Children, The Practitioner, Vol 233, 8th January 1989

This paper was to report the incidence and severity of clinical reactions before the start of the UK national MMR programme. MMR was offered to 10,000 children in three districts in the UK, with a post-vaccination follow-up of every child.

Two types of MMR were introduced, Immravax in Somerset, England, and Pluserix in Fife, Scotland, and North Hertfordshire, near London. Both vaccines contained Schwarz measles and Urabe 9 mumps vaccine, and both later had to be withdrawn in 1992 for safety reasons, in connection with risks of aseptic meningitis. These risks were not detected by this study.

The study found that:

Of the 7,247 children aged 1-2 years, 38% had either no symptoms or symptoms for only one day

18 had convulsions. Fifteen were admitted to hospital.

Of the children aged 4-5 years, 61% had either no symptoms or symptoms for one day. There were no convulsions and no hospital admissions.

Follow up was for 21 days. However, 114 children were followed up through diary records for a further 21 days, total 42 days.

Comparison of symptoms of children after MMR was made against symptoms of children after measles vaccination - not unvaccinated children.

The study concluded that symptoms reported after MMR appeared to be similar in nature, frequency, time of onset, and duration, to those recorded in earlier studies after monovalent measles vaccine

Comment: as with the original safety trials of MMR, follow-up was extremely short and only immediate/near-immediate reactions noted. The study did not look at autism, but effectively cleared the way for MMR’s general introduction into the UK. It is noteworthy that the study was co-authored by Dr. Elizabeth Miller, who subsequently authored or co-authored several of the studies that have been used as "proof" that there is no MMR/autism link. It is also noteworthy that, as noted, this study missed the aseptic meningitis problem of MMR, and that the brands of MMR with Urabe strain mumps virus subsequently had to be withdrawn, in 1992, at extremely short notice.

Overall verdict: this study fails to disprove an MMR/autism link

23. Gillberg Study, Sweden, Is Autism More Common Than Ten Years Ago?, British Journal of Psychiatry, 1991, 158; 403-409

The paper reported a study in Sweden by Gillberg et al, 1991. It has been partially updated since (see below).

Gillberg looked at tiny sample of autistic children (55 of typical autism, just 19 of atypical autism), in Goteburg and Bohuslan. The study, actually a mish-mash of three studies with differing criteria, does not mention vaccination, does not state the coverage of MMR, does not include data on uptake or demographic factors, and is therefore irrelevant to the MMR/autism debate.

It had tracked down cases of autism unscientifically, by word of mouth, doctors etc., then allocated them by d.o.b. to "pre-MMR" and "post-MMR" eras

The study’s case-selection being a few cases out either way would neutralise or completely reverse the findings of the study.

The paper does acknowledge that the rate of autism has increased but "explains" this through changes in population structure and "better diagnosis".

Overall verdict: this study offers little evidence that MMR does not cause autism, particularly as it is so small.

24. Paper by Gillberg and Heijbel, Commentaries, Autism, Vol 2 (4) 423-430, 1998

This further paper by Gillberg was published following the appearance of the Wakefield et al "Early Report" paper in The Lancet in early 1998.

Gillberg and Heijbel stated that they had re-analysed the data from their population study of autism performed in the late 1980s and published in 1991 (as above). The children in that study (n = 55) had been born in the ten-year period 1975-84. The authors claimed that as MMR was introduced in Sweden for 18-month-old children in 1982, with coverage increasing rapidly to 90%. The authors then argued that if there was an MMR/autism link, then children born from July 1980 onwards (i.e. The post-MMR generation) would be expected to be at increased risk. The 55 children were therefore divided into 34 (62%) pre-MMR and 21 (38%) post-MMR.

The authors then argued that had there been a strong effect of MMR, they could have expected more than 45% of the 55 cases of autistic children to have fallen into the post-MMR group. As this was not the case, then their study did not support the hypothesis of an association between MMR and autism

The authors also again claimed that in their parallel study of 19 atypical autism cases, there would have been a similar effect, and therefore that again there was no support for an association.

Overall verdict: as with the original study, these numbers were so small as to render this study, and its conclusions, as virtually without value in the context of proving/disproving an MMR/autism link. Statistical/epidemiological studies based upon cohorts numbering 55 and 19 cases are far too small. It is extraordinary that the UK Department of Health was using this study in the late 1990s to "disprove" the suggested association.

25. Letter by Dr. Eric Fombonne, Inflammatory Bowel Disease and Autism, Pediatrics, March 28th 1998

This letter set out two studies that attempted to prove that there was no connection between inflammatory bowel disease/Crohn’s disease and autism. The first study looked at UK clinical data collected by the Child & Adolescent Psychiatric Services of the Maudslay Hospital, London.

For ASD, three diagnostic groups were examined, autism, atypical autism including disintegrative disorder, and pervasive developmental disorder

Medical disorders were coded for a 25-year period, including Crohn’s and ulcerative colitis, for 8889 patients.

Of the 8889 patients, 987 were born in 1987 or later, and were therefore most likely to have been exposed to MMR. Of these, 201 had ASD.

Of the 8889 children, only two had Crohn’s, and both were non-autistic. None had ulcerative colitis.

For the second study, a similar approach was undertaken. Fombonne surveyed medical, behavioural and intellectual disabilities amongst 6100 French children.

He found 174 cases with autism.

One child of the 6100 had Crohn’s, and one had ulcerative colitis. Neither were autistic

The conclusion that Fombonne drew was that these data provide no support for the hypothesis of an association between IBD and autism.

Overall verdict: neither of these studies offer any evidence to disprove an MMR/autism link.

26. UK Committee On Safety of Medicines Study, Report of the Working Party on MMR Vaccine, Committee on Safety of Medicines, June 1999

This study looked at the medical records of some of the children who are now taking High Court action. Their details were provided by their lawyers.

The study admitted:

Information on the children was extremely variable in quality and completeness

It was "difficult" to draw conclusions about any causal association (verbatim quote: "the information evaluated has important intrinsic limitations as regards assessing whether the vaccines are or are not causally associated with the adverse effects")

It was not feasible to review the less common adverse side effects

The study was effectively run as knockout competition. Each case had to pass four hurdles (all four) to be counted as being caused by MMR. The four hurdles were: (1) have either the diagnosis or clinically relevant signs/symptoms been confirmed medically? (2) was the onset of the possible adverse effect within six weeks of immunisation with MMR? (3) was there history prior to immunisation relevant to the possible adverse effect? (4) was there evidence of other causes for the possible adverse effect?

Six weeks after immunisation was chosen as a cut-off point for a close temporal association because (quote) "this is the maximum period in which viral replication can be detected after immunisation". But this probably missed many cases, and is arbitrary. The Spitzer, Aitken et al study (see later) renders this six-week limit as irrelevant.

At every stage, the study looked for other "causes" to explain-away the cases, and took every opportunity to ascribe cases to these "causes". In most cases, it was assumed at every stage without scientific justification that autism was "caused" by other factor rather than MMR. But it is not known what causes autism. Therefore there is a gross study bias, and the study rests upon unscientific assumptions.

The other assumed "causes" were the child’s previous medical history, comprising having a parent/sibling with speech or behavioural problems, an obstetric history of pregnancy complications (these, alone, were not considered as "causes"), signs/symptoms of encephalopathy, a head circumferences larger than the 97th percentile, or history of unspecified viral illnesses, bronchiolitis, rubella, measles, or a minor head injury.

The study eventually only looked at 92 cases of autism in detail (plus 15 Crohn’s), and was left with a residue of 8 autism cases and four of the Crohn’s it could not "explain" away. These were then just set aside, without explanation.

What the study did was to introduce so many extraneous considerations, and accord these such an importance, that hardly any case with sufficiently-clear documentation remained to survive the appraisal process. This eliminated almost all cases. The study then appears to have then simply set aside the residue.

The study text commented that (quote) "it was impossible to prove or refute the suggested associations between MMR vaccine and autism or inflammatory bowel disease because of the nature of the information.". This would seem to inevitably render the study as inconclusive. But the study’s conclusions did not reflect this sentence.

The wording of the final conclusion left a small exit-route for any possible future U-turn: ""On the basis of all the available evidence, the demonstrated benefits of MMR or MR vaccines far outweigh any possible risks" (my emphasis).

The DoH’s press release 0342 of 1999 spun the study’s conclusions further - "Two New Independent Studies Have Not Found A Link Between MMR Vaccination And Autism"

Note: this is the only study to date to have both looked at the actual children reported to have been damaged and to have "cleared" MMR. But as the above criticisms show, the study was actually self-admittedly inconclusive. It also failed to medically examine the actual children.

Overall verdict: this study does not disprove an MMR/autism link.

27. Paper by Taylor, Miller, Farrington et al, Autism and Measles Mumps Rubella Vaccine: No Evidence for a Causal Association, Lancet 1999, 353, 2026-9

The study, designed by Dr Elizabeth Miller of the Public Health Laboratory Service, was wholly inconclusive, but has been widely presented as conclusive proof of the absence of any link between MMR and autism.

It only looked at 498 cases, far too small a sample for a robust statistical (case-series analysis) test. The study attempted to track-down children through special schools and local authority special needs registers - a method that is open to question, as it probably misses many cases. The study describes itself as "a large regional sample", but it was actually very small.

Taylor, Miller found a steep increase in autism, ("There was a steady increase in cases by year of birth"), but did not explain it.

Also, the study looked for a time-clustering of parental concern six months after MMR, found it, but then dismissed it unconvincingly by saying it was "related to the difficulty of defining precisely the onset of symptoms". But this method, of precisely identifying a date, was meant to be the very basis of their study.

Also, the study did not include in its post-MMR numbers those children born 1986-87 who later received it, nor those 2/3/4 year olds who had MMR at this older age.

It also missed children who had single vaccines, then MMR later. It not only misses these from "post-MMR" numbers, but added them to its pre-MMR numbers. The whole study is thereby compromised. The authors have since sought to clarify this in correspondence in The Lancet, but unconvincingly.

Autism is sometimes not diagnosed for years after. It is very difficult to pin down an actual "date" of diagnosis, and many children don’t receive any formal diagnosis anyway (contact National Autistic Society, which did a study on this, tel 0207 833 2299). The Taylor Miller study doesn’t recognise this.

The study seems to have been designed to clear MMR, not to test whether there is a link with autism. The study struggles, and fails, to disprove a link.

Also, the study is described by the UK DoH as "independent". But Taylor was co-author of a 1988 paper clearing the safety of triple vaccines, Miller was described in Daily Express press reports of 1/01 as "a colleague of Dr David Salisbury" (head of the DoH Immunisation & Communicable Diseases Branch, which runs the MMR programme), and the study was funded by the UK Medicines Control Agency, a satellite of the DoH.

The authors have been repeatedly challenged by other researchers to release their raw data but have refused. Yvette Cooper, the UK Minister for Public Health, has backed up their refusal.

Overall verdict: despite its claims, this study cannot be taken as proof of there being no MMR/autism link, due to its apparent serious methodological flaws.

28. Paper by Miller and Farrington to US Government Reform Committee Hearings, Written Testimony to the Congress of the United States Committee on Government Reform Hearing On The Challenges of Autism - Why The Increased Rates, April 2001

In their submission to the US House of Representatives Committee on Government Reform Hearing, which was investigating increases in autism and possible links with vaccination, Miller and Taylor re-stated:

"Our conclusion, based on the findings of our study, is that there is no evidence of a causal association between MMR and autism".

"The case series method has a proven track record with respect to identifying and measuring a risk of adverse events after various vaccines".

"In our study, we showed that the increase in the prevalence of diagnosed autism in recent birth cohorts occurred during a time when the coverage of MMR vaccine in the same cohorts has been constant. The rise cannot therefore be related to the use of MMR vaccine."

"There is no credible epidemiological evidence to support the view that measles vaccination is a risk factor for Crohn’s disease or any other inflammatory bowel disorder".

However, as explained in the section covering the original paper by Miller, Taylor and Farrington, there are major questions over the methodology of this paper; these, of course, can also be applied to Miller and Farrington’s paper to the Government Reform Committee.

29. Patja, Peltola et al Study, Serious Events Rarely Related to MMR Vaccine: Natural Diseases Outweigh Risks, Pediatric Infectious Disease Journal, 2000;19; 1127-1134 (December)

This Finnish study, usually referred to as the Peltola study, concluded that serious events rarely were related to MMR. The study was initiated in 1982, when MMR was introduced. A nationwide surveillance system was set up to detect serious adverse events, reviewing patients’ clinical records and where taken, serum samples. However, the study relied on passive surveillance - a fatal flaw - and only followed up acute adverse events - a further fatal flaw.

According to the report,

173 potentially serious adverse reactions were claimed to have been caused by MMR, out of almost 3 million doses.

There were 77 neurologic reactions, 77 allergic reactions, 22 miscellaneous reactions and one death.

Some 45% of these reactions were dismissed by the study as probably caused or contributed by other factors.

Peltola admitted on BBC Radio 4 on 13/1/01 that the Finnish study was not designed to look at either autism or inflammatory bowel disease. He confirmed that the study was not specifically designed to look for autism, as no-one had ever raised this issue at the time.

The Peltola study simply identified the 173 children (out of 1.8m persons, including troops), who had acute reactions to MMR, then followed only these children up. The study followed up the wrong children. No-one has ever suggested that autism follows an acute reaction.

There would almost certainly have been potential autism cases amongst the remainder of the 1.8m, but these were missed, because they were excluded from the study, as it had a 3-week cut-off for reporting reactions. After that point, the remaining (theoretically, 1,799,827) children/other persons were ignored.

Peltola relied on referrals from health workers out in the field, who would never have connected degeneration into autism, several months/years after MMR, as being a potential adverse reaction to a vaccine. The alleged syndrome was not known of by scientists, let alone by health-workers in the field, at that time.

The UK DoH interpretation of this study, widely trumpeted during 1/2001, is that Peltola "clears" MMR of a link with autism/IBD. It is difficult to accept that this "conclusion" has any degree of scientific justification. It appears that the DoH’s "conclusions" have been retrospectively bolted-onto an old and irrelevant study.

There are other awkward facts regarding the Peltola study:

The study was part-funded by Merck Sharp Dohme (MMR manufacturers).

The study barely refers to autism or IBD.

Reviews of the study (eg December 2000 Medscape) do not even mention autism/IBD, which are obviously not seen by the reviewers as a relevant aspect of this study.

Despite this, the Peltola study continues to be cited by the UK medical establishment as conclusive proof that there is no link between MMR and autism. As late as 12/2001, Dr. Simon Fradd of the General Medical Council’s Doctor-Patient Partnership quoted this study by Peltola on BBC Radio 4 as conclusive proof of the absence of any link.

The UK DoH also said in a personal communication, referring to all the various studies: "the follow-up time (three weeks) was based on knowledge of the replication rates of the vaccine viral components.....it is recognised that such a study could not establish a causal relationship with extremely rare events..... millions of children have received MMR in other countries such as Finland and the USA; no serious long-term complications have been identified...." (my emphasis).

Overall verdict: this study is wholly irrelevant to the issue of whether MMR can cause autism.

30. The Kaye, Melero-Montes and Jick Paper, MMR Vaccine and the Incidence of Autism Recorded by General Practitioners: A Time Trend Analysis, British Medical Journal, February 2001

This paper attempted to prove that there was no link between MMR and autism because, although autism increased when MMR was introduced, it has carried on increasing since, even though MMR’s coverage reached near-saturation almost immediately after its introduction into the UK in late 1988.

The study looked at 305 children (254 boys) aged 12 or under with autism diagnosed in the years 1988-99. It also looked at 114 boys aged 2 to 5 years born in 1988-93. It used the UK General Practice Research Database.

The study found that autism had increased sevenfold from 0.3 per 10,000 in 1988 to 2.1 per 10,000 in 1999 (note how low this figure is compared with other studies)

In the 114 boys born 1988-93, it found autism had increased fourfold, from 8 per 10,000 (1 in 1250) for boys born in 1988, to 29 per 10,000 (1 in 345) for boys born in 1993, during a period when MMR take-up was claimed to be constant at around 97%.

The study concluded that no correlation existed between MMR and autism, and that the explanation for increased autism remained uncertain

However, the authors acknowledge that their methods were a "second-best", because what they really wanted to do was compare vaccinated and unvaccinated cohorts of children. They said that this was impossible because only 3% of cases and controls did not receive MMR. Given the very small numbers of autism cases they in the event actually looked at, this seems an unconvincing argument for abandoning their preferred approach

The authors then argue that if MMR was a major cause, then the risk of autism should have stopped rising within a few years.

However, they also admit that the diagnosis of autism was not confirmed from original records, but conclude that "differential misclassification of the diagnosis in vaccinated and unvaccinated children is unlikely to vary over the period of the study", though no evidence is offered to back this claim.

They also acknowledge that time trend analysis is a "relatively crude method".

The study authors go on to speculate that the increase in autism that they found "could be due to increased awareness of the condition among parents and GPs, changing diagnostic criteria or environmental factors", without subjecting these "explanations" to any detailed scrutiny.

The authors also acknowledge the further limitation that they have not yet obtained and evaluated full clinical record information from GPs to describe more fully the characteristics of children diagnosed with autism and to explore other possible explanations. Yet they still dismiss MMR, despite this shortcoming.

It might be the case that the increase in autism that the authors find, over the period 1988 to 1997 (note - not 1999 - the study figures actually fall away after 1997) could be due to a hybrid explanation, with increases in the early years due to MMR and then continuing further increases in the later years due to better awareness. There is nothing in the study to refute this criticism

It is also unclear how the issue of re-vaccination has been dealt with. What of the seven million children vaccinated or re-vaccinated in 1994 in the UK "Operation Catch-Up" programme? Couldn’t the continuing rise in diagnosed cases in 1995-97 be due to Operation Catch-Up? The study does not mention it.

It is interesting that the Finland study team (Patja et al) said "Causality between immunisation and a subsequent untoward event cannot be estimated solely on the basis of a temporal relation." Yet the Kaye et al study uses a basically similar approach to "prove" there is no link, comparing temporally-linked trends in MMR take-up and autism increases.

There is also a question over the use of mercury-based preservative (thimerosal) in vaccines. This was used in the late 1980s and early 1990s, but has reported to have been largely phased-out in the US, with a free exchange system being operated by the manufacturers. No such exchange has operated in the UK, with existing thimerosal-based stocks being used up on the children. Autistic enterocolitis may involve thimerosal as part of the damage sequence.

If it did, and following a change in formulation, then this might well explain continued rises in autism through the 1990s, then a fall-away in increases at the end of the decade, as was actually found by Kaye et al. Did the industry change the preservative formulation as public concern grew? And has this affected the statistics of autism?

Overall verdict: this study offers no convincing evidence against an MMR/autism link.

31. Paper by Fombonne, Medical Research Council Child Psychiatry Unit and Institute of Psychiatry, Is There An Epidemic of Autism?, Pediatrics, January 2001

At the end of January 2001, a paper, "Is There An Epidemic of Autism?" was published by Dr. Eric Fombonne. The paper sought to deny that autism had really increased, and criticised the "poor research methodology" of Dr. Andrew Wakefield, and said "There is no need to raise false alarms on putative epidemics nor to practice poor science....."

Fombonne criticises the California increase on the basis of in-migration, possible changes within the population make-up, the change from DSM-III to DSM-IIIR in 1987, the introduction of diagnostic categories for Asperger, Rett and childhood disintegrative disorder in DSM-IV in 1994, the effects of earlier diagnosis adding to the totals, and other factors.

His most useful conclusion is that "we simply lack good data". He raises doubts about the apparent epidemic, but is then unable to refute it either.

In an excellent FEAT (parents’ group) critique (8th Feb 2001), Mark Blaxill goes carefully through Fombonne’s previous work and argues that Fombonne has become inconsistent. He points out key flaws in Fombonne’s previous work, and criticises his criticisms of the California data and his scientifically-unsupported assertions

32. Paper by Dales, Hammer and Smith, Time Trends In Autism and in MMR Immunisation Coverage in California, Journal of the American Medical Association, March 7th 2001 Vol. 285, No. 9, 1183-1185

This paper, entitled "Time Trends in Autism and in MMR Immunisation Coverage in California" is one of the least conclusive and least robust of all the research of recent years. It appeared in JAMA, March 7th 2001, but it is surprising that it achieved such a high profile within the UK, so weak was its hypothesis and so inconclusive its contents.

The paper attempted to determine if a correlation existed in trends of MMR immunisation coverage and autism occurrence. It did this by examining data from 21 regional centres covering the whole of the State of California.

During the years examined, 1980-94, MMR take-up was about 72% prior to 1988 and about 82% after 1988. Autism increased from about 200 in 1980 to about 1200 in 1994. The trend of increasing autism continued after the introduction of MMR and was claimed to be unaffected by the increase in take-up.

This hypothesis, of a correlation, could be criticised as not being useful to the detection of any MMR/autism link. Although immunisation coverage can be determined, with a specific "date of immunisation", autistic spectrum disorder ranges from the mild to the severe, its onset ranges from the rapid to the gradual, and its diagnosis varies from a timely and accurate diagnosis to no diagnosis whatever. This apparently was not taken adequate account of by Dales et al.

The study did acknowledge some weaknesses itself:

"Diagnosis is not always straightforward". This is an extreme understatement.

"California Department of Developmental Services’ report stresses that its patient caseload data cannot be used as a true measure of changes over time in autism incidence because other factors can affect trends in system case numbers"

"Observation of parallel trends over time.......generally do not constitute strong evidence for a causal association between the two events"

"As the system expanded and matured over time, the proportions of California children enrolling and the distribution of ages at enrolment likely (my emphasis) changed over time as a result". Clearly, the authors do not know, one way or the other, not do they attempt to quantify this to enable their reliance on the data to be validated, or appropriate potential distortions in the data eliminated.

"Also, the proportions of children enrolling in the system who were born outside California may (again, my emphasis) have changed over this time period". Again, they do not know, have not attempted to quantify this factor, and cannot correct for it.

"The data presented herein have some limitations. It would have been useful to examine individual immunisation and autism records on the same children; however, these could not be linked". What the authors are saying here is, they would like to have done a rigorous study, but they couldn’t obtain the data.

"Further, the childhood immunisation coverage data used in this study do not provide precise quantification of the percentage of children who received the combined MMR vaccine product vs. separate injections". This is an admission that one element of the two elements that provide the statistical comparison that is central to their hypothesis, is inaccurate. They go on to say that historical data from elsewhere in the US "strongly suggests" that the use of separate vaccines was "rare" for the 1984-94 birth cohort. How strong? How rare?

Despite this catalogue of drawbacks and "softness" - or complete absence - of data, the authors then go on to claim that they have been "unable to demonstrate a correlation between secular trends in early childhood MMR immunisation coverage and autism caseload". A dispassionate and objective observer would find this wholly unsurprising.

The assumption that there would be a plateau in the increase in MMR (to match a plateau in take-up of MMR) would only be valid if the background susceptibility of the infant population has remained constant. If successive generations of children became increasingly susceptible to an adverse event such as autism, caused by MMR, then this might well be reflected in a continuing rise in autism. This obvious possibility is not addressed. It does not have to be the case that the relationship between MMR and autism is a simple linear one, without other factors being involved.

Overall verdict: this study is not relevant to disproving an MMR/autism link If the study does have a value, it is to demonstrate that extremely weak studies are not only capable of achieving publication - apparently without attracting peer-review criticism - but also that they are then uncritically welcomed, and publicised, by one side of the argument. This in itself is illuminating.

33. Paper by DeWilde, Carey, Richards et al, Do Children Who Become Autistic Consult More Often After MMR Vaccination, British Journal of General Practice, March 2001

This paper appeared in the British Journal of General Practice, March 2001. It attempted to test the hypothesis that a degeneration into autism, with subsequent diagnosis, would be reflected in increased consultations with the child’s general practitioner.

This would appear to be an extremely weak hypothesis to test. For example:

It may be difficult to place a definite date upon degeneration

Parents may not seek assistance from their GP immediately, or even at all in some cases

Parents may seek advice from health visitors or other health professionals

Parents may see a GP only once, to obtain a referral to a specialist paediatrician

Parents may see their GP for reasons unconnected with autism, confusing the data in some cases

Parent may be extremely reluctant to see their GP, because of the sometimes extreme practical difficulties of taking an autistic child to a public surgery, with waits etc.

The study authors do not acknowledge any of these serious potential methodological flaws, nor do they attempt to quantify them in an attempt to validate the effectiveness of their methodology.

The authors looked at only 71 cases of autism, a small sample by any standard for testing a statistical hypothesis, and identified numbers of consultations from a primary health care database. It found that there was no significant difference between cases and controls for numbers of consultations in either the six months before/after immunisation, or the two months before/after immunisation.

The study also noted

that there was a significant fall-off in consultations in the six months after immunisation, in both cases and controls. However, it did not address the possibility that this might have been for two entirely different reasons, with healthy children not needing to be taken to their GP, and autistic children not being seen by their GP for other reasons such as those set out earlier. The study simply assumed that the fall-off in the cases and the control group was for the same reason, without evidence to underpin this assumption.

It acknowledged that it could be criticised because the study authors "cannot confirm that our cases truly suffer from autism"

The study, like almost all other studies that "prove" no MMR/autism link, did not specifically address the cohort of children alleged to have degenerated as a consequence of MMR, and who are now proceeding through the legal processes

It acknowledged that "some diagnoses will have been missed"

It admitted that "it seems unlikely (my emphasis) that these will be specifically those associated with MMR", although it offers no evidence to support this assumption.

The study notes that ""the clear difference in consultations in the six months before the diagnosis of autism" (between cases and controls) "emphasises that consultations were being recorded and that differences in consultation rates between cases and controls were detectable". But the study does not address the possibility that the higher frequency of consultations by cases is linked to a potentially-associated condition, such as otitis media (and consequent antibiotic use), and that cases moved from more frequent consultations than controls for such a condition, to more frequent consultations than controls for a wholly different and more serious condition.

Overall verdict: this study is not relevant to disproving an MMR/autism link. In short, there are so many caveats, acknowledged and unacknowledged shortcomings and other methodological limitations to this study that its conclusions are virtually valueless. Again, it is illuminating that it has been so well received by one side of the debate (the UK Department of Health).

34. Study by Davis et al, Measles-Mumps-Rubella and Other Measles-Containing Vaccines Do Not Increase the Risk of Inflammatory Bowel Disease, Archives of Pediatrics and Adolescent Medicine, 2001, 155: 354-359

This study was conducted in the US on the populations of four health maintenance organisations as part of a vaccine safety programme co-ordinated by the Centres for Disease Control and Prevention.

The study focussed on the following questions:

Was the age of first vaccination with MMR or other measles-containing vaccine, or receipt of vaccination itself, associated with an increased risk for Crohn’s disease or ulcerative colitis later in life?

Was receipt of MMR or other MCV associated with the acute onset of disease shortly following vaccination?

In each of the areas, trained staff reviewed medical records. Cases were of individuals enrolled since birth (some as early as 1958) to 1989. It was claimed that consistent criteria were used for definite and probable diagnosis of Crohn’s disease, ulcerative colitis or unspecified irritable bowel disease. This involved diagnosis by a gastroenterologist, "with signs and symptoms and a diagnostic test for IBD". Five controls were selected for each case, matched by sex, health organisation and year of birth. Dates of vaccination, type of vaccine and date of diagnosis were also recorded.

There were 155 cases of IBD with 152 definite or probable cases. Seven had no discernible onset, two were of "unspecified disease" and one was vaccinated when older than 10 years. This left 142 cases and 432 controls for further analysis.

The study found that:

the risk of inflammatory bowel disease was the same whether for vaccinated or unvaccinated people

there was an average of 140 months between vaccination and diagnosis for cases.

Only 1% of cases developed inflammatory bowel disease within a year of vaccination

Only 1% of controls developed inflammatory bowel disease within a year of vaccination.

Whether children were vaccinated before 12 months, between 12 and 18 months, or after 18 months, showed no difference in the risk of developing inflammatory bowel disease

However, the study team had to acknowledge several serious limitations to this study:

Only patients with a physician diagnosis (usually a gastroenterologist) were included. This could have potentially missed many cases, particularly if those missed were of an insidious new variant

The team acknowledged the inherent limitations of diagnostic accuracy in any retrospective study

They had little information on children or adults with non-specific colitis that did not lead to an eventual diagnosis of IBD - surely a key failure, given the nature of the research by the Wakefield team at the Royal Free Hospital in London

There was an acknowledged limitation over statistical power. The report admitted:: "We were able to effectively rule out associations larger than 2-fold between ever being vaccinated with MMR and developing IBD, and associations larger than 3-fold between vaccination with other measles-containing vaccines and IBD. However, we had a limited sample size from which to look at the independent associations between vaccination and either Crohn’s disease or ulcerative colitis, or at the relationship between timing of vaccination early in life and subsequent risk for Crohn’s disease or UC." This seems to be a serious self-criticism, yet oddly it does not seem to have had much effect on the study’s assertive conclusions.

The study’s reliance on patient records should also be questioned. The analysis of records can by definition be only as good as those records themselves. No study (as far as is known) has yet endeavoured to verify whether children suffering from acquired autism, ileal lymphoid nodular hyperplasia or non-specific colitis have medical records that accurately reflect these conditions. There are grounds for suspecting that the very reverse may be the case. The difficulties in obtaining a clear and timely diagnosis of autism are well known. The nature of the autism problem, with many patients without speech, means that the precise nature of the patient’s complaints and symptoms may be poorly recognised, and even more poorly recorded.

Overall verdict: although this study at first sight appears more persuasive than some others, it too fails to provide convincing evidence against an MMR/autism link. The study may be seriously flawed due to its retrospective nature, when the condition in question (acquired autism after MMR/MCV) has only recently received publicity, and because of doubt over records.

The Davis et al Paper ( Arch Ped Adolesc Med 2001; 155: 354-359) by Walter O. Spitzer, M.D.

35. Further Paper by Farrington, Miller and Taylor, MMR and Autism: Further Evidence Against a Causal Association, Vaccine, 19 (2001) 3632-3635

When it became apparent to Taylor, Miller and Farrington that the time-lapse for degeneration into autism might be a protracted one, they were obliged to re-analyse their earlier data.

Farrington, Miller et al repeated their view of the original Wakefield study, that it was very small (12 children) and that the interval between receipt of MMR and first behavioural symptoms varied from 24 hours to two months. However, the Wakefield study cohort subsequently grew to about 200, and this has not been acknowledged by Farrington, Miller et al in this further paper.

The Farrington, Miller et al study also has not taken account of the Spitzer, Aitken et al study and its implications (see later sections). They also maintain that they "found no evidence to support a causal association". But they themselves, in their first study, unconvincingly dismissed a clustering of parental concerns at around six months. They maintain this unconvincing stance.

Farrington et al concluded that the temporal association found by Wakefield et al was "a combination of selection bias and chance". This latter is a highly contentious conclusion, suggestive of wishful thinking, in the same way as the dismissal of the six-month clustering was.

In this second paper, the authors seek to re-test their earlier conclusions by removing any preconceived fixed-time interval between vaccination and the onset of autism. Again, they use a statistical methodology, self-matched case-series analysis, but once again with a very small (for this method) data set of just 64 cases of what they describe as "unvaccinated" children with autism - presumably, they mean "unvaccinated with MMR" - plus 231 cases of children with autism who had received one dose of MMR, and a further 62 cases of children who had received two doses of MMR (total 357 children).

The study found that:

for the 357 cases, the observation periods had a median of 89 months, a maximum of 191 months.

The oldest age at diagnosis was 180 months.

Some 64 did not receive MMR.

Some 43 received MMR after age 2 years, at median age 57 months, maximum 165 months.

Some 62 cases received a second dose of MMR, at median age 54 months, maximum 159 months.

The comparison of relative incidence for each group finds that there is little difference between those that had received MMR and those previously referred to as "unvaccinated", but which seems to have really meant "vaccinated with single-antigen measles vaccine" - the paper is not clear.

The major criticism of the earlier paper using this data (see above section) were that there was only a proxy for "onset of autism" (a questionable term in itself). The original study measured diagnosis, parental concern and regression (if applicable) from medical records. But these would be variably delayed from any actual "onset event". The very poor correlation between these proxies and the "event" means that the analysis loses all statistical power.

Major criticisms of this further re-worked paper’s statistical methodology are that:

Regarding the whole period following MMR as being "at risk" is questionable.

Looking to see if those who have MMR earlier have a proxy variable earlier is erroneous, when one observes the very narrow timescale for the application of MMR in this paper. When the input signal (the age of receipt of MMR) has very little variability, one would be unlikely to find this reflected in the output signal (date of diagnosis)

The above flaw means that the only statistical power left is coming from finding any difference between those who have MMR and those who have not. But most of those who do not have MMR are those older children who are of the pre-MMR generation. So Farrington et al’s analysis is effectively asking whether those who are older had had an earlier or later onset of autism (as measured by the proxy variables).

Overall verdict: this study fails to provide any convincing evidence against an MMR/autism link.

36. Paper by Fombonne & Chakrabarti, No Evidence for a New Variant of Measles-Mumps-Rubella-Induced Autism, Pediatrics, Vol. 108 No. 4 October 2001

This paper examined whether there is a new phenotype of autism involving regression and gastrointestinal symptoms.

It is suggested that where this paper is flawed is in the assumptions underpinning the hypotheses that are tested. All else stems from that. Fombonne & Chakrabarti assume that if autistic enterocolitis existed, then one or more of the following six predictions should be supported by empirical data:

Prediction (1) - "childhood disintegrative disorder has become more frequent". (The study found the prevalence of childhood disintegrative disorder to be 0.6/10,000, or 1 in 16,666. But this seems far too low in comparison with other recent studies).

Comment - historic data is not available to prove this either way. The claim that the present rate of 1 in 16,666 represents no increase is further undermined by its non-credible low level. Other studies have found rates very many times higher. This strongly suggests that the study is flawed.

Prediction (2) - "the mean age of first parental concern for autistic children who are exposed to MMR is closer to the mean immunisation age than in children who are not exposed to MMR."

Comment - the study found that there was no difference in the mean age at first parental concern between the two samples exposed to MMR (19.3 months and 19.2 months) and the pre-MMR sample (19.5 months). But no argument has been presented as to why there should be a difference. A difference might be expected, but its absence in itself does not prove anything. It is perfectly possible that childhood disintegrative disorder has several causes, and that the arresting of development could be noticed at around the same time. Pre-MMR children who became autistic may well have become so due to an adverse outcome from monovalent measles vaccine. This possibility does not seem to have occurred to Fombonne. There is also a simplistic focus upon MMR alone as a sole factor, working in isolation, rather than as part of a complex process.

Prediction (3) - "regression in the development of children with autism has become more common in MMR-vaccinated children." The study found that the rate of developmental regression reported in the post-MMR sample (15.6%) was not different from that in the pre-MMR sample (18.4%) and therefore there was no suggestion that regression in the development course of autism had increased in frequency since MMR was introduced. The study also found that in the epidemiologic sample, the subset of autistic children with regression had no other developmental or clinical characteristics, which would have argued for a specific etiologically distinct phenotype.

Comment - the samples were small. The study used three samples, a post-MMR sample of 96 children with PDD, a pre-MMR sample of 98 autistic patients, and a post-MMR sample of 68 autistic patients. These are very small numbers to use in a statistically-based study. Fombonne and Chakrabarti’s results should thus be treated with caution, as a few cases either way would impact upon their conclusions.

Prediction (4) - "the age of onset for autistic children with regression clusters around the MMR immunisation date and is different from that of autistic children". The study found that parents of autistic children with developmental regression detected the first symptoms at a very similar age (19.8 months) to those of autistic children without regression (19.3 months). The study also found that the mean intervals from MMR immunisation to parental recognition of autistic symptoms were comparable in autistic children with or without regression (248 days vs 272 days, not significant).

Comment - but regression would not be expected to "cluster round", but may follow MMR at a delay of weeks, months or years. There is no scientific justification for assuming that children with regression after MMR should have their condition recognised at a different time to those who did not regress after MMR. In any event, it is stated that the difference between 248 days and 272 days is not significant, but it is almost 10% different, and this difference has not been explained.

Prediction (5) - "children with regressive autism have distinct symptoms and severity profiles."

Comment - little scientific justification for testing this assumption is given in the study, which also refers to external features such as behaviour, when the real focus of interest should be on gut biopsies and ileocolonoscopies of the actual children, which of course were not done in this study. Not enough is known about autistic enterocolitis to make such an assumption about external characteristics into a key test.

Prediction (6) - "regressive autism is associated with gastrointestinal symptoms and/or inflammatory bowel disorder".

Comment - but the children in this study did not undergo ileocolonoscopy. Their condition was medically unresearched.

Other comments:

this is a statistical analysis of random groups of children, not of the children whose cases are going to the High Court. The numbers are extremely small, too small for a reliable interpretation to be made

The assumption seems to have been made that children could not have been damaged by vaccines other than MMR. The Lassiter court case outcome (US) means that there is evidence, that has been accepted in a Court that other multiple vaccines also trigger autism.

What this study set out to do was not to investigate the cause(s) of damage to specific children, but to clear MMR of any complicity. At first sight, it succeeds in the latter, but at closer analysis, it makes numerous unfounded assumptions that considerably weaken the strength of its conclusions. At worst, it demonstrates the central flaw of designing a study hoping to achieve a desired outcome, rather than to investigate a problem.

Overall verdict: this study fails to provide any convincing evidence against an MMR/autism link.

37. Paper by Taylor, Miller et al, Measles Mumps and Rubella Vaccination & Bowel Problems or Developmental Regression in Children with Autism: Population Study, published BMJ.Com, 8th February 2002

The objective of this paper was to investigate whether MMR vaccination was associated with bowel problems and developmental regression in children with autism, and to look for a "new variant" form of autism.

Some 278 children with what the authors defined as "core autism", and a further 195 with "atypical autism" were studied. These were identified from disability registers. The children were born 1979-1998.

The outcome measures that were studied were:

Recorded bowel problems lasting at least three months

Age of reported regression (where it was a feature)

Relation of these to MMR

Of the 473 children whose records were reviewed, 81 (17%) were reported to have associated bowel problems, comprising:

42 with constipation

7 with constipation and diarrhoea

19 with diarrhoea

7 with food allergy

2 with non-specific colitis with ileal-lymphoid nodular hyperplasia

(4 noted as "others")

The study reported that:

The proportion of children with developmental regression (25% of the overall) or bowel symptoms (17%) did not change significantly during the 20 years from 1979 (MMR being introduced in October 1988)

No significant difference was found in rates of bowel problems or regression in children who received the MMR vaccine before their parents became concerned about their development, compared with those who received it only after such concern, and those who had not received MMR.

A possible association between non-specific bowel problems and regression in children with autism was seen, but this was unrelated to MMR

The study concluded that its findings provided no support for an MMR-associated "new variant" autism, and further evidence against involvement of MMR

The study admitted that it had the "strengths and weaknesses of data based on case notes. Data was not recorded systematically and there was variability in the level of detail."

Comment - there are several major criticisms that can be made of this study.

Most importantly, it was an epidemiological study of case notes, not a clinical study (with examination and clinical analysis of samples) of the cohort of children believed to have been damaged.

No clinical examination appears to have been undertaken by the study team, and it is highly questionable whether such examination or analysis was ever undertaken in the past by paediatricians or specialists in the field, either. This greatly reduces the value of this study.

Equally importantly, the study relies heavily upon the accuracy of child health records. Experience suggests that the health records of autistic children do not accurately reflect their condition, with numerous specialists and agencies involved and with the records not necessarily accurately reflecting the information supplied by parents, due to poor reporting, poor recording and undervaluing of parental "anecdotal" evidence.

For health records to be relevant to an assessment of a novel syndrome, which was first only widely reported in 1998 (and has been repeatedly denied by the Department of Health ever since), health professionals would have to connect what the parents were reporting, and the condition of the children, with the new syndrome. They would also then have to have commissioned appropriate clinical examination of the children, and ensured that this was accurately recorded.

It is patently obvious that this would not have happened for the perhaps the first nineteen of the twenty years 1979-1999. The study is therefore trying to assess records made in an era before in-the-field awareness existed, and in all probability without any appropriate clinical examination or analysis ever having taken place in the past, as well as during the study.

These major criticisms would appear to leave the study seriously lacking relevance. Despite this, the study was described by the Department of Health as "elegant".

The independence of the study also must be questioned.

Dr. Elizabeth Miller, head of the Immunisation Division of the Government’s Public Health Laboratory Service, was a direct participant at the Department of Health’s re-launching of the MMR programme in January 2001, and thus cannot be regarded as a detached "outside" researcher.

And as long ago as December 1997, Professor Brent Taylor described Dr. Andrew Wakefield, in writing, as "a zealot.....who thinks that MMR is the cause of all the problems of the Western world." This suggests that Taylor’s stance towards the alleged MMR/autism issue was set several years ago. Researchers are entitled to their views, but, if these are expressed in such a highly charged manner, then it is only right that such prior remarks should be set alongside their study findings, particularly when such findings are regarded, and publicised, by Government as an "independent" study.

There are other serious methodological criticisms of this latest Taylor, Miller study:

The study looks at percentages of autistic children, giving the impression that background rates of autism aren’t increasing. What the study findings should also include is a plot of the actual numbers of cases diagnosed per year, and of inflammatory bowel disease/other aspects. This is a crucial omission. It is impossible from the study report to tell whether these numbers (as opposed to percentages) have changed over time.

The study does not reveal the sample sizes for each year. How many children fall in each year is not shown. It also therefore does not confirm whether the distribution is even, across the years. This makes the data impenetrable to outside scrutiny. (Note: on ITV’s "Dimbleby" discussion programme on 10th February, Prof. Taylor was challenged by the National Autistic Society to release his raw data for independent analysis, and declined to do so).

Following on from the above, any logistic regression on year of birth is going to be highly underpowered as a way of detecting any MMR effect.

The study does not make clear exactly how many of the 473 had MMR how many times, and precisely when. This is a fundamental failure in methodology.

Notably, the study does not take the most obvious route of all, of comparing a large group of MMR-vaccinated children (10,000+) with another large group (10,000+) of unvaccinated children. An epidemiological study could have been undertaken of such groups. A study of only 473 children is far too small to detect relatively-rare adverse outcomes. The study size is so small that in some years there may have been no more than a handful of children.

(Note: the study by Wakefield O’Leary et al looked at about 200 children, but this was a clinical study, not an epidemiological study. A cohort of 200 children in a clinical study is vastly more reliable than a cohort of 473 children in an epidemiological study).

As only 17% of the sample had "not had" MMR, and only 18% had "reported bowel problems", this means that the study inevitably is not very powerful.

According to Taylor Miller et al, their study identified just two children with ileal-lymphoid nodular hyperplasia, the novel syndrome being studied by Wakefield et al. This is either wholly inadequate because it is such a tiny sample, or it alternatively suggests that the case-notes missed many cases amongst the remaining 473 cases. It would be extremely surprising if the ILNH condition being studied by Wakefield only occurred in 2/473 children. What this suggests is that very few children out of the 473 have been clinically investigated to ascertain whether or not they have ILNH.

The cohort of children identified by the study as having "bowel problems lasting three months" is highly unspecific and vague. Records would be most unlikely to accurately reflect the extent, intensity, nature or length of time these "problems" consisted of.

The percentage of "regressing" children is identified as being 25%, yet Simon Baron-Cohen’s CHAT system uses a rigorous definition which gives a rate of 10%. This difference suggests that the Taylor Miller definition may have been unusually wide

"Parental concern" is not defined. It is not clear whether this equates to a visit to the GP, or to personal parental doubt. It is unlikely that health records would accurately reflect this, particularly if onset was insidious.

Perhaps the most interesting finding is that there is a reported highly significant association between developmental regression and bowel problems. But as 87% had MMR, and only 31 had bowel problems, one might expect 27/31 of those with bowel problems to have had MMR, and 4/31 to have not had MMR. This again has very little statistical power, because the numbers are so very small as to be capable of being influenced by pure chance, in addition to other methodological flaws described elsewhere such as poor or inaccurate records.

It is also not clear which children that had "had MMR", also had the booster as well as the early immunisation, the booster but not the early immunisation, or the early immunisation but not the booster.

The most extraordinary feature of this inconclusive study was the way it was hailed as providing conclusive irrefutable evidence that there was no link, despite is many serious drawbacks. Its publication was met with a further claim by the Scottish chief medical officer, Dr. Mac Armstrong, that any calls to mount clinical studies into the MMR/gut/autism issue would be "resisted". This line was repeated in a television interview by Dr. Elizabeth Miller on 13th February 2002.

Conclusion: this study offers no evidence against an MMR/autism link.

PART D

REVIEWS CONCLUDING THERE IS NO EVIDENCE OF A LINK

38. Medical Research Council Review By "Committee of 37 Independent Experts"

This was held as a one-off in March 1998 to examine the Wakefield team’s "Early Report" published in 2/98 in The Lancet. It concluded

that there was no current evidence linking bowel disease or autism with MMR

there was thus no reason, arising from the work considered, for a change in the current MMR vaccination policy" (my emphasis - note the careful wording)

This review has now been overtaken by subsequent events, yet it continues to be quoted by the UK Department of Health, as though time had stood still.

39. Paper, Conclusions on MMR Vaccine Safety by the All Party Parliamentary Group on Primary Care and Public Health, House of Commons, UK (based on a presentation by Dr. Elizabeth Miller, Head of the Immunisation Division, Public Health Laboratory Service)

This paper reported on its review of MMR’s safety, based upon a presentation by Dr. Elizabeth Miller of the Public Health Laboratory Service on 24th July 2000.

There are a number of serious concerns about this paper:

The conclusion of the APPG and its invitees was that MMR was safe, and that concerns about the alleged links with autism/inflammatory bowel disease were unfounded. However, this is a very strong claim, in the absence of appropriate comprehensive studies. If a link is "unproven", that does not necessarily mean that a concern is therefore categorically "unfounded".

Dr. Miller had demonstrated that MMR has enabled "excellent" control of measles, but that is not the point at issue.

There was concern at the fall in MMR take-up. This, too, is not what is under scrutiny. It is MMR’s safety that is in question. Concern over measles outbreaks and falling take-up may be legitimate, but are arguably being used here as a form of moral pressure.

The APPG expressed concern about measles outbreaks elsewhere, e.g. Holland. The same comment applies. It is MMR’s safety in the UK that is under scrutiny.

The statement that "all (hypotheses about a link) have originated from a single group of workers in the UK" (at the Royal Free), and "none has been endorsed by independent recognised medical experts anywhere in the world" is highly misleading. The Royal Free team have been at the forefront of research, but their work has been given backing by other researchers (to give just one example, the letter in the Lancet by Sabra, Bellanti and Colon, 1998), and the possibility of a link has been endorsed, or has been unable to have been ruled out, by other researchers. Other studies and reviews have been inconclusive either way. The position is still one of scientific uncertainty.

Claims that the Joint Committee on Vaccination and Immunisation "is composed of independent clinical and scientific experts" are open to question. The JCVI does not include gastroenterologists - which is the key area of science under scrutiny in this issue. Its independence can also be questioned on two counts. Firstly, a number of its members have declared financial links with the pharmaceuticals industry. This could be argued to part-compromise their independence. Secondly, there is a collective professional interest in eliminating infectious diseases through immunisation. Such a body is therefore not wholly "independent" when it comes to assessing evidence for adverse side effects from vaccines, particularly if it involves a syndrome which, if acknowledged, could damage confidence in vaccines and lead to a resurgence in communicable diseases.

The Committee on Safety of Medicines is also questionably "independent". It is a matter of record that 37 members of the CSM had between them, at the end of the 1990s, nearly 190 separate declared financial links with the pharmaceuticals industry, about one-half of which were personal financial links. Some of these links involve the manufacturers of MMR. The 190 links include shareholdings, consultancies, research funding and non-executive directorships. An impartial observer would find that these links could arguably weaken any claims of "independence".

The claim that "there is no evidence" (for a link) is factually incorrect (see elsewhere).

Claims of "overwhelming evidence" (against any link) do not address the inconclusive nature of many of the studies involved. There is still no hard evidence against a link. These studies also conflict with the direct first-hand accounts of the parents of the children believed to have been damaged.

It is disappointing, if understandable, that the All Party Group should produce such a report. The Group appears to have been given a presentation of only one side of the argument.

This review too has been overtaken by subsequent events.

40. The Medical Research Council’s Report, Report of the Strategy Development Group Sub-Group on Research into Inflammatory Bowel Disorders and Autism, March 2000

This was yet another review group which, upon failing to prove that there was a link, then drew the unproven conclusion that, because they could not find one, it automatically followed that there was no link. Membership of the group was messrs. McGregor (chairman), Driscoll, Frith, Jewell, Meade, Sewell, Smith, Tedder, Ward, Wing, Wright. The sub-group met four times, 1998-99.

The group was to develop a strategy for further research, monitor and steer future MRC support, and report at least annually.

The subgroup recognised that the level of MRC support, particularly for IBD (but why not autism?) was "relatively weak".

The subgroup found that the case for autistic enterocolitis was unproven, and that the California autism increase "may be due to wider definitions and increasing awareness", though it offered no scientific evidence to support this comforting claim.

It concluded that much remained unknown about autism and IBD, that MRC support for research was weak, and that "between March 1998 and September 1999 there had been no new evidence to suggest a causal link" (again, note the careful wording).

For autism, its recommendations included:

Investigation of risk factors, large-scale epidemiological studies concentrating on late-onset cases (this led directly to the Professor Andrew Hall three-year study at London School of Hygiene & Tropical Medicine, but seemingly, to little else)

Development of tests to investigate gastrointestinal involvement in autism (no progress on this has since been reported)

Maintaining a watching brief for further evidence of any link

Despite the above, which implied continued vigilance, the chairman was openly dismissive of even the possibility of a link emerging, Professor Alan McGregor telling Reuters "We see this as the end of the story" (Reuters, 3/4/00).

41. Review By US Institute of Medicine, 2001

The Institute of Medicine undertook a review of the link between MMR and autism during 2001.

The Immunisation Safety Review Committee was asked to assess not only the scientific plausibility of the hypothesised association between MMR and autism but also the significance of the issue in a broader context. In the IoM’s view, the plausibility assessment involved two components:

An examination of the causal relationship between the vaccine and the adverse event

An examination of any pathogenic mechanisms that support the hypothesis

The IoM set out a number of important reservations regarding the heavy reliance on epidemiological studies to prove/disprove any MMR/autism link:

Studies may not have sufficient precision to detect very rare occurrences at a population level

A poor understanding of the risk factors and a failure to use a standard case definition may also hamper the ability of epidemiological studies to detect rare adverse events

Since MMR is virtually universal in developed countries, elucidating any association with adverse outcomes requires the creative use of administrative and other data sets and complex research designs

The rarity of the individual autistic spectrum disorders, and the difficulty in determining their exact onset, and therefore the temporal relationship between onset and vaccination, makes certain epidemiological study designs (e.g. cohort studies) impractical.

The IoM Committee concluded that the evidence favours rejection of a causal relationship. However, the Committee also noted:

Its conclusion did not exclude the possibility that MMR vaccine could contribute to autism in a small number of children

The epidemiological evidence lacks the precision to assess rare occurrences of a response to MMR leading to autism

The proposed biological models linking MMR vaccine to autism, although far from established, are nevertheless not disproved

In a critique of the IoM Review in Autism Research Review International Newsletter, Vol. 15, No. 2, 2001, Dr. Bernard Rimland of the Autism Research Institute stated:

The IoM did in fact NOT reject the hypothesis that MMR is a possible cause of autism (the IoM review is regularly quoted by the UK Department of Health as having "cleared" MMR of any link with autism)

the IoM report actually supports, not refutes, what the parents contend.

It should be the medical establishment’s burden to have proved that the vaccines are safe, not the critics’ burden to prove them unsafe - a key point.

Two of those who issued the IoM press release had links with the manufacturers of MMR

42. Paper by Elliman, Bedford & Miller, MMR Vaccine - Worries Are Not Justified, Archive of Disease in Childhood, 2001: 85: 271-274 (October)

This review paper (by Elliman and Bedford) offered no new evidence, as was the case with the supporting commentary (by Dr. Elizabeth Miller), but simply re-presented previous work. The main conclusions were:

Children are more at risk from separate measles, mumps and rubella injections than from the combined MMR

There has been no research into the long-term effectiveness of single injections (Comment - but, again, the point at issue is the safety or otherwise of MMR, and damage to specific children - not the effectiveness of single vaccines)

The study authors acknowledged the receipt of funding from vaccine manufacturers to attend meetings and conduct research.

Dr. Elizabeth Miller’s commentary included an attack on The Lancet for publishing the 1998 Wakefield "Early Report": "Publication in respectable medical journals of (these) papers.....is a disservice to patients and health professionals alike". Dr. Miller’s commentary included the quote that MMR’s "safety evidence is so overwhelming".

The Department of Health welcomed this latest "research" (which it was not), stating that "single vaccines would put children at unnecessary risk and would have no scientific support whatsoever".

The Elliman and Bedford paper did not review the work of Singh, amongst others.

43. Review By UK Medical Research Council, Review of Autism Research - Epidemiology and Causes, December 2001

The UK Department of Health and Medical Research Council jointly announced on 5th March 2001 that the DoH has asked the MRC to conduct a detailed review of the current state of knowledge about autism.

The review was chaired by Professor Eve Johnstone of the University of Edinburgh and Royal Edinburgh Hospital. The review was to suggest possible areas for further research development, including obtaining a clear and comprehensive picture of what is currently known about the incidence, prevalence and causes of autism, and how strong the evidence is which underpins that knowledge.

The main findings of the review, reported in December 2001, were:

It found no association between autism and MMR (this was later misrepresented by the UK Department of Health as equating to "clearing" MMR and "proving" that there was no link - which the review did not)

The prevalence of autism is higher than had been thought (a rate of 1/166 was quoted)

The review claimed to have had "extensive" input from lay people. However, several refused on the grounds that at least four of the expert-group participants were already signed-up to the MMR manufacturers as paid witnesses in the forthcoming UK High Court cases. There was also strong concern from the outset from parents about balance in the review and its outcome.

Most of the increase in autism was "explained" away by changes in definition and increased awareness. The report thus heavily played down any uncomfortable conclusion that the increase might be real

Autism was found to result from several causes, with a genetic component. The interplay between genetic and environmental factors "was not yet known".

The review accepted that a number of studies (reviewed elsewhere in this briefing note) offered "evidence" that there was no MMR/autism link, or alternatively, did not offer evidence to the contrary.

Various priorities for further study were identified,.

What was most notable in the review’s report was how few studies for/against an MMR/autism link were covered at all, seven at most against a link and only one (plus Wakefield) for.

For "evidence" against a link, the review reported on just a handful of scientific studies - Taylor, Miller et al, Kaye et al, Smeeth et al (which had yet to report), De Wilde et al, Fombonne & Chakrabarti, Dales et al, and Patja, Peltola et al. Each of these studies is covered elsewhere in this briefing note, and each is shown to be flawed or inconclusive in its outcome. Yet the MRC review accepted all of these as "evidence" of no MMR/autism link.

For evidence for a link, even less satisfactorily, the MRC rejected the hypothesis of Wakefield et al, and reviewed only one scientific study to support an MMR/autism link, this being Spitzer, Aitken et al (also reviewed elsewhere in this briefing note). The only conclusion the MRC drew from this study, which would of course have been in conflict with the MRC’s no-link conclusions, was that the average age at diagnosis of UK children with autism was 4 years.

By disparaging the possibility of any link between MMR and autism, the review was able to sidestep having to suggest any research in this area. So "no evidence" meant "no future studies" in this controversial area - and "no future studies" will thus ensure "no evidence". It was clearly desirable for the MRC to avoid raising further concern about MMR in its conclusions.

44. Further Review By the US National Academy of Sciences Institute of Medicine on Child Vaccinations and Autoimmune Dysfunction, February 2002

This found that:

Scientific evidence from epidemiological studies on whether asthma and allergy can be caused by multiple vaccinations was conflicting, and that the evidence "was inadequate to accept or reject a causal relationship"

Epidemiological studies to date favoured rejection of a causal relationship between multiple immunisations and increased risk for infections and for type 1 diabetes

There was some biological mechanism evidence that vaccines could increase the risk of immune dysfunction in some children, that could lead to increased infections and allergy, including asthma. The IoM stated that "the biological mechanisms evidence regarding increased risk for infections is strong".

On vaccine-induced neuroimmune dysfunction, the IoM Committee stated:

"The Committee was unable to address the concern that repeated exposure of a susceptible child to multiple immunizations over the developmental period may also produce atypical or non-soecific immune or nervous system injury that could lead to severe disability or death. There are no epidemiological studies that address this. Thus the Committee recognises with some discomfort that this report addresses only part of the overall set of concerns of some of those most wary about the safety of childhood immunizations"

The Committee also expressed a new note of caution: "As the array of available vaccines and disease-targets expands, the current emphasis on universal recommendations and on State mandates for vaccine use should be re-assessed".

A critique of the IoM report by the US parents’ group PROVE pointed out that the report was drawn up only after a review of past literature, and did not involve new research, and that many of the authors of these past studies had conflicts of interest. Conflicts of interest were also held by some of those that contributed "constructive criticism" to the report, and some researchers who had identified links between autoimmune conditions and vaccines had not been permitted to make presentations to the IoM Committee.

PART E

THE MMR ORIGINAL SAFETY TRIALS DEBATE

This section looks at a review of the original evidence for MMR’s safety, published by Wakefield and Montgomery, subsequent comments from other researchers, and the response of the manufacturing industry and the UK Department of Health.

(Note: it is worth stating the obvious, that it should be for the manufacturers to prove that their product is safe, not for the parents of damaged children to prove otherwise - though this latter is what is now in effect occurring.)

45. Wakefield & Montgomery Through A Glass Darkly Paper (A Look Back At MMR’s Safety Trials), Journal of Adverse Drug Reactions, 2000 19(4), 265-283)

Wakefield & Montgomery reviewed the 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. The following is an abbreviated summary of their findings:

The Buynak study identified viral "interference". The follow-up period was only 12 days

The Stokes study revealed persistent gastrointestinal problems in the US trial children. The follow-up was only 28 days. Stokes compared 228 MMR children with 106 unvaccinated controls. Data, from Philadelphia and Costa Rica and San Salvador, was merged - a serious methodological error.

Gastroenteritis was found to be significantly more common in the Philadelphia vaccinees (24%) compared with the unvaccinated Philadelphia controls (5.6%). No significant difference was found between the vaccinated and the 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.

There was also significant "unrelated" illness in 39% of Philadelphia vaccinees (otitis, allergy, viral infection, abdominal pain), compared with 12.2% in controls. The potential relevance of this was not seen at time.

The Minekawa study confirmed viral interference. The follow-up period was only 15 days.

The Schwartz study also merged its data, so provided insufficient insight. Follow-up was only 21 days. The study looked at two different populations, 282 children in Ohio and 926 children in Santo Domingo, Dominican Republic. Again, the merging of data from different countries was a serious error. No data was provided to permit analysis of adverse events.

Crawford and Gremillion’s study of USAF recruits confirmed viral interference. The follow-up period was only 19 days. Some 512 vaccinees were compared with 835 unvaccinated controls. The study noted increased fever and diarrhoea in those that received measles and rubella vaccines simultaneously. But the potential effect of trivalent vaccine was not additive but synergistic - a key point.

The Eddes study (a small UK study) 1991 compared reactions to MMR with monovalent measles vaccine. High rates of gastrointestinal disorders (41.9% and 37.8%) were found. The authors dismissed these as normal background illness.

The Miller study noted that diarrhoea was common (26% of vaccinees). The follow-up was only 21 days. This was a major missed opportunity to follow up a large cohort. (NB this was Dr. Elizabeth Miller, who has been so vociferous in criticising the Wakefield findings and in defending MMR, and who was co-author, and designed, the heavily-criticised 1999 Taylor, Miller North London study)

The Stokes, Schwartz, Miller and Eddes studies were therefore all too small or too superficial to pick up uncommon adverse events.

The Plesner et al study of gait disturbance following MMR (Acta Paediatrica, 2000, 89, 58-63) confirmed an association, and indicated that more severe cerebellar ataxias following MMR may be associated with residual cognitive deficits.

It is also worth noting that the Wakefield and Montgomery paper is actually an argument for vaccination - but not using triple measles-containing vaccines. Wakefield and Montgomery are not anti vaccination per se. They argue that their duty is to the patient. Dr. Wakefield has been investigating the children brought to him, not campaigning against the UK DoH for its own sake. He is simply relating what he is finding.

46. Dr. Peter Fletcher Commentary, Journal of Adverse Drug Reactions & Toxicology, 2001, 20(1), 47 63 Oxford University Press

The peer review comments on Wakefield & Montgomery paper were very powerful. Peer reviewers included Dr Peter Fletcher, former Principal Medical Officer in the Medicines Division (now MCA), who was medical assessor to the Committee on Safety of Medicines. These are some summaries of his comments:

"Evidence on safety was very thin", and "Too few children were followed for a sufficient time"

"Big numbers were necessary, and computerised databases were already in place to permit this, but it was not done"

"Caution should have ruled the day", and "There should have been strong encouragement to conduct a 12-month observational study on 10,000-15,000 children" (this was not done)

"The granting of a product licence was premature"

47. Dr. Stephen Dealler Commentary, Journal of Adverse Drug Reactions & Toxicology, 2001 20(1), 47 63 Oxford University Press

A subsequent letter was published in the Journal of Adverse Drug Reactions & Toxicology, 2001 20(1) from Dr. Stephen Dealler, Consultant Microbiologist at Burnley General Hospital, Lancashire UK. Dr. Dealler stated:

The finding that measles virus ribose nucleic acid (RNA) in the gut wall of almost all the autistic children that had not suffered measles but had received MMR, when compared to non-autistic controls (O’Leary, Dublin) must be investigated further

Research in the US showing that inflammation can be found not just in the large bowel and terminal ileum but in the duodenum and jejunum as well should not be ignored

Data must be found to determine whether the measles virus is actually causative, or merely retained because of inflammation as a result of some other factor

Autism that might be produced will not necessarily appear at a specific point after vaccination

Complex long term control trials may be required to show MMR to not be involved in the pathogenesis of autism

Research into the background pathogenesis of autism is currently shockingly inadequate

48. Dr. Edward Yazbak Commentary, Journal of Adverse Drug Reactions & Toxicology, 2001, 20(1), 47 63 Oxford University Press

In a further letter to the Journal of Adverse Drug Reactions & Toxicology, Dr. F. Edward Yazbak MD FAAP and Kathy Lang-Radosh MS of TL Autism Research, Falmouth Massachusetts, stated that:

Many children with the new or acquired autism syndrome are normal until past their first birthday, and then develop symptoms in the second or third year of life, or even later

These children actually lose previously-acquired skills

Children with the new autism have gastrointestinal, neurological, sensory and endocrine difficulties

They also have an inordinate number of infections, for which frequent and repeated courses of antibiotics have been used, often leading to candida overgrowth, with further consequent damage to the gastrointestinal tract and increased ileal permeability

Additionally, sulphur transferase deficiency in certain children with autism causes decreased sulphating, which results in inadequate detoxification and reduced mucin formation, which further compromises mucosal integrity. The result is excessive absorption of noxious polypeptides

While recent research has pointed to a genetic contribution of autism, a more likely aetiology of the apparent familial aspects of autism may simply be a family predisposition to immune disorders.

49. The Wakefield/Watson/Shattock Rebuttals - "Anything You Can Rebut, I Can Rebut Better"

The Through A Glass Darkly safety paper by Wakefield and Montgomery was strenuously 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 the University of Sunderland Autism Research Unit. The only aspects that cannot be bottomed-out by Shattock are where the studies referred to by Watson 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". The trial was therefore 28 days, with only queries for arthritis etc beyond this. The Wakefield version is 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 questions whether studies are published or secret. Wakefield & Montgomery 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 response: the technology has failed to isolate measles virus RNA in affected children, but further progress is 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 response: so mutant measles can persist but vaccine strains cannot? - challenge for evidence to substantiate this claim.

Shattock also makes the important 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 were 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 response: was the 1982 study published?/where? Also, the 2000 Peltola 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 response: 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 response: where are publication details?

Watson: numerous post-marketing studies of MMR have been conducted and published. Shattock response: 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 in a novel syndrome with (up till 1998) no publicity, delayed onset, and an official refusal to count reports as an "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, thereby keeping its safety record relatively 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. (NB: In Oliver Thrower’s case, the BBC TV Newsnight report of 8/97 was the first clue, nine years after vaccination, as to the cause of his autism. In his case, vaccination had never previously been mentioned or considered as a possibility by health professionals. He was added to the UK Medicines Control Agency 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 of the industry’s "MMR or be damned" culture.

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 the 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?)

50. UK Department of Health Statement, Combined MMR Vaccines - Response of the Medicines Control Agency and the Department of Health, UK (Repudiation of the Wakefield & Montgomery Through A Glass Darkly Paper)

The UK Department of Health’s response was summarised in its press release of 21st January 2001. The main points are set out below, with the DoH’s text 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, were followed up for longer than a few weeks. Thus 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". The same comments apply. There is an autism problem in all these countries too. Perhaps MMR is implicated elsewhere outside the UK.

"A publication in 1988 lists 30 published studies where combined MMR vaccines were studied and follow-up was extended up to ten years". The 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 purely literal sense, but the reviews have been mis-designed and halfhearted or inconclusive (Quote: "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 strongly argue that the Committees quoted are neither wholly independent (see other references) nor expert in the field of gastroenterology, as opposed to immunology.

"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? If the evidence either way is fuzzy, do they give the benefit of the doubt to the parents who allege their children degenerated, or to the vaccine manufacturers?

"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 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 Department of Health was unable to refute this detail - indeed, it largely avoided addressing it.

PART F

STUDIES THAT POINT TOWARDS AN MMR LINK

51. Paper by Eggers, Autistic Syndrome (Kanners) and Vaccination Against Smallpox, Klinical Paediatrics, 1st March 1976 (944354 PubMed, 76172565 Medline)

This paper reported that 3-4 weeks following an otherwise uncomplicated first vaccination against smallpox, a boy then aged 15 months and last examined at age 5.5 years, gradually developed a complete Kanner syndrome (autism). The question whether vaccination and early infantile autism might be connected was being discussed.

It noted that "A causal relationship was considered extremely unlikely, but vaccination is recognised as having a starter function for the onset of autism" (my emphasis).

(Note: this paper is most notable for drawing attention to a possible vaccination/autism link as long ago as 1976. If such a link was recognised a quarter of a century ago, why has so little been done since to research it?).

52. 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

53. 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

54. Paper by Dr. H. Fudenburg, Dialysable Lymphocyte Extract In Infantile Onset Autism: A Pilot Study, has been published (date/journal not identified), NeuroImmuno-Therapeutics Research Foundation, 1092 Boiling Springs Road, Spartanburg, South Carolina (fax 803 591 0622)

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

55. 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

56. Warren and Singh Paper, Immunogentics, 1992, 36: 203-207

In a study by Warren and Singh published in the journal Immunogenetics, it was 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

It was also 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

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

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.

It was further noted there was a 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

57. 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, and 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.

58. Paper by Dr. Vijendra Singh, College of Pharmacy, University of Michigan, Ann Arbor, joint with the late Professor Reed Warren, Professor of Biology, Centre for Persons with Disabilities, Utah State University in Logan and Adjunct Professor of Psychiatry, University of Utah, and also Dennis Odell, published in Brain Behaviour, March 1993

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.

59. 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

60. US paper by Theresa C. 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, 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

61. Letter by Anne-Marie Plesner, Department of Epidemiology, Statens Seruminstitut, Copenhagen, Lancet, Vol 345, Feb 4th 1995

This letter reported:

That there had been 24 notifications of temporary gait disturbances after MMR vaccination

At a median of 6 days (range 3-25 days) after vaccination, the children developed unsteadiness. Usually the children recovered after a short time (median 8 days, range 1-100 days). One child had not recovered after three months.

A possible cerebral disorder was reported in 8 children, with unusual screaming in 5.

In company reports of MMR vaccines, gait disturbance was mentioned as a rare complication.

Plesner et al later reported on a study of gait disturbance following MMR (Acta Paediatrica, 2000, 89, 58-63)

62. Paper by Gupta, Aggarwal and Heads, Dysregulated Immune System in Children with Autism - Beneficial Effects of Intravenous Immune Globulin on Autistic Characteristics, 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.

63. Paper by Montinari, Favoino and Roberto, Role of Immunogenetics in the Diagnosis of Postvaccinal Central Nervous System Pathology, presented at a conference at Naples held by the Associazione per la Libera Universita Internazionale de Medicina Omeopatica, 9th May 1996.

This study involved the observation of 30 patients with post-vaccinal pathology of the CNS and other symptoms, where the first symptoms appeared concomitantly with or immediately after administration of a vaccine. Patients were subjected to serological testing for herpes virus (IgG and IgM) and to HLA (A, B, C) and HLA-DR-DQ tissue typing to see if there was any correlation between the emergence of CNS pathology and these antigens, to show a possible autoimmune type immunogenetic basis for any demyelinisation process.

The authors reported that 30 Italian patients were observed between April 1994 and October 1995. Clinical signs were dermatitis, food allergies, constipation and reflux, and these followed vaccination with the Salk or Sabin polio vaccine, DT, measles, DPT, anti-tuberculosis or Hepatitis-B vaccines. All patients had had convulsions with or immediately after vaccination, with very high fever or diarrhoea. The patients were children 3-9 months old.

Results of tests showed that:

Serologic investigation for herpetic virus (IgG and IgM) were positive in all patients for IgG and negative for all patients for IgM

Seropositivity (IgG) for Epstein-Barr virus was estimated at 73.8%, for cytomegalovirus of 71.4%, for Herpes Simplex virus of 47.6%, and for Varicella-Zoster virus of 21.4%

In all patients, diminished sideremia and a deficit of IgA and IgG were noted

All of the patients had been normal prior to administration of the first dose of vaccine. Physicians had administered follow-up doses of vaccines, leading to stabilisation of conditions presented, and progressive clinical deterioration.

Patients were also subjected to HLA tissue typing (A, B, C) and serologic HLA DR-DQ to check a possible correlation with the emergence of CNS pathology. These antigens indicated a possible autoimmune immunogenetic basis for the demyelinisation process.

An increase in the HLA-A3 antigen was found (43.3% vs. 25% in the normal population) and the HLA-DR7 antigen (48.3% vs, 24.1% in the population).

The presence of A3 and/or DR7 was observed in 22/30 (73.3%) of the patients.

The authors noted the problems of molecular resemblance, of discriminating between self and non-self antigens, and of determining the function of the Class 2a CMI molecules.

They noted that any interference with the process of presentation of the antigen can predispose to an autoimmune disease.

They also noted that "alterations which do not occur can be due to the action of viral agents which compromise the specific immune response, because of their resemblance to the "self" tissue antigens.

The authors note that the consequence is persistence of the infective agents and a tendency to provoke - through a marked reaction - induction of an autoimmune disease. This can present in conditions of marked reactivity to some viruses and to myelin antigens.

In 66% of patients there was an obstinate constipation. In 31% there was proctic symptomatology with emission of mucus and blood.

The authors concluded that autoimmune pathology was more frequent in countries where vaccination was more widespread, i.e. in countries defined as "clean" from the virologic or microbiologic point of view. They also noted that the use of thiomersal in vaccines (see elsewhere) could demonstrate the possibility of changes in the aminoacids of the molecules which preserve the antigen.

64. 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

65. Paper by Cook, Courchesne et al, Laboratory of Developmental Neuroscience, University of Chicago, 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

66. Paper by Diane E. Griffin, D. E. Hussy et al, John Hopkins University, US, 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

67. Paper by Martinez et al, 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

68. Paper By Zecca, Graffino et al, New Jersey Medical School, Children’s Hospital of New Jersey, Newark NJ, Elevated Rubeola Titers in Autistic Children, presented at a meeting of the National Institutes of Health, Bethesda, Maryland, September 1997

This paper reported that:

The authors had evaluated the possible role of MMR in the pathogenesis of autism by comparing rubeola titers in autistic and normal children.

Amongst 16 children diagnosed with autism followed in their clinical practice, it had been found that these children had a threefold increase in their rubeola titers over the expected normal range. These had been compared with the rubeola titers from 13 normal controls.

Subjectively, parents had stated that their children’s developmental milestones deteriorated following MMR vaccination.

The elevated titers of anti-measles antibodies in autistic children may signify a chronic activation of the immune system against this neurotropic virus. MMR may therefore play a role in the pathogenesis of autism.

69. 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?

70. Study by Wakefield et al, Inflammatory Bowel Disease Study Group at the Royal Free Hospital, London, Ileal Lymphoid Nodular Hyperplasia, Non-Specific Colitis and Pervasive Developmental Disorder in Children, Lancet, 28th February 1998

This is the "Early Report" that started the major public debate in the UK and beyond about a possible link between MMR and autism.

Dr. Wakefield and colleagues suggested 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, initial findings suggested that the hypothesis was plausible.

The Royal Free Hospital group’s report 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, and 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 markedly 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 hard evidence (in terms of the examination of actual affected children or the disproving of this theory) to contradict this hypothesis has been offered to date by the UK Department of Health or others, 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.

Note: the study only looked at 12 children. By the end of 2001, over 200 children had been examined. It has been reported in the UK press that virtually all fitted the same pattern as the original 12.

71. Paper by Montgomery, Morris, Pounder and Wakefield, Inflammatory Bowel Disease Study Group, Dept. Of Medicine, Royal Free Hospital, London, Paramyxovirus Infections in Childhood and Subsequent Inflammatory Bowel Disease (details of date and journal of publication awaited)

This study investigated the patterns of infection that are risks for SSPE, early infection and a close temporal relationship between measles and another infection, as potential risks for IBD.

The data was from 7019 members of a nationally representative 1970 UK cohort study. The ages of five childhood infections were recorded before the onset of IBD symptoms. Diagnosis of IBD and insulin-dependent diabetes mellitus (IDDM) as a control disease were identified by age 26 years. The results were:

Mumps infection before age 2 years was a risk factor for ulcerative colitis

Measles and mumps infections in the same year of life were significantly associated with ulcerative colitis and Crohn’s disease, but not with insulin-dependent diabetes mellitus

These relationships were independent of each other and of sex, social class at birth, household crowding in childhood, and family history of IBD.

The study concluded that atypical paramyxovirus infections in childhood may be risk factors for later inflammatory bowel disease.

72. 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

73. Paper by Singh and Yang, Department of Biology and Biotechnology Center, Utah State University, University of Michigan College of Pharmacy, published Clinical Immunology and Immunopathology, October 1998

This paper suggested 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

Most autistic children with virus antibodies also had brain autoantibodies

The more virus antibodies they had, the more likely they were to have the brain antibodies

None of the non-autistic children had brain autoantibodies

The strongest link was between measles virus antibodies and anti-MBP, suggesting that exposure to the measles virus may cause the immune systems of children with autism to attack myelin

None of the autistic children in the study had had measles in the past, but all had had MMR vaccine

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

Singh commented that the most likely explanation for the connection between autism and measles virus was that some autistic people were genetically predisposed to the disorder. Measles or the MMR vaccine may somehow prompt their immune systems to act in a negative way whilst leaving other people unharmed.

Singh stated that, of 88 autistic cases that he had examined, 51% said that their child’s autism had followed MMR vaccination, and 36% had said it had followed DPT vaccination.

74. Paper by Uhlmann, Sheils et al, Measles Virus In Reactive Lympho-Nodular Hyperplasia and Ileo-Colitis of Children, (publication date not known), Department of Pathology, Coombe Womens’ Hospital, Dublin, Trinity College Dublin and Royal Free Hospital London.

This paper noted that measles virus nucleoprotein (N antigen) had been detected in association with follicular dendritic cells (FDC) in patients, and sought molecular confirmation of this result. It found that:

Solution phase RT PCR yielded specific MV N gene amplification in affected children (10/10)

Distinct measles virus genome was identified in FDC reactive follicular centres by in-cell RNA amplification

None of the normal controls showed any evidence of measles virus genome

The data highlighted a possible causal link between measles virus infection and ileo-colonic lymphoid nodular hyperplasia in affected children

75. Paper published by Bitnun et al, Measles Inclusion-Body Encephalitis Caused By the Vaccine Strain of Measles Virus, Clinical Infectious Diseases Journal, 1999; 29 855-61, (October)

This 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.

76. Paper by Dr. Vijendra Singh, University of Michigan College of Pharmacy, to the US House of Representatives Committee on Government Reform, 2000

Dr. Singh explained that he had set out in his studies to answer two questions:

Do autistic children have a hyperimmune response (or increase of antibodies) for a specific virus?

Is there a relationship between virus antibodies and brain autoantibodies in autism?

In his studies, he reported two important observations:

There was indeed a hyperimmune response to a virus, and it was specifically for the measles virus, but not for the other viruses tested (human herpes virus 6 (HHV-6), rubella virus and cytomegalovirus)

There was an association between measles virus antibodies and myelin basic protein autoantibodies (i.e. The higher the measles virus antibody level, the greater the chance of brain autoantibody)

Also:

He had previously already found that many autistic children had antibodies to a specific protein of the MMR vaccine

These viral antibodies were also related to positive titers of brain MBP autoantibodies.

This was probably the very first laboratory-based evidence to link measles virus and/or MMR vaccine to autoimmunity in children with autism.

These observations led Dr. Singh to speculate that autism may be caused by a measles-induced, or MMR vaccine-induced, autoimmune response, but further research was being delayed by a lack of funding.

Dr. Singh reported his own anecdotal survey of apparently vaccine-injured children with regressive autism. He found that 93% of cases had autistic symptoms shortly after vaccinations. Of these, 52% were post-MMR, 8% post MMR and DPT, and 33% post-DPT. Just 7% were not linked by the parents to any vaccination. He acknowledged that the survey was non-scientific.

Dr. Singh’s conclusion was that:

Rapidly-accumulating evidence strongly implicated autoimmunity in autism

In many, this may have resulted from a vaccine injury

There was a possibility of an atypical measles infection in autism, but the evidence also suggested an MMR vaccine infection

The Congressional Committee should explore the possibility that the manufacturers had never properly evaluated the safety of vaccines in the first place.

77. Paper Presented to US Congressional Oversight Committee on Autism and Immunisation, Professor John O’Leary, Dublin Womens Hospital, April 2000

This paper reported a study using biopsy material from children examined at the Royal Free in London. Dr. Wakefield at the Royal Free had posed three questions to the O’Leary team,

(1) was measles virus present in gut biopsies of affected children?

(2) where was measles virus located in the gut biopsies of the affected children?

(3) how much virus was present?

The O’Leary team used in-situ hybridisation (with/without tyramide signal amplification), in-cell PCR, solution-phase PCR, TaqMan quantitative PCR and DNA sequencing to determine the answers to these questions.

Using TaqMan PCR the team was able to quantify the measles virus copy number per 1,000 mucosal cells using gene dosage correction formulations. The copy number of measles virus in gut biopsies from children with autistic enterocolitis was low, at approx. 30-50 measles virus genomes per 2,000 mucosal cells (inc. Gut, epithelial,lymphoid and dendritic cells).

Confirmation of the presence of measles virus genomes was achieved using positive and negative strand sequencing of cDNA measles amplicons.

The results were that 24 out of 25 (96%) of the autistic children were positive for measles virus, including 2 children from the USA who were included in this analysis

In the controls, only 1 of the 15 children (6.6%) was positive for measles virus.

The study therefore localised, quantified and sequenced measles virus genomes in gut biopsies of children with autistic enterocolitis. The study team then posed the question, "how did it get there?".

78. Paper by Kawashima, Takayuki et al, Detection and Sequencing of Measles Virus from Peripheral Mononuclear Cells from Patients with Inflammatory Bowel Disease and Autism, Digestive Diseases & Sciences Vol. 45, No. 4, April 2000, pp723-729

Following reports that measles virus might be present in the intestines of children with Crohn’s Disease, a new syndrome was reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases after MMR vaccine, was reported (see papers by Wakefield et al). It was not known whether the virus, if confirmed as present in these patients, derived from wild strain or vaccine strain.

This study carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in 8 patients with CD, 3 patients with UC and 9 patients with autistic enterocolitis. As controls, the study used 8 cases of either healthy children or children with SSPE, SLE or HIV-1. The results were:

1/8 patients with CD, 1/3 with UC and 3/9 with autism were positive. Controls were all negative

The sequences from patients with CD shared the characteristics with wild-strain virus.

Sequences from patients with UC and children with autism were consistent with vaccine strain measles.

These results were consistent with the exposure history of the patient.

This study is obviously particularly important because it points to infection with vaccine-strain measles virus.

79. Paper by Hagenbuch, Kullak-Ublick et al, Department of Medicine, University Hospital, Zurich, Transport of Opioid Peptides Across the Blood Brain Barrier, Journal of Pharmacological Exp. The., July 2000,

This paper looked at organic anion-transporting polypeptides (OATPs), a rapidly growing gene family of polyspecific membrane transporters. The study looked at the human OATP. The results:

demonstrated that OATP-A can mediate transport of the analgesic opioid peptides DPDPE and deltorphin II across the human BBB.

indicated that members of the Oatp/OATP gene family of membrane transporters play an important role in carrier-mediated transport of opioid peptides across the BBB and blood-cerebrospinal fluid barrier of the mammalian brain.

These findings were not specifically linked to autism, but help to support the opioid-peptide theory aspect of autism.

80. Paper by Wakefield, Anthony et al, Enterocolitis in Children With Developmental Disorders, American Journal of Gastroenterology, September 2000, Vol. 95, No. 9, pp 2285-2295

This study described endoscopic and pathological characteristics in a group of children with developmental disorders that are associated with behavioural regression and bowel symptoms, and compares these with pediatric controls.

Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 years, range 3-16, 53 male)

Developmental diagnosis were autism (50), Aspergers (5), disintegrative disorder (2), attention deficit hyperactivity disorder/ADHD (1), schizophrenia (1), dyslexia (1).

The results were that ileal-lymphoid nodular hyperplasia (ILNH) was found in 54/58 affected children (93%) but only 5/35 (14.3%) controls.

Colonic LNH was present in 18/60 (30%) affected children but only 2/37 (5.4%) controls.

Reactive follicular hyperplasia was present in 46/52 (88.5%) ileal biopsies from affected children and only 4/14 (29%) UC controls, but not in IBD controls.

Active ileitis was present in 4/51 (8%) affected children but not in controls.

Chronic colitis was identified in 53/60 (88%) affected children compared with 1/22 (4.5%) controls and in 20/20 (100%) with UC.

Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls.

81. Statement by Professor Walter O. Spitzer, Emeritus Professor of Epidemiology, McGill University, Montreal

Although not a study (but see later), the statement by Professor Spitzer deserves coverage. Professor Walter O. Spitzer, Emeritus Professor of Epidemiology, McGill University, Montreal, stated on December 6th 2000:

"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".

82. Furlano, Anthony et al Study, Colonic CD8 and T-Cell Infiltration With Epithemial Damage in Children With Autism, Journal of Pediatrics, 2001; 138: No. 3, 366-72

Following reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism, this study was undertaken to characterise this lesion and determine whether LNH is specific for autism:

Ileocolonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms.

Blinded comparison was made with 8 children who had a histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn’s disease and 14 with ulcerative colitis.

Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness.

In the results, histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal cell density were significantly increased above those of all other groups, including patients with inflammatory bowel disease.

CD8+ density and intraepithelial lymphocyte numbers were higher than those in the Crohn’s disease, LNH and normal control groups

CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups.

Epithelial, but not lamina propria, glycosaminoglycans were disrupted.

However, the epithelium was HLA-DR-, suggesting a predominantly TH2 response.

The interpretation of these results was that immunohistochemistry confirmed a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected, and that this was consistent with increasing evidence for gut epithelial dysfunction in autism.

83. Jyonouchi, Sun and Le Study, Innate and Adaptive Immune Responses in Children With Regression Autism: Evaluation of the Effects of Environmental Factors Including Vaccination, Journal of Allergy and Clinical Immunology, February 2001, Part 2, Vol. 107 No. 2. Presented at the AAAA 57th Annual Meeting, New Orleans, March 2001

This study investigated the alleged causal association between the onset of regression/autistic behaviour and infant immunisation, viral infection and adverse reactions to common foods. In the study, the authors hypothesised that children with regressive autism may have an aberrant immune response against these common, usually benign, factors. The study:

Determined innate and adaptive immune responses in children with autism spectrum disorders (n = 35, age = 2-14 years, median 6 years, 24 males, 9 females)

It found that the autistic children produced a higher TNF-?, sTNFRII and IL-6, with a low dose of LPS, than controls. This was due to a subset of patients who produced large amounts of these cytokines

27/35 (77%) of the study cohort produced higher than the maximum levels of TNF-?, sTNFRII and IL-6 and/or IL-1? observed in controls

The study also observed elevated serum levels of these cytokines in 8 out of 18 autistic children

Results indicated a high frequency of excessive innate immune responses in children with regressive autism

These results may partly explain the apparent association between the onset of regression or autistic behaviour and immunisation in these children

The study also assessed T1/T2 responses:

The ratio of IFN-?/IL-5 did not differ between autistic children and controls

7 and 8 out of 35 autistic children produced significantly high IL-12p40 with recall antigens IL-12 and IL-18 respectively

10 and 11 out of 35 subjects produced high amounts of IL-10 with PHA and tetanus respectively

12/35 subjects produced significantly low IL-10 with PHA as compared to controls

The study team concluded that these results also indicated aberrant production of regulatory cytokines for T cell responses in subsets of autistic children.

84. Further Study by Jyonouchi, Sun and Le, Department of Pediatrics, University of Minnesota, Proinflammatory and Regulatory Cytokine Production Associated With Innate and Adaptive Immune Responses in Children With Autism Spectrum Disorders and Developmental Regression, Journal of Neuroimmunology, 120 (2001) 170-179

The study determined innate and adaptive immune responses in 71 children with developmental regression and autism spectrum disorders (ASD), in 23 developmentally normal siblings and in 17 controls. The study found:

A number of ASD children produced excessive proinflammatory and regulatory cytokines associated with innate immunity compared to controls

Some siblings of ASD patients showed abnormalities in production of these cytokines

The findings may indicate the presence of aberrant immune responses in ASD children with developmental regression at high frequency

The study team also observed:

Many parents report the onset of regressive autism following immunisation and/or benign childhood infections, and aggravation of symptoms following benign viral infection/immunisation.

Data supporting the role of infection/immunisation/dietary protein Ag in ASD are scarce and inconclusive

Many ASD patients also suffer from recurrent/chronic ear infection, sinusitis, viral infection and chronic diarrhoea/constipation

Jyonouchi et al commented: "Vaccination was developed to provide protective immunity by stimulating the immune system with killed or attenuated microbes. It is well known that purified protein Ags are poor immunogens and will not induce immunity if not given with adjuvenants. Adjuvenants augment Ag-specific immune responses by activation of innate immunity, by facilitating co-stimulatory molecule expression, Ag processing and production of pro-inflammatory cytokines by APC".

Jyonouchi et al hypothesise that ASD patients with developmental regression may have aberrant innate immune responses that could result in increased risk for adverse reactions to benign childhood infection, and even to immunisation. They also hypothesise that aberrant innate immunity results in abnormal adaptive immune response and intolerance to common environmental Ag such as dietary proteins

The study report concluded: "Our results indicate for the first time that a number of ASD children with developmental regression are likely to demonstrate aberrant innate immune responses that may also result in aberrant adaptive immune responses".

85. Paper By Spitzer, Aitken et al, The Natural History of Autistic Syndrome in British Children Exposed to MMR, Journal of Adverse Drug Reactions and Toxicology, 2001, 20(3) 160-163

This paper found that:

Just over 900 families whose children had had MMR were seeking legal redress in the UK, and so reviewed a set of 493 of the children’s National Health Service records. Some were ineligible for various reasons, and the study therefore focussed on 369 eligible cases.

Of these cases, there was classic ICD-10 autism in 259 cases, atypical autism in 25, Aspergers in 30, specific language impairment in 10, disorders of attention, motor control and perception (non-ICD-10) in 2, and other childhood disintegrative disorders in 2. There were no cases of Rett’s syndrome.

Of the cases of classical and atypical disorders, 112 (39%) regressed, from "normal" function pre-MMR, to unequivocal major deficits in function that fit conventional criteria. A further 115 (40%) were "failure to develop" following MMR immunisation. A further 30 (11%) manifested both regression and failure to develop.

The median delay from first dose of MMR to diagnosis was 2.5 years, with the range being 0.5 years to 11.8 years. The interquartile interval was 1.8 years to 4.2 years. Virtually none of the cases would have been classifiable if followed for only six weeks after MMR.

The project was acknowledged to be passive surveillance of an unrepresentative group of children, almost certainly affected by major underreporting.

The key finding is the delay between exposure to MMR and the emergence of autistic symptoms or the delay to definitive diagnosis of an autistic syndrome.

The median the authors report for delay to diagnosis is 2.5 years within an interquartile interval of 1.8 to 4.2 years. That means that the assumptions about delay and the distribution of delay in many published articles and safety assessments are invalid.

This paper was dismissed in a Parliamentary Written Answer by Lord Hunt, Government Health Spokesman in the UK House of Lords on 3rd January 2002. Lord Hunt stated that ".......it provides no scientific evidence to link MMR vaccine with autism, (it is) strongly suggestive that MMR played no role", and its findings "are also counter to the paper by Dr. Andrew Wakefield and colleagues published in the Lancet in 1988, which reported rapid onset of behavioural symptoms, median 6.3 days, after MMR".

86. Paper by Dr. Ken Aitken to the Scottish Society for Autism, published in the Society’s "In Touch" magazine, 2001

In this paper, Dr. Aitken sets out several, possibly interacting, biologically plausible mechanisms to link autism with immunisation:

An autoimmune reaction. This would be where the body’s immune system raises antibodies to a vaccine virus, and those antibodies go on to directly affect the functioning of the central nervous system. A parallel might be drawn with disorders known as PANDAS, where a movement disorder (Sydenham’s chorea) occurs after a streptococcal infection, and can be cured by removing the antibodies from the bloodstream. A number of recent autism papers point to autoimmune problems

A gastrointestinal dysfunction, where interference with intestinal function leads to alteration to endogenous opiate systems or to food related opiate-like substances passing into the bloodstream, reaching the brain and causing autistic-like behaviour. The opioid hypothesis receives support from a range of studies. Endoscopic research published to date demonstrates abnormalities of both the oesophagus (Horvath et al) and the intestine (Wakefield et al)

A direct viral infection of the central nervous system, although evidence for this is more limited, being to date three deaths from chronic measles infection of the nervous system (subacute sclerosing panencephalitis, or SSPE), which have been reported within the group of UK children whose cases are making their way to the High Court

87. Paper by Imani and Kehoe, Division of Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Asthma and Allergy Center, Balltimore, Infection of Human B Lymphocytes with MMR Vaccine Induces IgE Class Switching, published in Clinical Immunology, Vol 100, No. 3, September 2001, pp 355-361.

The authors noted that circulating immunoglobulin E (IgE) is one of the characteristics of human allergic diseases including allergic asthma. The authors had previously showed that infection of human B cells with rhinovirus or measles virus could lead to the initial steps of IgE class switching, and that, as many viral vaccines are live viruses, they speculated that live virus vaccines may also induce IgE class switching in human B cells. To examine this, they selected the MMR vaccine.

In their study, they showed that infection of a human IgM+B cell line with MMR resulted in the expression of germline e transcript

In addition, infection of freshly prepared human PBLs with MMR vaccine resulted in the expression of mature IgE mRNA transcript

The authors concluded that their data suggested that a potential side effect of vaccination with live attenuated viruses - in this case, specifically MMR - may be an increase in the expression of immunoglobulin E

88. Paper by Dr. Timothy Buie, Harvard Massachusetts General Hospital, Presented to the Oasis 2001 Conference for Autism, Portland, Oregon, November 2001

Dr. Buie reported that he had performed over 400 gastrointestinal endoscopies with biopsies, and evaluation of digestive enzyme function in children diagnosed with autism. The results of his testing were reported to be similar to the observations of Dr. Andrew Wakefield and colleagues at the Royal Free Hospital, London. Buie had found:

The presence of chronic inflammation of the intestinal tract, although the incidence was noted to be less frequent than in the RFH group.

Biopsy results indicated the presence of chronic inflammation of the digestive tracts, including esophagitis, gastritis and enterocolitis

Lymphoid nodular hyperplasia had been found in 15 of 89 children examined

Results of enzyme testing had paralleled that of Dr. Karoly Horvath and colleagues at the University of Maryland School of Medicine

The autistic children examined showed disaccharide/glucoamylase enzyme levels below normal

Some 55% of the children had lactase deficiencies (which break down lactose in milk), as well as deficiencies of the enzyme sucrase (responsible for digestion of table sugar).

Buie shared the opinion of a growing number of clinical researchers: "These children are ill, in distress and pain, and not just mentally, neurologically dysfunctional".

89. Paper By Uhlmann, Wakefield, O’Leary et al, Potential Viral Pathogenic Mechanism For New Variant Inflammatory Bowel Disease, Journal of Clinical Pathology, Molecular Pathology, 2002, 55, 0-6, published 6th February 2002

This study investigated the presence of persistent measles virus in the intestinal tissue of 91 patients with new variant inflammatory bowel disease, and examined a group of controls, using molecular analysis.

Patient samples were provided by the Department of Gastroenterology, Royal free Hospital, London. The 91 patients had a median age of 7 years, age range 3-14, 77/91 were boys.

The 70 developmentally normal controls had age range 0-17 years, 47/70 were boys. These included 19 children with normal ileal biopsies, 13 children with mild non-specific chronic inflammatory changes, 3 children with ILNH investigated for abdominal pain, 8 children with Crohn’s disease, one child with ulcerative colitis, 26 children who had undergone appendicectomy for abdominal pain including appendicitis.

Biopsies from the terminal ileum of affected children and normal controls were examined. Measles virus fusion (F) and Haemagglutinin (H) genes were detected by Taqman reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in-situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody.

Measles virus positive control material included 2 cases of SSPE and MV-infected Vero cells. Negative control material included uninfected Vero cells and human tissues, control RNA extracted from Raji cells (Applied Biosystems, Foster City, California) and normal peripheral blood mononuclear cells.

The results of the study were:

75 of 91 patients with a histologically confirmed diagnosis of ileal-lymphoid nodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with 5 of 70 controls.

70 of 91 affected children were positive for MV compared with 4 out of 70 controls as analysed by TaqMan RT-PCR

Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,000 copies/ng total RNA.

Of the paediatric controls, MV was not detected in normal children or children with isolated ILNH. However, 4 out of 26 appendicectomy samples harboured the MV genome. The study noted that the prevalence of MV in the general population is unknown, and that this warrants further investigation.

The conclusion is that the data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder

The study did not exclude the presence of alternative infections to MV, and that viruses might exist elsewhere or exert a transient effect. The study concluded that its findings raised many questions - most importantly, does measles virus play an aetiological role in intestinal inflammation in developmental disorder? But the study raises for the first time an association between MV infection and ileocolonic lymphonodular hyperplasia and ileocolitis in children with developmental disorder.

90. Paper by Singh and Nelson, Utah State University, Logan, Utah, Abnormal Measles Serology and Autoimmunity in Autistic Children, abstract released online in January 2002 (no publication details available yet)

Following their finding that many autistic children have autoantibodies to brain myelin basic protein (MBP) and also elevated levels of measles virus antibodies, Singh and Nelson conducted further serological studies. These included measles virus (MV), mumps virus (MuV), rubella virus (RV) cytomegalovirus (CMV), human herpes virus-6 (HHV-6), MMR, DPT, diptheria-tetanus (DT), and hepatitis B (Hep-B). These were then studied for correlations with MBP autoantibodies.

Antibodies were assayed in the sera of autistic children (n = 125) and in normal children (n = 92) by ELISA or immunoblotting methods. The study findings were:

Autistic children have significantly higher than normal levels of MV and MMR antibodies, compared with controls

The antibody levels of MuV, RV, CMV, HHV-6, DPT, DT and Hep-B did not significantly differ between autistic and normal children

Immunoblotting analysis showed the presence of an unusual MMR antibody in 60% (75 out of 125) of the autistic children, but in none of the 92 controls

By using MMR blots and monoclonal antibodies, Singh and Nelson found that the specific increase of MV antibodies or MMR antibodies was related to measles hemagglutinin antigen (MV-HA), but not to mumps or rubella viral proteins, of the MMR vaccine

In addition, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a causal association between MMR and brain autoimmunity in autism

The authors concluded by suggesting that an "atypical" measles infection, in the absence of a rash but with neurological symptoms, might be etiologically linked to autoimmunity in autism.

PART G

OTHER POTENTIALLY RELEVANT PAPERS

91. US Developmental Delay Registry Report, 1994

A US 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

92. Paper by Stratton et al, Adverse Events Associated With Childhood Vaccines, National Academy Press 1994, 64-65)

This 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".

93. Unpublished Paper by Kathryn M. Carbone, Laboratory of Pediatric & Respiratory Viral Diseases, Division of Viral Products, OVRR, Centre for Biologics Evaluation and Research, Food & Drug Administration, Bethesda, MD 20892, US, Vaccine Safety Pathogenesis of Virus Vaccine Neurotoxicity

The report received on this study, which is ongoing, states that:

Since the developing nervous system is uniquely sensitive to damage following virus infection, postnatal CNS development during the first year of life provides continued susceptibility of the infant CNS to damage by viral infection after birth.

Administering neurovirulent vaccines to infants also places the child’s CNS at increased risk for injury.

Wild type mumps virus, and some strains of mumps vaccine virus (Urabe Am9, Leningrad 3) are amongst the most neurotropic of the early childhood viruses, and new MMR combinations continue to be proposed that include new strains of mumps vaccine virus.

It is important to develop valid molecular biological, inn-vitro and in-vivo models to evaluate the pathogenesis of the neurotoxic effects of vaccine viruses. Information obtained in these studies about mumps virus vaccines will be likely to be useful in generalising to other potentially neurovirulent vaccines, e.g. Measles.

Study progress on molecular markers of neurotoxicity:

We have identified vaccine virus related perturbations in CNS gene expression by standard semiquantative RT-PCR and by differential display techniques, including endogenous immune mediators of the CNS.

We have recovered un-characterised gene products from new genes that are altered by virus infection of the brain.

We have initiated RPA to compare changes in endogenous immune mediators in the CNS in animals infected with low and high neurovirulence strains of mumps virus

On animal models of CNS diseases following childhood virus infection:

Viruses are known etiologic agents of autism (e.g. rubella). Therefore concerns are raised regarding a possible relationship between childhood vaccines and autism. Because no valid animal model exists to study the pathogenesis of the neuroanatomical and behavioural signs of autism, we developed a rat model of autism using neonatal infection with neurotropic viruses.

We have characterised autistic-like changes in neuroanatomy, neurological disease and behaviour in these rates. In addition, we have identified regional and developmental changes in neurotransmitters, including serotonin and norepinephrine.

A developmental study of damage to developing brains (e.g. Cerebellum) in virus infected rats was performed, demonstrating anatomical, behavioural and neurological consequences.

94. Iizuka, Saito et al Study, Akita Prefectural Institute of Public Health, Japan, No Evidence of Persistent Mumps Virus Infection in Inflammatory Bowel Disease, published Gut, 2001; 48; 637-641 (May)

This study was conducted to clarify the validity of a causal link between persistent mumps virus infection and inflammatory bowel disease.

The study used amplification of the mumps virus genome by reverse transcription-polymerase chain reaction (RT-PCR).

The mumps virus genome was not detected in intestinal specimens or peripheral blood lymphocytes.

It concluded that it could not find any evidence to support a causal link with the mumps virus (note that this study did not look at the measles virus component of MMR)

95. Statement, Is MMR Linked To Autism? - Epidemiological Perspectives, Testimony to the Congress of the United States of America, House of Representatives Committee on Government Reform, Walter O. Spitzer, April 25th 2001

Spitzer’s testimony included the following:

(Commenting on safety studies) "I have not found scientifically sound safety studies"

(On length of follow-up period) "I shall present new data (see earlier) supporting the view that British evaluations on safety of MMR in respect to autism invoked inappropriately short lengths of follow-up".

(On single vaccines) "The intrusion of the authorities in the legitimate freedom of choice of responsible parents by proscribing monovalent products is self evident"

(On evidence for/against a link) "The data about biological plausibility of an MMR/autism link has gradually become more persuasive."

(On the view held by Fombonne, described earlier, that there is no evidence of a rise in autism) "Declaring a non-epidemic flies in the face of official statistics in government files and several published papers.......Fombonne’s arguments do not explain away such steep rises in occurrence of AuS anywhere.......His letter gives inadequate attention to the rate changes of subsets of AuS, such as regressive autism. A worldwide epidemic of autism is in progress. That demands serious scientifically admissable inquiries about possible determinants."

(On the Kaye et al study, reviewed earlier, hailed by the UK Department of Health as evidence of no MMR/autism link) "The Kaye-Jick study is the best published descriptive epidemiological study to date demonstrating that an epidemic of autism exists."

(On the UK Medicines Control Agency’s Yellow Card passive reporting system for adverse events) "Passive surveillance, pioneered by the British Yellow Card system and emulated world-wide, was designed to raise warning flags on safety. The system was never intended to be used the other way round, to confirm safety"

(On Patja, Peltola et al, the Finnish study) "I find no evidence that the study was set up to be sensitive to AuS, nor that the surveyors or the reporters of events looked for autism events at any time........A large scale study as was done in Finland is not automatically well designed or adequately reported because of its size.....There were no controls.....There was no discussion about such uncontrolled surveys.....There is no indication in the report about the length of follow-up.....There is no information about the nature or content of briefings to health care personnel before the study started, in relation to the types of reactions and the inclusion of autism as a reportable side effect.....Any assertion that the Patja-Peltola paper "clears" MMR is unfounded."

(On Taylor, Miller et al, reviewed earlier) "The study and its report are seriously, if not fatally, flawed.......Complete ascertainment of all cases of autism in the eight districts (of North London) is uncertain.......(there is) inadequate classification of the various diagnoses within the autistic spectrum.......There is a failure to correct for "catch-up" components of the immunisation campaign (this is a reference to 7.5m older children immunised in the UK in 1994).....An incorrect analytic method was used. The case-series method used by Taylor, Miller, applies primarily to acute events......One does not expect autism to develop acutely.......(There was a) failure to discriminate between types of MMR vaccine."

Spitzer concludes that the Taylor, Miller et al paper ".......which is incorrectly interpreted as demonstrating safety, provides much better evidence in the opposite direction, consistent with MMR being associated with some AuS categories. Moreover, an uncontrolled study is uninterpretable as the basis to demonstrate a link between MMR and AuS, or to dismiss it aside, unless the findings were dramatic and very clear."

PART H

FUTURE PAPERS INVESTIGATING A LINK

The following are brief details about known UK studies investigating an MMR/autism link, but which have yet to report:

96. Unpublished Study by Fombonne et al, A Case-Control Study of Autism In General Practice, UK, Study Period September 2000-August 2002

This study, based at the Maudsley Hospital, Denmark Hill, London (tel 0207 836 5454 email spjwerf@iop.kcl.ac.uk) is to assess if exposure to MMR immunisation is a risk factor for autism, and to assess the exposure to viral infections, both prenatally and postnatally.

The study will use UK GP data, hospital reports and a parents’ questionnaire. It will use over 400 cases of autism and four times as many controls, selected from a GP database. It is funded by the Medical Research Council (£351,000). No date has been given for publication of the findings.

(Note: since this study commenced, Professor Fombonne has also agreed to appear at the forthcoming UK High Court cases as an expert witness on behalf of the manufacturers of MMR, against the children. His current role within the study is not known. It is also not known whether the control group will be "unvaccinated with MMR", "unvaccinated with MR", "unvaccinated with any measles-containing vaccine", "unvaccinated with thiomersal-containing vaccines" or "totally unvaccinated", or what the vaccination status of the control group children’s mothers will be. These may affect any study findings).

97. Charman et al, Epidemiological Study of Autism, Current Prevalence & Medical Risk Factors, Study Period February 2000-July 2003

This study, based at the Behavioural Sciences Unit, Institute of Child Health, Guilford Street, London, tel 0207 242 9789 email t.charman@ich.ucl.ac.uk) will look at a representative population sample (but see caveats in previous section, final paragraph) of 8 year olds who have received a diagnosis of childhood autism or a related pervasive developmental disorder (PDD).

The study will address the following questions:

Is the prevalence of autism in this population confirmed as five times the established figure?

Alternatively, is the reported rate due to inaccurate over-diagnosis?

What is the rate of metabolic medical risk factors in autism?

To what extent are they specific to autism as opposed to other neurodevelopmental and learning problems?

Do they distinguish between autism and related PDDs?

What evidence is there in this representative sample that onset of symptoms is associated with MMR vaccination?

The study is funded by the Wellcome Trust (£461724).

98. Study By Hall, Smeeth & Fombonne, A Case-Control Study of Autism and MMR Vaccination Using the General Practice Research Database, London School of Hygiene and Tropical Medicine

This study, using the UK GP database, commenced in 2000, and is expected to report in 2002. The study, to investigate the causes of autism, including an assessment of the potential role of MMR, will use case-control and case-series statistical approaches. The electronic general practice records in the database will be supplemented by record interviews of all cases and questionnaires to both parents of affected children and of controls.

A protocol paper of this study was reported in BMC Public Health 2001, 1 (1): 2 in February 2001. The study is designed to determine:

If autistic children are more likely to have received MMR vaccine prior to disease onset

To examine whether there is any association between clinical onset of disease and the timing of MMR vaccination.

In July 2001, the research team, Hall, Smeeth and Fombonne, wrote to the British Medical Journal, stating that "the failure (of other studies) to find an association between the time trends in vaccine coverage and the incidence of autism codes in children’s electronic general practice records, does not exclude a causal association".

(Note: Fombonne confirmed in summer 2001 that he was being retained as an expert witness on behalf of the manufacturers of MMR, and against the children, in the forthcoming UK High Court cases).

99. Study by Takahashi, Arai et al, Infectious Disease Surveillance Centre, National Institute of Infectious Diseases, Tokyo, Autism and Infection/Immunisation Episodes in Japan, Japanese Journal of Infectious Diseases, 54, 2001

The notification report of this current study (final reporting date not known) stated that:

The prevalence of autism in Japan during the 1980s was 5-16 per 10,00, and was 21.1 in 1996. The apparent increase by 1996 was difficult to interpret, because it may have been due to recent improved screening and other factors.

MMR was introduced in 1989 in Japan. The vaccination programme was unsuccessful, on account of the higher incidence of associated aseptic meningitis, and in 1993 the Ministry of Health & Welfare discontinued MMR

During 1989-1992, 2.2 million doses of MMR and 3 million doses of monovalent measles vaccine were distributed in Japan

The 1988-89 birth cohort received approximately 1.3 million doses of MMR and 1.7 million doses of monovalent measles vaccine

It was noted that Kawashima et al had claimed that symptoms developed soon after MMR in the majority of autistic cases

A case control study of the 1988-89 cohort would therefore be of value for elucidating a possible relation between autism and MMR

100. Study by the M.I.N.D. Institute, University of California at Davis, US

This study is seeking explanations for the 273% increase in cases of autism in California between 1987 and 1998. It will examine a number of possibilities, including:

Whether there is a real underlying increase

Whether the criteria used in diagnosis has changed over time

Whether children have been misclassified in the past or at the present time

Whether the number of families already with an autistic child, and then later moving into California, has accounted for part of the increase

If and how the characteristics of children with autism have changed over time

The study will also ascertain the incidence amongst children with autism of:

Specific medical or developmental problems such as retardation, allergies, gastrointestinal disorders, and any pregnancy and birth complications

Regression, whether the children had a normal birth and developed normally, then lost skills and regressed, as has been widely reported by parents

Estimating how much regression now occurs, and whether this has changed between the two age groups in the study

The study has enrolled 1,000 children, including 500 diagnosed with autism and 500 with other developmental disabilities, selected at random from the developmental services database. One group of children with either of these characteristics will be drawn from 15-17 year olds, and one group with either disability from 5-7 year olds. The study will be completed and report to the California State Legislature in early summer 2002.

PART J

THE THIOMERSAL ISSUE

101. Thiomersal’s Possible Role

If MMR "opens the gateway" to autism in genetically or medically susceptible children, what does the actual damage to the brain? A number of possibilities have been, and are being, put forward. These may include thiomersal.

It is understood that thiomersal, a mercury-based preservative, has been used in a number of UK and US vaccines over many years. It is believed that it is not used in MMR itself, but it may yet prove to have been used in the manufacturing process. If this is the case, it is believed that no declaration has to be made on the manufacturer’s information sheet, as it is not an actual MMR constituent.

Worldwide, thiomersal has been used for about the past 60 years. Ethyl mercury constitutes about 49.6% of its weight, and mediates the antimicrobial effects. Thiomersal has been used to prevent bacterial contamination during the vaccine manufacturing process, as well as in vials where repeated puncture may allow contamination to occur.

It is believed that levels of thiomersal have been reduced over the years in vaccines, and removed altogether in some cases. In the US, in 2001, a free exchange system was instigated by the manufacturers, to remove stocks.

In the UK, the Department of Health has refused to acknowledge that there might be a problem with thiomersal, and no free exchange system has been offered, or sought.

In the US, a September 2001 survey of 65,909 vaccines at provider centres found that 5.5% still contained thiomersal. Some 36% of these were DtaP-Hib for the fourth dose. A depot survey of 837,174 vaccine doses found that 1% still contained thiomersal. Of these, 80% were for DtaP.

102. Joint Statement of American Academy of Pediatrics and Public Health Service, Thiomersal In Vaccines, July 1999

In 1999, researchers calculated that a low-birthweight baby could receive a cumulative dose of mercury (187ug) that would have exceeded the safety recommendations of the US Environmental Protection Agency.

In July 1999 the AAP and the PHS issued a joint statement on thiomersal in vaccines, noting that the US Food & Drug Administration Modernization Act of 1997 called for the FDA to review and assess the risk of all mercury-containing food and drugs.

The joint statement was generous in its self-reassurance:

"Thiomersal has been used as an additive......since the 1930s......"

"There is a significant safety margin incorporated into all the acceptable mercury exposure limits"

"There are no data or evidence of any harm caused by the level of exposure that some children may have encountered" (Comment - but this may reflect lack of studies or lack of monitoring, not lack of harm)

"Infants and children who have received thiomersal-containing vaccines do not need to be tested for mercury exposure" (Comment - as an example of complacency, this statement is in a class of its own).

"The recognition that some children could be exposed to a cumulative level of mercury over the first six months of life that exceeds one of the federal guidelines on methyl mercury now requires a weighing of two different types of risk.....The large risks of not vaccinating children far outweigh the unknown and probably much smaller risk, if any, of cumulative exposure to thiomersal-containing vaccines" (Comment - this is an tautological statement, and is revealing. What the AAP/PHS are saying is, the risks from thiomersal are unknown, are probably small, and are far outweighed by another risk - which of course is an impossible deduction to draw if the risks from thiomersal are unknown. One cannot say for certain that A is larger than B if there is no way of determining the size of B, or if the size of B is unknown because it has been historically overlooked, and thus not measured).

"Nevertheless, because any potential risk is of concern, the PHS, the AAP and the vaccine manufacturers agree that thiomersal-containing vaccines should be removed as soon as possible".

Key action agreed was:

A formal request to manufacturers for a clear commitment and a plan to eliminate or reduce mercury content of vaccines

A review of data

Expedited FDA review of manufacturers’ supplements to their product license applications, to eliminate or reduce mercury content

Studies to better-understand the risks and benefits of this safety assessment

103. UK Vaccines With Thiomersal

Vaccines in the UK that are believed to still contain, or until recently contained, thiomersal are:

DTaP (Diptheria and Tetanus and acellular pertussis) made by Lederle Laboratories
HIB (haemophilus influenza type B) made by Connaught Laboratories
DPT (Diptheria and tetanus and pertussis) made by Glaxo SmithKline
Energix-B (Hepatitis B) made by Glaxo SmithKline
HibTiter (Haemophilus influenza type B) made by Lederle
Fluvirin influenza virus vaccine made by Medeva Pharma
FluShield made by Wyeth-Ayerst
Menomune (Meningococcal polysaccharide vaccine) made by Connaught
Rabies vaccine made by Glaxo SmithKline
Recombivax (Hep B recombinant vaccine) made by Merck & Co.

It is understood that the UK introduced an accelerated schedule of DPT vaccination in the late 1980s/early 1990s, which would have significantly increased the thiomersal intake of infants.

It is known that MMR does not contain thiomersal, but it is thought that thiomersal may be used in its manufacturing process.

When the thiomersal issue was reviewed in the UK general practitioners’ magazine Pulse, the report concluded: "Another drawn-out public debate might damage public confidence, and falling vaccine uptake rates could cause the resurgence of preventable diseases". This may be true, but this approach is also a potential charter for complacency and secrecy. At what point should safety concerns be publicly debated?

104. Scientific Review of Vaccine Safety Datalink Information By The US Centre for Disease Control, Simpsonwood Retreat Center, Norcross, Georgia, June 7th-8th 2000.

This meeting was convened by the US CDC to discuss the findings of Dr. Verstraeten in relation to the positive statistical association between thiomersal-containing vaccines and neurodevelopmental disorders (thiomersal is a mercury-based preservative that has been extensively used in the UK and US, and elsewhere).

The confidential version of the study reviewed at this meeting clearly demonstrated that an exposure to more than 62.5 micrograms of mercury within the first three months of life significantly increased a child’s risk of developing autism. Specifically, the study found a 2.48 times increased risk of autism.

In the US, courts of law have held that a relative increased risk of 2.0 or higher is sufficient to substantiate that a given exposure causes disease (in the case of Cook v. United States, 545 F. Supp. 306, at 308, Northern District, California, 1982, the Court stated that "in a vaccine case, a relative risk greater than 2.0 establishes that there is greater than a 50% chance that the injury was caused by the vaccine").

The key findings of the Vaccine Safety Datalink analysis were that there was a statistically significant association between:

A cumulative exposure to thiomersal-containing vaccines at 2 months of age and unspecified developmental delay

A cumulative exposure at three months of age and tics

A cumulative exposure at six months of age and attention deficit disorder

A cumulative exposure at 1, 3 and 6 months of age and language and speech delay

A cumulative exposure at 1, 3 and 6 months of age and neurodevelopmental delays in general

The report noted that "the consultants were unanimous in their opinion that further investigations should be pursued with a degree of urgency".

These are some extracted comments from some of the key participants:

Dr. Weil: "There are just a host of neurodevelopmental data that would suggest that we’ve got a serious problem"

Dr. Verstraeten: "We have found statistically significant relationships between the exposures and outcomes for these different exposures and outcomes. First, for two months of age, an unspecified developmental delay which has its own specific ICD9 code. Exposure at three months of age, Tics. Exposure at six months of age, an attention deficit disorder. Exposure at one, three and six months of age, the entire category of neurodevelopmental delays, which includes all of these plus a number of other disorders."

"Now for speech delays, which is the largest single disorder in this category of neurologic delays. The results are suggestive of a trend with a small dip. The overall test for trend is highly statically significant above one".

"After excluding this speech group, the trend is also apparent in this group (developmental delays, less those with speech delays) and the test for trend is also significant for this category excluding speech".

Dr. Davis: "In terms of a search for pre-disposing factors.....serious and chronic otitis media by history, being mentioned by the pediatrician or the specialist, was present 38% of the time". (US parents’ note: doesn’t this sound familiar to all of you parents with autistic children?)

Dr. Johnson: "This association leads me to favour a recommendation that infants up to two years old not be immunised with thiomersal-containing vaccines if suitable alternative preparations are available......there are probably implications for this internationally".

Congress also ordered the Institute of Medicine (IoM) to investigate the autism/MMR link, or identify another cause(s). The IoM is a division of the National Academy of Sciences, whose members serve as advisers to Congress. The IoM met in 2001, and also looked at eight other vaccine-related safety concerns.

105. Waters & Kraus Press Release of March 17th 2002

In March 2002, the lawyers Waters and Kraus, acting on behalf of US children in the thiomersal/autism class action, stated that their discovery process in their case of Counter v. Eli Lilly (manufacturers of thiomersal) had demonstrated that thiomersal was known by Lilly as early as April 1930 to be dangerous. These included the following studies/warnings deposited with Lilly:

(1947) "It may be dangerous to inject a serum containing merthiolate into a patient sensitive to merthiolate"

(1963) "It seems advisable to use a preservative other than merthiolate for injections into merthiolate-sensitive people"

(1972) Merthiolate in vaccines caused six deaths - "The symptoms and clinical course of the six patients suggest subacute mercury poisoning"

(1982) The (FDA) Panel concludes that thiomersal is not safe for OTC topical use because of its potential for cell damage if applied to broken skin, and its allergy potential".

In 1991, Lilly ceased the manufacture and sale of thiomersal, but licensing agreements have revealed a continuing profits stream until at least 2010.

106. UK Medicines Control Agency Position On Thiomersal

In May 2001, the UK MCA instructed manufacturers to warn doctors and patients of potential allergic reactions to vaccines containing thiomersal.

However, unlike the US, the UK has not moved to remove existing stocks, which are being used up.

The magazine Pulse also reported that the UK Government planned to reduce levels of thiomersal in infant vaccines, including DTP, HiB and the pre-school DT booster.

It also reported that the UK Government was set to adopt guidance from the European committee for proprietary medicinal products, urging manufacturers to implement a stepwise reduction in thiomersal levels in vaccines.

PART K

FLAWED REGULATION AND MONITORING

107. Fighting Measles, Missing Autism, Overlooking Damage

The UK DoH has traditionally failed to commission research into the causes of autism. It seemingly prefers uncontroversial research into detailed behavioural manifestations, or genetic research that offers little insight into triggers. Also:

The UK Medicines Control Agency (MCA) has failed to properly monitor adverse reactions to all vaccines, including MMR

The DoH repeatedly demonstrates an entrenched bias in favour of maintaining public confidence in the vaccination programme, and against investigating the causes of autism

The DoH repeatedly demonstrates dual standards of robustness of evidence for/against an MMR/autism link, and repeatedly shows this in its embracing of studies and findings that suit its case

The studies that the DoH quotes (Taylor, Miller, the Committee on Safety of Medicines study, Gillberg, Peltola) are, when critically examined, inconclusive or largely irrelevant in terms of disproving any MMR/autism link.

The adverse reaction monitoring system has never been properly reformed, because it would probably greatly increase adverse reaction statistics, and this in turn would prompt political pressure over possible vaccine damage, which in turn might undermine public confidence

Autism has never been recognised as an adverse reaction, so has not been reported as such (thereby potentially giving false reassurance about vaccine safety records)

There also appears to be a very determined resistance on the part of the UK DoH to understanding that slow descent into autism takes place - it is not an acute adverse reaction, like other alleged adverse drug reactions. The DoH is determined to continue to ignore this, because acknowledging it would invalidate many of the studies it quotes as "proof" of MMR’s safety, eg the original safety trials, the Peltola study, etc.

The greater their resistance, the stronger the suggestion is that the DoH understands rather more about this syndrome than it wishes to acknowledge publicly.

108. Has The UK Medicines Control Agency Missed The Syndrome?

The (then) Medicines Division, predecessor of the MCA, was admitted by its then management to have been in a disorganised and dysfunctional state in 1988, the year that the MMR programme commenced in the UK (see Draft Factual Account 17 of Evidence to the BSE Inquiry, pp 31-33).

It had no effective method of finding files

It had severe staff shortages in key areas

Product licence renewals were handled purely administratively without scientific input. MMR wasn’t a renewal, but may have been treated as little more than one, as the single vaccines were already licensed, and the long-term complications and link with autism were not foreseen. It is therefore very possible that MMR obtained its UK licence "on the nod", with minimal investigation.

The Medicines Control Agency’ adverse reaction warning system, known as the Yellow Card system, by their own admission only picks up 10-15% of even serious adverse reactions (source: Guidance on Interpretation of Yellow Card Data, MCA, 1997). The system is thus officially acknowledged to be woefully weak.

Yellow Card was unable to identify the potential problem over autism because it must be shown that an adverse event occurs more frequently in a vaccinated than unvaccinated population. This is very difficult to do when almost all children are vaccinated. (source: personal communication of the MCA of 21/8/98)

Yellow Card depends on doctors, dentists, coroners and hospital pharmacists to file reports (source: MCA). But these are unlikely to be able to make the link between autism and MMR.

Adverse reaction reports are added to the ADROIT database, introduced in 1991. However, the database can only deal with the data it actually receives. If a syndrome is missed completely, then there will be no data in the database.

Yellow Card is voluntary for health professionals, but compulsory for pharmaceuticals manufacturers. But this depends on adverse reactions being reported to manufacturers - again, unlikely.

Parents must also be able to make link between MMR/autism. This was not possible pre-1998, as publicity had never been given to a connection between vaccination and later degeneration into autism

In any case, "it has been estimated.....that only 10-15% of serious ADRs (adverse drug reactions) are reported" (1997 Guidance Sheet issued by MCA), and "....it is accepted that spontaneous reporting schemes have limitations" (source: personal communication of the MCA of 29/3/99).

And more telling still, "Autism has been very rarely reported as an adverse drug reaction.....These figures are unsurprising since autism is not a recognised ADR to any particular medicinal substance" (Source: personal communication of the MCA of 29/3/99). Once again, this is a chicken-and-egg argument.

And a potentially-significant admission, "Evidence from the Yellow Card scheme is unlikely to resolve the issue as to whether or not autism could be causally associated with MMR vaccine" (Source: personal communication of the MCA of 29/3/99)

The MCA’s estimate of only 10-15% of ADRs being reported may even itself be optimistic. The West Midlands Centre for Adverse Drug Reactions Reporting did a survey and found a rate of only 6.3% of all ADRs being reported.

All recent improvements to Yellow Card have been irrelevant to autism detection (extension of the system to hospital pharmacists, GP prescribing systems, community pharmacists, nurses)

A similar situation appears to apply in the USA - "On the basis of Vaccine Adverse Event Reporting System alone, we don’t have proof that vaccines are not contributing to (vaccine-related problems)(source: Caveats to Interpretation of VAERS Data, Centre for Biologics Evaluation & Research, VAERS, 1998)

The whole monitoring system is therefore highly passive, and potentially 100% irrelevant to detecting a link between immunisation and autism, in the way it has operated.

109. UK Department of Health Re-Launch of MMR, 22/1/01

On 22/1/01, the UK DoH launched a £3m publicity campaign for MMR and rejected the Wakefield & Montgomery "Through A Glass Darkly" MMR safety-test paper, without:

announcing any investigation into the affected children

offering any explanation as to why autism is rising so steeply in UK and around the developed world (although the Medical Research Council’s 2001 review was announced soon afterwards - in the event, the latter proved to be yet another missed opportunity)

The DoH also released the 15-page paper, "Combined MMR Vaccines: Response of the Medicines Control Agency and DoH" referred to above, to attempt to refute the Wakefield and Montgomery paper. However, the DoH paper merely re-assembles previous studies quoted by the Department, 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".

Professor Michael Langman, chairman of the JCVI, said "My Committee has independently considered all the issues and reached the same position as the Committee on Safety of Medicines".

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 very significant. The Department’s actions seem to have not countenanced this potential future scenario.

The Medicines Control Agency has attempted to prevent single vaccines from being administered, banning the importing of further supplies and threatening any GP who administers single vaccines with prosecution for breaching laws on importation, sale or supply of unlicensed vaccines

In early 2002, press reports indicated a fresh major "push" for MMR take-up:

North Cheshire Health Authority launched a major advertising campaign

In both Scotland and Wales, there were press reports that consideration was being given to making MMR compulsory for all children starting at nursery schools. Any such move would be highly controversial, and probably capable of successful legal challenge.

In February 2002, the UK Health Minister, England & Wales Chief Medical Officer and Scottish Medical Officer announced an intensification of the programme of persuasion that there was no link between MMR and autism.

However, at the same time, there also appeared to be a shift of policy in early 2002 as to the actual threat of a measles outbreak.

In 2001, the Public Health Laboratory Service’s Communicable Diseases Surveillance Centre stated: "We are below the critical threshold at which point we run the risk of getting a large number of cases. We will have to reverse that trend because there is a significant chance we will get a major measles outbreak or an epidemic".

Then, in January 2002, the Chief Medical Officer for England and Wales stated: "There is no epidemic of measles and there is no concern that there will be. There are not large numbers of children dying of this disease".

PART L

UK AND US POLITICAL INITIATIVES

110. House of Commons Health Committee, Westminster

The House of Commons Health Committee strongly urged in 1997 that a register be established of numbers of children with autism. This was ignored by the Department of Health.

Evidence to the Health Committee was given on the MMR/autism issue as part of its wide-ranging Inquiry into Adverse Outcomes From Medical Care, June 1999. However, the Committee’s report did not make any specific recommendation in relation to the issue.

The Health Committee Chairman, David Hinchliffe MP, says he still has questions over MMR issue, that there have been serious concerns raised in his own constituency, and that he needed to look for answers, and was to team up with members of Scottish Health Committee to further investigate the MMR issue (report in Daily Express 21/1/01)

111. UK All Party Parliamentary Group On Autism (APPGA), Westminster

An All Party Parliamentary Group on Autism has been formed at Westminster. It is currently looking at diagnosis, education, care and causation issues. The Chair is Dr. Stephen Ladyman MP (Labour, Thanet South). Vice-Chairs are Lord Clement-Jones (LibDem), Stephen Hesford MP (Labour), and Tim Loughton MP (Conservative). The Treasurer is Brian Cotter MP (Labour). Some 150 Members of Parliament are members of the APPGA.

The All-Party Group has called for clear progress on data-gathering by Government. However, the APPGA has not implied that there is any reason to question MMR’s safety at this stage.

112. Scottish Parliament, Edinburgh

The Health Committee of the Scottish Parliament appointed a Reporter, Mary Scanlon MSP, in Autumn 2000, to examine the issues surrounding the MMR/autism link and to report back to the Committee. The Committee subsequently requested further work, and set up an Expert Group to give advice. The Group reports in February 2002. It is expected by the parents to reject an MMR/autism link, as to do otherwise would prompt a major controversy. Some elements of the expert committee appear completely unpersuadable over MMR and autism. In February 2002 the expert committee was reported to be split.

In February 2002, the Scottish Chief Medical Officer stated that calls to research the link between MMR and autism would be "resisted".

Susan Deacon MSP, the then Scottish Health Minister, has said that the issue of single vaccines is a "reserved matter", ie the power remains in Whitehall. However, Scottish MPs at Westminster no longer cover health. So the Scottish democratic representation is in Edinburgh, but the power is still in London, and so this issue may yet cause a constitutional problem.

The Scottish National Party and Tommy Sheridan MSP of the Scottish Socialist Party have both called for the re-introduction of single (monvalent) vaccines in Scotland

113. UK Liberal Democrats

In February 2002, Nick Harvey MP, Liberal Democrat health spokesperson, stated in a personal communication that "We do not doubt the integrity with which (Dr. Wakefield) approaches his work, which is still at an interim stage. We note that Dr. Wakefield’s opinions are not currently shared by the vast majority (of the medical establishment). However, there are also a number of parents who are convinced that the MMR vaccine has been the cause of their children developing autism......Liberal Democrats......respect the right of parents to choose to have the vaccinations administered separately, this being preferable to children slipping through the net entirely".

However, the current Liberal Democrat Health Spokesman in the UK House of Commons, Dr. Evan Harris, has repeatedly insisted that MMR is safe, and has opposed calls for the re-introduction of single vaccines.

114. UK Conservatives

The Conservative health spokesman, Dr. Liam Fox, has expressed his support for MMR but has also expressed his view that the provision of single vaccines would be preferable to children being unimmunised at all, and would reflect the wishes of parents for being offered a choice. In February 2002, this became Conservative policy. The usual cross-party consensus on vaccination policy has therefore broken down. This is without known precedent.

A Conservative MP, Ms. Julie Kirkbride, has vigorously promoted a Private Member’s Bill to bring about the re-introduction of single vaccines. In February 2002, her call for the re-introduction of single vaccines to give parental choice was publicly endorsed by another Conservative MP, George Osborne.

115. US House of Representatives

In April 2000, Rep. Dan Burton, Chairman of the US House of Representatives Committee on Government Reform, initiated a series of hearings into the relationship between vaccination and autism. Some of the submissions of evidence to the hearings have been described in earlier sections.

In a statement on 15th June 2000, Burton criticised the Food & Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and the Centers for Disease Control and Prevention’s Advisory Committee on Immunisation Practices (ACIP)

Members of these committees, including chairmen, were found to own stocks/shares in the companies that make the vaccines.

Individuals held patents for vaccines under consideration

The CDC granted conflict-of-interest waivers, a year at a time, to its committee members

The CDC’s committee had no public members, and the FDA’s committee had only one.

Burton concluded that "conflict of interest rules employed by the Food and Drug Administration and the Centre for Disease Control have been weak, enforcement has been lax, and committee members with substantial ties to pharmaceutical companies have been given waivers to participate in committee meetings".

The Committee on Government Reform found that the majority of members of both the FDA and CDC committees had financial ties to vaccine manufacturers or held patents on vaccines under development.

The Committee Chairman, Rep. Dan Burton, said: "For the public to have confidence in the decisions made by their government, they must be assured that those decisions are not being affected by conflict of interest. It has become clear over the course of this investigation that the FDA’s Vaccines & Related Biological Products Advisory Committee and the CDC’s Advisory Committee on Immunisation Practices are dominated by individuals with close working relationships with the vaccine producers. This was never the intent of the Federal Advisory Committee Act, which requires that a diversity of views be represented on advisory committees" (my emphasis).

Parents giving evidence to the Committee on Government Reform told repeatedly-similar stories of how their child had developed normally, then received triple vaccines (MMR or DPT) and had gradually become autistic.

A number of researchers in the field gave detailed evidence on autism incidence and its steep climb to near-epidemic (for a supposedly-rare condition) proportions

The cause of autism could not be explained away by genetics, because genetics do not cause epidemics within only two decades - the two decades that multiple vaccines have become standard

The US agencies defending MMR made their own presentations. Some acknowledged financial links with vaccine manufacturers. Others said they were "looking into" the MMR/autism connection, but their stance suggested an entrenched hostility to the concept of any link.

Overall, these agency representatives displayed indifference and an unconvincing grasp of the facts. (Note: an entire industry of "looking into it" has developed, both in the US and the UK. In the US, this has reported to have consumed $100m in two decades of lack of progress).

Controversial areas of research are being avoided, in favour of more abstract genetic-background research. Key leads are not followed up, so progress is understandably very poor.

At every turn, the researchers try to prove that MMR and DPT are not involved. Obvious approaches, such as comparing significant-sized cohorts of triple-vaccine-immunised and unimmunised children - the most promising line of any scientific exploration - are not taken.

Further hearings by the Government Reform Committee are planned.

Other relevant points:

In February 2002, Rep. David Weldon, a Florida physician and member of the US House of Representatives, urged the American Academy of Pediatrics to fully inform parents of their choice in having MMR separated-out and administered at different times. He stated that he was "very disturbed" by the recent Uhlmann, Wakefield, O’Leary et al paper, and that there was an "epidemic" of autism among US children.

There has been strong criticism of the US regulatory mechanisms for drugs and adverse drug reactions by the Committee on Government Reform, and by others. The consumer group Public Citizen found that only 13% of 88 follow-up studies required as a condition for the licensing of drugs launched in the early 1990s were actually completed. Public Citizen’s Health Research Group said that the neglect of follow-up studies could mean that side effects are going undetected.

A "USA Today" investigation of FDA advisory committees between 1/1/98 and 30/6/00 found that at 55% of meetings, half or more of the FDA advisors present had conflicts of interest. At some meetings, over 90% of advisors present had conflicts of interest.

Federal law generally prohibits the FDA from using experts with financial conflicts of interest, but this has been side-stepped by using waivers. The FDA issued more than 800 waivers between 1998 and late 2000. Some 300 advisors serve on 18 advisory committees.

PART M

SOME BROAD CONCLUSIONS AND QUESTIONS

116. Some Broad Conclusions

The above puts "under one roof" a considerable amount of information on the MMR/autism issue, though it cannot possibly be an exhaustive coverage, given the many issue involved and the ongoing scientific debate. However, it demonstrates that:

There is considerable evidence of (in relative terms) an autism epidemic, with large increases being reported, though being dismissed by some observers. It also begs the question "how large an increase in the numbers is needed before the authorities accept there really is an increase?". But common sense suggests a sharp rise.

There are many studies that seek to deny an MMR/autism link, but it is possible to demonstrate that each is flawed in several ways. These studies are also statistical/epidemiological-type studies - not studies of the actual children involved. They are also based upon small (for statistical-type studies) samples.

There are strong grounds for believing that the safety studies of MMR were cursory, that the potential for damage was not recognised, and that subsequent safety follow-up has been conspicuously lacking

There are many papers that point - some of them powerfully - to an MMR/autism link. Some of these studies involve analysis of samples of the actual children involved

Putting the above conclusions together, there appears to be strong grounds for believing that children have been damaged, and are still being damaged, by MMR. No alternative credible explanation has been put forward for these children’s condition. The explanation that their degeneration into autism is biologically linked to MMR is also supported by the accounts of the parents of the actual children.

117. Some Unanswered Questions

Some outstanding questions, which the media may find useful to bear in mind, are offered here...

(Q1) Does the DoH/Minister accept that parents’ reports are to a consistent pattern?

(Q2) Why was autism rare a couple of decades ago but now much more common?

(Q3) Why do reviews such as the 2001 review by the Medical Research Council stretch out so hard to reach the comforting explanation that it’s mainly a matter of better recognition and improved diagnosis, when they have no scientific justification or hard data for doing so?

(Q4) Just how large an increase in autism numbers is required for it to be recognised as a real increase?

(Q5) why were most autism cases prior to the late 1980s, the time of introduction of MMR, of children who failed to develop in very early infancy, whereas very many cases nowadays - paradoxically, when there is now much better recognition of the condition (i.e. when it is much less likely to be missed in early infancy) are now of acquired autism, after a normal infancy?

(Q6) does the DoH etc accept that the alleged new syndrome involves slow degeneration over many weeks/many months/several years, rather than an acute event within a few days, or at most three weeks, of MMR vaccination?

(Q7) does the DoH accept that many autistic children have extreme multiple food allergies, and that the onset of these approximately coincided with the onset of their autism?

(Q8) Ditto question for bowel conditions.

(Q9) related question: does the DoH etc accept that simultaneous or sequential onset of gut/bowel/autism problems could be interlinked causationally?

(Q10) is the DoH monitoring England/Wales autism numbers centrally? (they are not!)

(Q11) are UK health authorities/Boards monitoring autism locally, to a consistent degree? (they are not!)

(Q12) is the UK DoH aware of the well-documented huge increase in autistic pupils in the US, 1993-2001 up from 12,222 to 78,717? (the UK DoH likes to quote that "MMR is safely used in the US")

(Q13) what research has the DoH etc commissioned into possible causes (as opposed to the genetic susceptibility aspect) of autism. What is its £ value over how many years?

(Q14) What new research into causes has been recently commissioned?

(Q15) has the DoH (or anyone in the UK Government?) made any estimate of the national financial costs of autism? (health, education, social services care, etc multiplied by numbers of cases multiplied by years of life expectancy)?

(Q16) was the UK Medicines Division in complete disarray and chronically understaffed in 1988, the year MMR was introduced? (it was - see BSE Inquiry evidence, Draft Factual Account 17, pp 31-33)

(Q17) did the Taylor, Miller et al North London study find that autism was increasing?

(Q18) did the 2001 Medical Research Council review into autism find that autism was running at a rate of 1/166?

(Q19) is it admitted that the Patja, Peltola et al (Finland) study only followed up 173 of the 1.8m children/troops/other persons long-term?

(Q20) is it true that all these 173 cases were only those with acute gastrointestinal or other problems (vomiting etc), not slow long-term degenerative problems?

(Q21) was the study designed to look at autism? (Peltola has publicly admitted it wasn’t), and would local paediatricians in Finland have connected autism with vaccination at all at that time? (they certainly wouldn’t, no-one had ever suggested it then, 15 years ago)

(Q22) does the DoH etc concede that long-term (six months plus) follow-up was not undertaken of a sufficiently convincingly large sample (10,000-plus) children prior to MMR licensing, and that the UK was in effect trusting to safety because MMR was already widely used elsewhere, eg the US? (they’ll never admit this, but keep trying)

(Q23) did the Medicines Division license MMR on the basis that it was only the amalgamation of three existing licensed vaccines, without considering that their combination could have a synergistic effect?

(Q24) is autism now recognised and recorded even as a potential adverse reaction, nowadays, by the Medicines Control Agency as part of the Yellow Card warning scheme? (very important question)

(Q25) are UK doctors now specifically advised by the DoH to look out for degeneration as a potential adverse consequence of immunisation? (Lord Hunt recently confirmed in a Parliamentary Written Answer to Lord Clement-Jones that they were not).

(Q26) Has there been any further recent guidance on this, in the light of the study by Spitzer, Aitken et al? (there has not).

(Q27) why has the UK Medicines Control Agency not instructed health authorities to replace existing stocks of thiomersal-containing vaccines with non-thiomersal containing vaccines, when there is concern over adverse reactions to thiomersal, and when the manufacturers are operating a free-exchange scheme in the US?

(Q28) how will the Department of Health/whoever rebuild confidence in the immunisation programme if the children win in the forthcoming UK High Court cases?

(Q29) will the Chief Medical Officer, Minister for Public Health (whoever), resign if MMR children win in the High Court?

(Q30) who else will be expected to resign?

18th March 2002