UPDATED [July 2004] MMR and Acquired Autism (Autistic Enterocolitis) - A Briefing Note by David Thrower

MMR and Acquired Autism (Autistic Enterocolitis) - A Briefing Note
David Thrower February 2003

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. UK Families Taking Legal Action
6. UK Vaccine Damage Payment Scheme
7. Families Taking Legal Action in the US over Thiomersal and Autism
8. MMR Litigation in Japan
9. The UK Department of Health's Position over MMR
10. Position of the US Center For Disease Control on MMR/Autism
11. The Parents Have Seen What They've Seen.....

Part B: The Costs of Autism
12. The Financial Costs - Autism Is Costing Billions
13. Estimates
14. Failure to Monitor Increases In UK Autism Numbers
15. "Now Almost Everyone Knows Someone Who's Autistic"
16. University of Cambridge Research
17. University of Sunderland Research
18. UK National Autistic Society Estimates
19. Report by Fiona Loynes for UK All Party Parliamentary Group, Dec. 2001
20. Report for the National Autistic Society, Autism In Schools, May 2002
21. Is Autism Increasing? - Some Recent Official UK Pronouncements
22. Autism In The USA
23. Autism Elsewhere

Part C: Evidence That Increases Are Real
24. California
25. The MIND Study, California
26. New Jersey
27. Atlanta Study

Part D: Reviews Questioning the Autism Epidemic
28. Paper by Fombonne, UK Medical Research Council, Pediatrics, January 2001
29. Paper by Wing, Centre for Social & Communication Disorders, London 2002
30. Position of Dr. B. S. Siegal, University of California, 2002
31. Study by Croen et al, July 2002
32. Editorial by Fombonne, Journal of the American Medical Asscn., January 2003

Part E. Studies That Have Been Used To Disprove An MMR/Autism Link
33. Stokes et al paper, Journal of American Medical Association (JAMA), Oct. 1971
34. Study by Peltola and Heinonen, Lancet, April 1986
35. Paper by Miller, Miller et al, The Practitioner, January 1989
36. Gillberg Study, Sweden, British Journal of Psychiatry, 1991
37. Commentary by Gillberg and Heijbel, Autism, 1998
38. Letter by Fombonne, Pediatrics, March 1998
39. UK Committee on Safety of Medicines Study, June 1999
40. Paper By Taylor, Miller and Farrington, Lancet, June 1999
41. Paper by Miller & Farrington to US Government Reform Committee, April 2000
42. Patja, Peltola et al Study, Finland, Pediatric Infectious Disease Journal Dec. 2000
43. Kaye, Melero-Montez and Jick Study, British Medical Journal, 2000
44. Dales, Hammer and Smith Study, JAMA, March 2001
45. De Wilde, Carey & Richards Study, Br. Journal of General Practice, March 2001
46. Davis et al study, Archive Pediatrics Adolescent Medicine, 2001
47. Further Paper by Farrington, Miller and Taylor, Vaccine Journal, 2001
48. Fombonne & Chakrabarti Study, Pediatrics, October 2001
49. Further Paper by Taylor, Miller et al, BMJ.com, February 2002
50. Review by Donald and Muthu, Bazian Limited, pub British Medical Jnl June 2002
51. Study into Childhood Gastrointestinal Disorders and Autism, August 2002
52. Study, Madsen et al, Population-Based study, MMR/Autism, Denmark, Nov 2002
53. Paper, Neurologic Disorders after MMR Vaccination, Makela et al, Dec 2002

Part F: Reviews Concluding There Is No Evidence Of A Link
54. Medical Research Council Ad-Hoc Review, March 1998
55. Presentation by Miller to UK All Party Parl. Group on Primary Health Care, 2000
56. Medical Research Council Sub-Committee Report, March 2000
57. Review by US Institute of Medicine, 2001
58. Review by Strauss and Bigham, Health Canada/Un. Of British Columbia, 2001
59. Elliman, Bedford and Miller Review, Arch. of Diseases in Childhood, Oct. 2001
60. Medical Research Council Review, July-December 2001
61. Further Review by US Institute of Medicine, February 2002
62. Review of the Scottish Executive MMR Expert Group, April 2002

Part G: The MMR Original Safety Trials Debate
63. Wakefield & Montgomery "Through A Glass Darkly" MMR safety-studies paper
64. Dr. Peter Fletcher Commentary, Journal of Adverse Drug Reactions, 2001
65. Dr. Stephen Dealler Commentary, Journal of Adverse Drug Reactions, 2001
66. Dr. F. Edward Yazbak Commentary, Journal of Adverse Drug Reaction, 2001
67. The Wakefield/Watson/Shattock Rebuttals
68. The UK Department of Health's Repudiation of "Through A Glass Darkly".

Part H: Studies That Point Towards The Plausibility Of An MMR/Gut/Autism Link
69. Paper by Eggers, Klinical Paediatrics, March 1976
70. Weizman, Weizmann, Szekely et al Study, Am. Journal of Psychiatry, Nov. 1982
71. Delgiudice-Asch and Hollander Study
72. Paper by Dr. H. Fudenberg
73. Paper by Dr. Reed Warren
74. Warren and Singh Study, Immunogenetics, 1992
75. Singh, Warren, Odell, Warren and Cole Paper, March 1993
76. Singh, Warren, Odell et al Study, Brain Behaviour, March 1993
77. Oleske and Zecca paper
78. Binstock paper
79. Anne-Marie Plesner Letter, Lancet, February 1995
80. Paper by Thompson, Montgomery, Pounder & Wakefield, Lancet, April 1995
81. Gupta, Aggarwal and Heads Study, Journal of Autism and Dev. Disorders, 1996
82. Montinari, Favoino and Roberto paper, Naples conference May 1996
83. Auwaerter and Griffin paper, Clinical Immunology and Immunopath., May 1996
84. Cook, Courchesne et al Paper, Molecular Psychiatry, May 1996
85. Griffin and Hussy Study, Journal of Infectious Diseases, June 1996
86. Martinez et al Study, Proceedings of National Academy of Sciences, 1997
87. Paper by Zecca, Graffino et al, Meeting of National Inst. of Health, Sept. 1997
88. Weibel, Caserta and Evans Study, March 1998
89. Wakefield et al "Early Report", Lancet, February 1998
90. Paper by Montgomery, Morris et al (publication date/details not yet known)
91. Sabra, Bellanti and Colon letter, Lancet, July 1998
92. Further Paper by Singh and Yang, Pharmaceutical Journal, October 1998
93. Uhlmann, Sheils et al Paper
94. Bitnun et al Study, Clinical Infectious Diseases Journal, October 1999
95. Paper by Dr. Singh to the US Committee on Government Reform, April 2000
96. O'Leary Paper Presented to US Congressional Oversight Committee, April 2000
97. Kawashima, Takayuki et al Study, Digestive Diseases and Sciences, April 2000
98. Hagenbuch, Kullak-Ublick et al Study, Journal of Pharm. Exp. Ther., July 2000
99. Wakefield et al Paper, American Journal of Gastroenterology, September 2000
100. Statement by Professor Walter O. Spitzer, December 2000
101. Furlano, Anthony et al Study, Journal of Pediatrics, 2001
102. Study by Jyonouchi, Sun and Le, J. Allergy & Clinical Immunology, Feb. 2001
103. Study by Jyonouchi, Sun and Le, J of Neuroimmunology, 2001
104. Paper by Spitzer, Aitken et al, Journal of Adverse Drug Reactions & Tox., 2001
105. Paper by Dr. Ken Aitken to the Scottish Society for Autism, 2001
106. Paper by Imani and Kehoe, Clinical Immunology, September 2001
107. Paper by Dr. Timothy Buie, Oasis 2001 Conference for Autism, Portland, US
108. Paper by Uhlmann, Wakefield, O'Leary et al, J. of Clinical Pathology, Feb. 2002
109. Paper by Singh and Nelson, February 2002
110. Review by Wakefield, Puleston, Montgomery et al, Aliment Pharm. Ther. 2002
111. Report of Study by Comi et al, Johns Hopkins Hospital, Baltimore, April 2002
112. Paper by Torrente, Ashwood, Day et al, Lancet, May 2002.
113. Paper to 102nd GM of American Soc for Microbiology by Singh et al, May 2002
114. Study by O'Leary et al, to be presented to Path Soc of GB and Ireland July 2002
115. Wakefield Paper Presented to US Government Reform Committee, June 2002
116. Paper to US Government Reform Committee by Dr Krigsman, June 2002
117. Unpublished Research by Dr Paul Shattock, University of Sunderland, June 2002
118. Paper by Sheils, Smyth, Martin & O'Leary, Trinity College Dublin, 2002
119. Paper by Dr. Vijendra Singh, Utah State University, August 2002
120. Paper by Finegold, Molitoris, Song, J. Of Clinical Infectious Diseases, Sept 2002
121. Further paper by Jyonouchi, Sun & Itokazu, University of Minnesota, Oct 2002
122. Paper, Treatment of Late Onset Autism, Matarazzo, Univ. of Sao Paulo, Nov 2002
123. Unpublished letter by Dr. Wakefield to the New Eng. J. of Medicine, Nov 2002
124. Study by Croonenberghs et al, University of Antwerp, December 2002

Part J: Other Relevant Papers
125 US Developmental Delay Registry Report, 1994
126 Stratton et al Study, National Academy Press, 1994
127. Paper by Carbone.
128. Iizuka, Saito et al Study, Gut, May 2001 (Mumps Study)
129. Statement by Spitzer, US House of Repres. Govt Reform Committee, April 2001
130. Statement by Dr. Jefferson, Cochrane Collaboration, Oxford, October 2002

Part K: Future Papers Investigating A Link/Prevalence
131. Fombonne et al Study, London
132. Charman et al Study, London
133. Study by Professor Andrew Hall, London
134. Study by Takahashi et al, Tokyo
135. Study by Rall, Fox Chase Cancer Center, US
136. Studies Commissioned by the US Center for Disease Control
137 UK National Institute for Biological Standards and Control Study
138. Study by University of California at Davis into Environmental Factors
139 Other UK Studies funded by the Medical Research Council
140 Study by Autism Center, University of Medicine & Dentistry, New Jersey, US
141. Study by Center for Disease Control, New Jersey, US
142. Study by Robert Wood Johnson Medical School, New Brunswick, US
143. Survey by New Jersey Answers for Autism

Part L: The Thiomersal Issue
144. Thiomersal's Possible Role
145. Thiomersal In Vaccines: Statement of US AAP/Public Health Service, July 1999
146. UK Vaccines With Thiomersal
147. Scientific Review by US Center for Disease Control, Simpsonwood, June 2000
148. Press Release by Waters and Kraus, March 2002
149. UK Medicines Control Agency Position
150. US CDC Thiomersal Studies
151. Pichichero et al Study into Mercury Concentrations, Lancet, November 2002.

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

Part N: UK and US Political Initiatives
155. UK House of Commons Health Committee, Westminster
156 UK All Party Parliamentary Group on Autism, Westminster
157. Scottish Parliament, Edinburgh
158. UK Liberal Democrats
159. UK Conservatives
160. US House of Representatives Government Reform Committee

Part P: Some Conclusions and Some Unanswered Questions
161. Some Broad Conclusions
162. Some Unanswered Questions

EXECUTIVE SUMMARY

PART A

A NOVEL SYNDROME

1: What Is Acquired Autism/Autistic Enterocolitis?

2: The New Syndrome

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

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:

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.

It is also interesting to see that numerous adverse reactions to MMR have actually been reported in the past, as well as adverse reactions to single vaccines. Although links between adverse events and vaccines are invariably routinely denied by medical and health bodies, it is stretching credibility to suggest that all of these reported adverse events are unconnected with prior vaccination.

The following statistics are taken from the US VAERS (vaccine adverse events reporting system) database, covering the period from 1st January 1990 to 6th March 2001.

The table below also includes some other vaccines, for comparison. It should also be noted that a very small percentage indeed - perhaps as low as 1% - of adverse events are actually reported to VAERS in practice, and the real numbers will therefore be very much higher. Many of these reactions are extremely minor and transitory, but a considerable number are also very serious, and some reactions are fatalities.
(vaccine) Reported adverse events Reported serious adverse events Reported deaths % of total events reported as serious** % of adverse events reported as deaths**
Dipther Tet

1,492

189

15

    
DTAP

10,348

1,422

283

    
DipTetPert

21,163

3,286

794

    
DTPH

6,212

928

254

    
Flu

15,351

2,082

324

    
Hepatitus B

32,209

4,676

662

    
HibV

21,726

3,905

932

    
Measles

414

61

7

15%

2%

Measles M

34

25

2

74%

6%

MMR

20,974

2,586

132

12%

1%

Measles R

117

23

0

20%

0%

Mumps

54

19

3

35%

6%

Polio live or

24,702

3,541

970

    
Pneumococ

5,841

712

95

    
Rubella

685

100

1

15%

0%

Tetanus Dip

9,566

520

12

    
Varicella

12,635

590

31

    
TOTALS*

201,815

27,768

4,965

14%

2%

Notes: * totals include a number of other vaccines, not included in the table,

** percentages only calculated selectively for components of MMR. Full titles of those vaccines itemised in the table are (1) dipitheria tetanus, (2) diptheria tetanus acellular pertussis, (3) diptheria pertussis tetanus, (4) diptheria pertussis tetanus haemophilus B, (5) influenza, (6) hepatitus B, (7) haemophilus B, (8) measles virus live, (9) measles mumps virus live, (10) measles mumps rubella virus live, (11) measles rubella virus live, (12) mumps, (13) poliovirus live oral, (14) pneumococcal, (15) rubella virus live, (16) tetanus diptheria adult, (17) varicella.

It is noteworthy that MMR and the various other components of vaccines for measles, mumps and rubella appear to account for 2,814 reported serious adverse events and 145 deaths. This has to be set against the many millions of doses administered, but also against the likely levels of under-reporting. For the autism issue, under-reporting is likely to be very high indeed, perhaps even almost total, due to lack of knowledge on the part of both parents and health professionals.

4. Contraindications to Receiving MMR

This list of potential contraindications 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:

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. UK Families Taking Legal Action

6. UK Vaccine Damage Payment Scheme

It is sometimes alleged that parents are all too ready to turn to litigation to seek damages for autism, as part of the "compensation culture". However, caring for a child with autism is expensive over a lifetime. It destroys or very severely damages the child's quality of life, and their opportunities for earnings. It also severely damages family quality of life, and frequently reduces family income dramatically.

The only recourse other than to litigation has been the UK Vaccine Damage Payments Scheme (VDPS). However, no cases of autism have succeeded in the VDPS to date, and indeed, the scheme has a history of rebutting claims of all kinds.

The VDPS was introduced in 1979 by the Callaghan Government as a response to the 19878 Pearson Report. One of the latter's conclusions had been that "the Government.....should be liable in tort for severe damage suffered by anyone (adult or child) as a result of vaccination which has been recommended in the interests of the community".

The VDPS is administered by the Vaccine Damage Payments Unit, which gives effect to the decisions of the "SEMA Group", a medical agency sub-contracted to the Government's Department of Work and Pensions. Any subsequent appeals on both fact and law are made to Vaccine Damage Appeal Tribunals, and there is no further appeal avenue, although the Secretary of State may reverse a Tribunal decision.

The VDPS does not provide compensation per se, but a "contribution" towards the expenses of bringing up a disabled child. VDPS payments are not admissions of negligence, nor are they the result of strict liability (I am grateful to researcher Dr. Stephanie Pywell, University of Hertford, UK, for this and subsequent information).

In June 2000, substantial changes to the VDPS were announced, in response to heavy public criticism and press campaigns. Three changes were proposed:

However, the scheme remains deeply adversarial, and very few payments are made, not surprisingly as the process involves ordinary members of the public taking on the medical establishment, without funding for studies or access to advocacy resources. The award rate data for the VDPS is as follows (1978-2000):

A survey of the scheme was undertaken by the UK parents' group JABS. It found that rejection rates were especially high in MMR cases. Just six out of 93 claims succeeded. Three of these related to the early Urabe strain of MMR vaccine, which was very hurriedly withdrawn by the UK Department of Health in 1992.

7. Families Taking Legal Action in the US over Thiomersal and Autism

It is also noteworthy that there is a legal precedent in the US courts 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 judgment 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:

However, the progression of the US litigation over vaccines and autism has been made very much more uncertain by the insertion of four clauses in the US Homeland Security bill in December 2002, debarring families from filing lawsuits against Eli Lilly & company over thiomersal. The inclusion of these clauses has been strongly criticised by a range of US politicians, including Rep. Dan Burton (R-Indiana), Sen. Debbie Stabenow (D-Michigan), and Sen. Patrick Leahy (D-Vermont).

A move to seal all documents was also made, then withdrawn in December 2002, by the US Department of Justice.

In January 2003, a Bill was to be introduced in Congress which would focus solely upon the reversal of clauses 1714/15/16/17 of the December 2002 Homeland Security Bill, which were the clauses that protected Eli Lilly from lawsuits. This bill was introduced by Sen. Debbie Stabenow, and co-sponsored by Sen. Barbara Boxer (D-California), Sen. Tom Daschle (D-South Dakota), Sen. Mark Dayton (D-Minnesota), Sen. Christopher Dodd (D-Connecticut, Sen. Byron Dorgan (D-North Dakota), Sen. Richard Dunbin (D-Illinois), Sen. Dianne Feinstein (D-California), Sen. Mary Landrieu (D-Los Angeles), Sen. Frank Lautenberg, Sen. Patrick Leahy (D-Vermont), Sen. Carl Levin (D-Michigan) and Sen. Paul Sarbanes (D-Maryland).

Documents relating to thiomersal's original testing by Eli Lilly have been subpoenaed by the House of Representatives Committee on Government Reform (see also later sections on thiomersal and on the US Congress and Government Reform Committee). Thiomersal is believed to have only ever been tested on 27 people (who were dying from meningitis) in 1929. Eli Lilly maintain that, although all 27 died, it was not due to the thiomersal. Further details are in the later sections.

8. MMR Litigation in Japan

Only limited information has been obtained on litigation under way in Japan. This information is based upon a press report in the Yomiuri Shimbun (Daily Yomiuri).

9. The UK Department of Health's Position On MMR

(UK Department of Health's "Top 10 Truths")
(Department of Health "Truth") (Critical Response of Parents)
MMR is safest way to protect children Does not address the alleged damage
Over 500m doses of MMR have been used in over 90 countries Almost all those countries have no autism database. Only US has good data - and this shows a steep rise in autism
No country in the world recommends single vaccines No country in the world has yet acknowledged that there may be an MMR/autism link, either, but that may yet follow in time. Some countries permit single vaccines as a choice.
Children who are not immunised with MMR increase the chance of infection in others. True. But those children could still receive single vaccines. And there may yet be a massive loss of confidence in all vaccination, if the children win in the High Court. It would therefore be prudent to think of this possibility, and permit choice now.
The evidence is that MMR does not cause autism or IBD (a number of studies are quoted, but only those which suit the Department's stance) There is evidence that suggests that it may do. Every one of the quoted studies that "disproves" an MMR/autism link can be flawed (see elsewhere in this document).
Wakefield et al in 1998 said "We did not prove an association". True. The research is still unfolding. Time did not stop in 1998.
Single vaccines put children at risk The Department's argument is based upon a supposition that some children would not complete the full course of vaccines. But if the children win in the High Court, and the Department is shown to have misled the public (either unknowingly or knowingly), the damage will be far greater. And already, some children are avoiding any measles vaccine. The Department's argument is already having a perverse consequence, and may eventually massively backfire..
MMR was thoroughly tested before introduction into the UK in 1988. In the context of adverse outcomes with an insidious long-term onset, MMR was not properly tested. Advice at the time to explore possible adverse effects was not followed up. By disputing historical facts, the Department reveals its bias.
Two doses of MMR are needed to protect children. The efficacy of MMR in terms of preventing measles is not the point at issue.
There are very few children with genuine contraindications. This does not address the MMR/autism link. It also does not square with the manufacturer's own information sheets, which imply a substantial number of possible adverse effects.

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")
(Department of Health "Myth") (Critical Response of Parents)
Getting protection by catching the disease is better. This is not the issue in dispute.
Three viruses given at the same time is too much for children. It may yet prove to be. The Department has no evidence (in the context of the MMR/autism debate) to the contrary, in relation to live viruses.
Other countries recommend that MMR is given as separate vaccines. Of course they don't. Perhaps this is because no country has yet woken up to the problem. As yet, there is insufficient evidence to alter this position.
Measles, mumps and rubella are rare in the UK so there is no need to immunise. This is not the issue in dispute.
MMR causes autism and bowel disease. There is evidence pointing towards an MMR/autism/IBD connection. Until this area is thoroughly researched, it is scientifically untenable to rule it out.
There was a scientific paper that linked MMR and autism/IBD There have now been a number of such papers. They form part of an unfolding story.
Giving MMR as separate vaccines reduces the risk of side effects. It is not possible to prove/disprove this until proper clinical research has been funded and conducted.
The vaccine was not properly tested. In the context of the MMR/autism debate, and the alleged link, this is factually true, and it is extraordinary for the Department to claim otherwise. Even the Department cannot re-write history.
My child has already received one dose, so does not need a second dose. This is not the issue in dispute.
My son does not need protection against rubella, my daughter does not need protection against mumps. This is not the issue in dispute.

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.

The position in the US is no different. In summer 2002, the US Center for Disease Control (CDC) updated its "Frequently Asked Questions" (FAQs) on the MMR/autism issue. It asked the question: "What have studies found regarding MMR vaccine and autism?".

Its answer was "Epidemiologic studies have shown no relationship between MMR vaccination in children and development of autism". However, what it did not acknowledge, or discuss, was that "studies" in the original question should have included both clinical and epidemiological studies, with greatest weight being attached to clinical findings. Its answer ducked the issue of clinical studies, focussing solely on epidemiological studies (see later for a critical review of these).

10. Position of US Center for Disease Control on MMR/Autism

The position of the US Center for Disease Control is summarised as follows (taken from their website in February 2002, but believed to be unchanged as at February 2003):

Comment: the above is neither comprehensive nor balanced, and its one-sided reassurance is therefore unhelpful. The details of the above could even be challenged on the grounds of factual accuracy. Point one is particularly threadbare.

11: 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

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.

PART B

THE COSTS OF AUTISM

12: 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:

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?

13: Estimates

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

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

14. Failure To Monitor Increases In UK Autism Numbers

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

In December 2002, a Parliamentary Written Question (84502) confirmed that there is now in place a "Good Practice Guidance on Autistic Spectrum Disorders", in the UK, published by the Government's Departments of Education & Skills and of Health. This is intended to raise awareness amongst schools and local education authorities. However, it is probably just one of many thousands of such well-intentioned documents, is non-statutory, and is probably lost in the stream of paper raining down on local government from central government.

UK schools and local education authorities have a duty to identify, assess and make suitable provision for children with special educational needs. However, there seems to be no duty upon either the health authorities at the local level or the Department of Health at Government level to improve the data position over autism - doubtless to the latter's relief. Perhaps centrally-collated figures showing steep increases would beg uncomfortable questions as to the causes. The UK Department of Health seems to regard autism as a problem for local education authorities - not for the Department.

15. "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:

On December 22nd 2002, the UK Observer newspaper carried a report on the apparent epidemic of behavioural problems amongst UK schoolchildren. Whilst not confined to autism (the report cited hyperactivity and attention-deficit disorder), the Observer's report suggested a steep rise in the incidence of problems. Figures obtained by the newspaper suggested that numbers of schoolchildren with attention-deficit disorder (ADD) or attention-deficit hyperactivity disorder (ADHD) had reached 345,000, and that one child in twenty between the ages of 6 and 16 years had one or other condition. The Observer also found out that prescriptions for Ritalin, to counter these disorders, had increased markedly, from 91,100 in 1997 to 208,500 in 2001.

In the US, the Brown University Child & Adolescent Behavioural Letter (18(3): 1: 304, 2002) carried the following details:

16. 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.

The study aimed to establish prevalence of the broader autistic spectrum, including Asperger syndrome in 5-11 year olds in Cambridgeshire, UK. Cases of diagnosed autism spectrum condition in children who were in Cambridgeshire schools and aged 5-11 on 31st December 1999 were sought out using public records, screening instruments, educational psychology and special educational needs coordinator records.

It found that:

17. 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.

18. UK National Autistic Society Estimates

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

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.

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

The purposes of this report included:

The findings included the following:

20. Report, "Autism In Schools - Crisis or Challenge", National Autistic Society UK, May 2002

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

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

22. Autism In The USA

State 1992-1993 2000-2001 Percentage Increase
Alabama

68

765

1,025

Alaska

8

195

 (almost infinite)
Arizona

199

1,119

462

Arkansas

30

671

2,137

California

1,605

10,557

558

Colorado

14

453

 (almost infinite)
Connecticut

164

1,225

647

Delaware

15

263

1,653

District of Columbia

0

103

 (infinite)
Florida

582

3,926

575

Georgia

262

1,916

631

Hawaii

52

276

431

Idaho

39

291

646

Illinois

5

3,103

 (almost infinite)
Indiana

273

2,621

860

Iowa

67

537

701

Kansas

74

619

736

Kentucky

38

864

2,174

Louisiana

409

1,145

180

Maine

37

444

1,100

Maryland

28

1,933

 (almost infinite)
Massachusetts

493

575

17

Michigan

288

4,075

1,315

Minnesota

296

2,448

727

Mississippi

0

385

 (infinite)
Missouri

336

1,589

373

Montana

20

163

715

Nebraska

4

337

 (almost infinite)
Nevada

5

394

 (almost infinite)
New Hampshire

0

342

 (infinite)
New Jersey

446

2,925

559

New Mexico

16

225

1,306

New York

1,648

5,943

260

North Carolina

786

2,374

202

North Dakota

9

118

 (almost infinite)
Ohio

22

2,217

 (almost infinite)
Oklahoma

31

666

2,048

Oregon

37

2,516

2,516

Pennsylvania

346

3,304

855

Puerto Rico

266

473

78

Rhode Island

19

309

1,526

South Carolina

141

852

504

South Dakota

36

227

531

Tennessee

304

935

208

Texas

1,444

6,023

317

Utah

105

584

456

Vermont

6

160

 (almost infinite)
Virginia

539

1,983

268

Washington

476

1,620

240

West Virginia

101

312

209

Wisconsin

18

1,823

 (almost infinite)
Wyoming

15

94

527

Total

12,222

78,717

 overall increase 644

(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".)

As in the UK, health officials in the US have tried to explain away these increases as being the result of greater awareness, better recognition and broader diagnostic definition. Doubtless these play a part, but the authorities seem to want to use these factors to explain all the increase, without having any hard evidence to support their stance.

In April 2000, giving evidence to the Government Reform Committee hearings into autism's increase, Dr. Coleen Boyle, Associate Director for Science and Public Health at the Center for Disease Control, stated that UK rates in 1966 had been 4 to 5 per 10,000 (1 in 2,500-2,000). Studies from outside the US since 1985 had indicated 12 per 10,000 (1 in 833). Recent studies had been higher still. There had been only two population-based studies in the US, both in the 1980s, indicating prevalence of 1.2 to 3.3 per 10,000 (1 in 8333 to 1 in 3030).

Two years on, giving evidence to the same Congressional committee, Dr. Coleen Boyle acknowledged the case of Brick Township New Jersey, where the CDC had found a rate of ASD of 6.7 per 1,000 (note: per ONE thousand), or 1 in 149. She stated that the previously-accepted background rate was 1-2 per 1,000 (comment - but this does not square with her evidence in the year-2000 Washington hearings?). She stated "We cannot determine whether rates are increasing or not, because we do not have comparable data from earlier years".

But the thrust of her earlier comments implied that, even if increases were demonstrated, this was down to better awareness etc., and at no point did she appear to confront the possibility that increases were real, and then confront the (very difficult) question, "What was causing the increase?". The CDC strategy seems to be to cast doubt upon the increase, rather than seek the cause. The CDC strategy might be summed up as follows:

By early 2003, evidence that increases were real was beginning to accumulate - see next main section.

23. Autism Elsewhere

Information on autism in Canada does not appear to be anything like as comprehensive as that in the US, but press reports are indicating a recent increase. In May 2002, a study by the Ontario government health ministry indicated that numbers were increasing sharply, with 800 children younger than six years of age being newly diagnosed during 1998. This represented a 53% increase over numbers diagnosed two years earlier.

The Ontario government study also found that 2,863 children younger than seven were diagnosed with autism between 1991 and 1998. The study was not released until the efforts of a parent, Professor Marianna Ofner-Agostini of the University of Toronto, forced the issue.

The issue is now being debated in other developed countries elsewhere in the world. A New Zealand doctor, Dr. Mike Godfrey, wrote to the UK Scotsman newspaper in early 2002 as follows: "I have so far analysed 866 children's histories, with 260 being unvaccinated. There are no cases of autism, epilepsy or Crohns Disease and only a handful of other diseases in this latter (unvaccinated) group. There are 16 autistics, 12 epileptics, 8 cases of Crohns, plus cases of other illnesses, in the vaccinated 606 children."

PART C: EVIDENCE THAT INCREASES ARE REAL

24: California

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

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.

Statistics on autism in the individual regional centres in California, run by the state Department of Developmental Services, also show a sharp rise in the period 1998-2002:
(regional centre) At 7th Jan 1998 At 3rd Jan 2002 Increase %
Alta

400

683

71%

Central Valley

150

361

141%

East Bay

606

1,087

79%

E. Los Angeles

443

976

120%

Far Northern

125

217

74%

Golden Gate

371

499

35%

Harbor

639

1,113

74%

Inland

568

1,195

110%

Kern

141

262

86%

Lanterman

418

842

101%

North Bay

215

350

63%

N. Los Angeles

742

1,746

135%

Orange

670

1,621

142%

Redwood Coast

76

103

36%

San Andreas

360

666

85%

San Diego

609

1,186

95%

San Gab/Pomona

581

937

61%

S. Central LA

549

874

59%

Tri-Counties

352

725

106%

Valley Mountain

153

373

144%

Westside

613

986

61%

(Statewide Total)

8,781

16,802

91%

Since this data was released, further rises have been recorded:

Comment: the above suggests a major rise in autism incidence in California.

25. The MIND Study, California

Following mounting concern at the apparent steep increase in autism in California, an urgent study was launched by the MIND Institute. Its findings were released on 17th October 2002, and appear to finally confirm (but see other contradicting studies in the following section) that autism has risen steeply.

The study was led by Dr. Robert Byrd, whose team had previously enrolled 684 Californian children who were receiving services from one of the Department of Developmental Services regional centers. Byrd's team systematically gathered information for children in two age groups, 7-9 year olds, and 17-19 year olds. These were drawn from families of 375 children with a diagnosis of full-syndrome autism, and families of 309 children with a diagnosis of mental retardation without full-syndrome autism.

The study findings were that:

Comment: the above study appears to offer firm evidence of a major rise in prevalence.

26. 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:
age

6

7

8

9

10

11

12

13

nos

514

505

465

439

360

257

208

165

age

14

15

16

17

18

19

20

21

nos

145

124

81

73

58

63

30

14

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.

In an article published by the US Autism Autoimmunity Project at the end of December 2002, Dr. Ed Yazbak set out the evidence for there having been a huge rise in autism in Rhode Island, New Jersey:

Comment: the above seems to confirm that the recent very steep rises in California are also being witnessed elsewhere in the US.

27. Atlanta Study, Prevalence of Autism in a US Metropolitan Area, by Yeargin-Allsopp, Rice et al, published in the Journal of the American Medical Association, 2003, Jan 1st, 289: (1): 49-55

This study was at last an acknowledgment at the US Center for Disease Control & Prevention that autism was at a higher real level than two decades ago. Its conclusions directly undermined the evidence of one of its participants, Dr. Coleen Boyle, to the US House of Representatives Government Reform Committee, only a short time earlier, that autism was a very rare condition.

Comment: this study, too, supports the view that autism has greatly increased. The study is notable for being a CDC-sponsored study, using CDC personnel.

PART D:

REVIEWS QUESTIONING THE AUTISM EPIDEMIC

Despite the evidence that autism has increased very greatly since the 1970s and early 1980s, several researchers maintain that this is not the case.

28. 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....."

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

29. Paper by Lorna Wing, Centre for Social & Communication Disorders, Elliot House, Bromley, Kent, UK and David Potter, UK National Autistic Society, The Epidemiology of Autistic Spectrum Disorders: Is The Prevalence Rising?, 2002

This paper noted that:

Comment: these views have been strongly contradicted by:

31. Study by Croen, Grether, Hoogstrate and Selvin for the California Department of Health Services, July 2002

The authors conducted a population-based study of eight successive birth cohorts to examine the degree to which improvements in detection and changes in diagnosis have contributed to the observed increase in autism prevalence. Children born in 1987-1994 who had autism were identified from State registries. To evaluate the role of diagnostic substitution (re-assignment from other categories), trends in prevalence of mental retardation without autism were also investigated.

32. Fombonne, editorial, Journal of the American Medical Association, January 1st 2003 Vol 289, No.1 49

At the start of 2003, Dr. Eric Fombonne wrote an editorial in the Journal of the American Medical association that appeared to acknowledge that there had been some real increase in autism, but which also attempted to explain this away to as great a degree as possible through the usual recourse to references to better awareness, less restrictive criteria and a greater willingness to diagnose.

Fombonne's key points were that:

Fombonne concluded that a rate of 41-45 per 10,000 (1 in 222) might be a more accurate rate of prevalence. He noted in his editorial that other studies suggested rates of 60 per 10,000 when pervasive developmental disorder-not otherwise specified (PDD-NOS) and Aspergers syndrome were taken account of.

He then addressed the issue as to whether the prevalence of autistic spectrum disorder (ASD) had increased over time. His benchmark was the 1970s Wing and Gould study in Camberwell, London, which pointed to a rate of 20 per 10,000 for severe-impairment cases. Other earlier studies had point to rates of 4 or 5 per 10,000, and more recent studies cited by Fombonne pointed to rates of more than 10 per 10,000. Fombonne's conclusion was that the most recent rates of prevalence were three or four times higher than 30 years ago.

Fombonne, seemingly searching for an uncontroversial explanation for any increase, then examined whether this increase implied a broadening of criteria and improved methods of case-finding during studies. He pointed to what he described as the "major" changes in criteria:

He argued that there was strong evidence that differences in methods for case finding could account for a "huge" proportion of the variability of prevalence estimates between surveys. Referral rates were also unreliable, due to confounding factors. This, and other factors, he concluded, combined to offer "good" evidence to support the contention that higher rates of prevalence reflected changes in diagnostic practice, improved identification and availability of services. The hypothesis of an increasing trend in the incidence of autism could not, in his view, be fully tested because of the inadequacy of studies to date. Fombonne dismissed any association with MMR (citing his own study work and studies by Madsen and by Taylor and Miller as proof), and dismissed evidence of any connection with thiomersal as being "weak".

Fombonne was also quoted in the New York Times of 31st December 2002 as stating: "No strong candidate environmental exposures have been identified.....Claims of an association with MMR have not been borne out by recent studies, and evidence for causal association with other exposures such as mercury-containing vaccines is weak".

The study being commented on by Fombonne was that by Dr. Marshalyn Yeargin-Allsop et al, detailed earlier.

Comment: the editorial by Fombonne offers no hard evidence against a vaccine/autism link, and, whilst offering some arguments in favour of questioning the precise scale of the apparent major rise in autism prevalence, fails to demolish the central assertion of many parents, that autism has grown immensely in a couple of decades. No alternative explanations for the rise are offered by the Fombonne editorial.

PART E

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.

33. 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).

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

34: 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.

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

The authors did actually acknowledge this, stating:

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

35: 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:

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

36. 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).

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

[Feb 2003] Professor Christoper Gillberg

37. 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.

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

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

39. 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:

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?

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.

40. 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.

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.

(Note: this study has been claimed by the UK Medical Research Council to represent "strong positive evidence" of there being no MMR/autism link)

41. 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:

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.

42. 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,

There are other awkward facts regarding the Peltola 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.

43. 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.

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

44. 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:

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.

45. 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:

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

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).

46. 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:

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:

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

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.

47. 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.

The study found that:

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:

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

(Note: this study has been claimed by the UK Medical Research Council to represent "strong positive evidence" of there being no MMR/autism link)

48. 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:

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.

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.

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.

Comment - but regression might not necessarily 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.

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.

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

Other comments:

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

(Note: this study has been claimed by the UK Medical Research Council to represent "strong positive evidence" of there being no MMR/autism link)

49. 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:

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

The study reported that:

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.

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:

(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).

In subsequent British Medical Journal correspondence, the paper was also heavily criticised over its statistical methodology and the refusal to release raw data. These criticisms were by Aubrey Blumsohn, a Senior Lecturer at the University of Sheffield, UK. His main points were that the authors provided no statistical confidence limits in relation to several key findings

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 of argument was repeated in a UK television interview by Dr. Elizabeth Miller on 13th February 2002.

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

(Note: this study has been claimed by the UK Medical Research Council to represent "strong positive evidence" of there being no MMR/autism link)

50. Review by Donald and Muthu, Bazian Limited, London UK, published in the British Medical Journal, June 2002

This was not a new study, but a review of existing studies. It claimed that it followed the most in-depth analysis of the scientific literature to date, looking at 2,000 existing studies and papers, and offered clear reassurance for parents. However, only 36 studies were actually cited, the remainder having apparently been disregarded on the basis of self-imposed restrictive criteria for inclusion in the review.

The study found:

Comment: there are a number of fundamental (and severe) criticisms that can be made of this review's methodology:

The study (inexplicably) took only the February 1998 paper by Wakefield et al as being the published evidence for any MMR/autism link, and appeared to disregard a considerable number of subsequent papers (all of which are reviewed later in this Briefing Note).

In effect, all the study could reasonably have concluded is that there is a lack of published research that is relevant to the question. However, the researchers claimed that their paper should signal the end of the MMR/autism debate. Dr. Donald appeared on BBC Radio 4's Today programme and stated that "It was time for the parents to stop chasing shadows" (re MMR).

Conclusion: this review offers no hard evidence whatever against the possibility of an MMR/autism link.

51. Study into Relationship Between Childhood Gastrointestinal Disorders and Autism: Nested Case-Control Study Using Data from the UK General Practice Research Database, British Medical Journal Volume 325, pp 419-421, Boston University (researchers' details not known), August 2002

This study identified 96 children with autism from the UK General Practice Research Database between 1988 and 1999 (MMR was introduced into the UK in October 1987). Each case was matched with up to five controls without autism. The study considered the time relation between MMR vaccination and the onset of gastrointestinal symptoms among the cases. Findings were:

The authors acknowledged that they could not exclude the possibility that some children in the study had sub-clinical gastrointestinal symptoms before their presentation with autistic behaviour. However, they commented that the children described by Wakefield and colleagues had symptomatic gastrointestinal disease.

The authors also could not exclude the possibility that severe gastrointestinal disease might be associated with the development of autism in certain individuals. However, they thought that this was likely to be uncommon.

Comment: the authors themselves acknowledge the shortcomings of their methodology. Further criticisms are that child health records are unlikely to fully reflect a novel gastrointestinal condition that is subtly different to Crohn's Disease or ulcerative colitis. No children were examined. The study apparently failed to distinguish between late-onset regressive-type autism and autism from infancy or birth.

Conclusion: this study does not disprove a link between MMR and certain sub-types of autism.

52. Study by Madsen, Hviid, Vestergaard, Schendel, Wohlfarht, Thorsen, Olsen and Melbye, A Population-Based Study of Measles-Mumps Rubella Vaccination and Autism, New England Journal of Medicine, November 2002, 347: 1478-1482.

This study paper attracted a great deal of attention, largely uncritical, when it was published towards the end of 2002, mainly because of its claimed size and, of course, its conclusion that there was no evidence of any MMR/autism link. The paper featured:

After initial uncritical review by the press, this study received a very thorough analysis by the parents, notably Dawn Richardson of the US parents' group PROVE and Sally Bernard of the group Safe Minds. Richardson's and Bernard's key criticisms were:

Comment: there are many shortcomings to this study. No child was evaluated for immune system dysfunction, inflammatory bowel disease or the presence of measles RNA in their blood, intestines or cerebral spinal fluid.

53. Paper, Neurologic Disorders after Measles-Mumps-Rubella Vaccination, Makela, Nuorti and Peltola, Hospital for Children and Adolescents, Helsinki University Central Hospital, and Department of Infectious Disease Epidemiology, National Public Health Institute, Helsinki, Finland, published in Pediatrics, Vol 110 No. 5, November 2002, pp 957-963.

This was yet another retrospective study. The objective of the study was to assess whether an association prevails between MMR vaccination and encephalitis, aseptic meningitis and autism.

The study was based on the linkage of individual MMR vaccination data with a hospital discharge register. It was conducted amongst 535,544 one to seven year olds, who were vaccinated between November 1982 and June 1986 in Finland.

For encephalitis and aseptic meningitis, the numbers of events observed within a three-month risk interval after vaccination were compared with the expected numbers estimated on the basis of occurrence of encephalitis and aseptic meningitis during the subsequent three-month intervals.

Changes in the overall number of hospitalizations for autism after vaccination throughout the study period were searched for.

In addition, hospitalizations because of inflammatory bowel disease were checked for the children with autism.

The results were:

The following criticisms of this study were offered by Dr. Ed Yazbak of New Jersey:

Conclusion: despite the supposedly large scale of this study, its fundamental methodological flaws mean that it cannot be deduced from its findings that there is no link between MMR and autism.

PART F

REVIEWS CONCLUDING THERE IS NO EVIDENCE OF A LINK

54. 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

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.

55. 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:

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.

56. 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.

For autism, its recommendations included:

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).

57. 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:

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

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

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:

(see also later for IoM review of the thiomersal preservative issue)

58. Review by Strauss, Field Epidemiology Training Program, Health Canada, Vancouver, British Columbia, and Bigham, Communicable Disease Epidemiology, University of British Columbia, Centre for Disease Control, Vancouver, BC, published in the Canada Communicable Disease Report journal, Minister of Health, Canada 2001

This was simply a review of published literature, and of course has become outdated by subsequent events. However, just as with other similar reviews, it did not appear to be particularly comprehensive in its scope even at the time of publication.

Between November 2000 and February 2001, the researchers conducted an internet search of Medline for publications from 1980 to December 2000, related to MMR vaccination or MMR infection and autism. Concurrently, they conducted a similar literature search for published articles from 1996 to December 2000 that examined the association between MMR vaccination or MMR infection and inflammatory bowel disease.

The authors noted that several population based studies "provided evidence that MMR vaccination is not associated with autism". The purview of their study in this respect included the studies (referred to elsewhere in this Briefing Note) by Gillberg, Taylor/Miller, Kaye et al, Patja et al and Fombonne.

In their discussion, they concluded that:

The authors concluded that the evidence does not support a causal association between MMR and autism, and although there may be biologic plausibility for an association, there is lack of evidence in five of the classic attributes of causality, (a) consistency, (b) strength of the association, (c) specificity, (d) dose response, and (e) experimental evidence.

Comment: this review has a number of weaknesses:

This review, like several others, turns the precautionary principle on its head. It takes the stance that, until there is comprehensive evidence of any MMR/autism/IBD link, then MMR is safe. The burden of proof is then thrown upon the parents (and a few researchers, who have obvious difficulty in attracting funding) to prove that there is a problem, rather than for the manufacturers of the vaccine and the administrators of public health medicine to prove that it is safe. This might seem reasonable when there are no emergent problems, but is profoundly questionable in the context of a novel syndrome and a clinical-research (as opposed to epidemiological-research) "black hole".

Conclusion: this review fails, despite its conclusions, to disprove an MMR/autism/IBD link, and has been overtaken by events.

59. 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:

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.

60. Review By UK Medical Research Council, Review of Autism Research - Epidemiology and Causes, July-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:

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.

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.

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

This found that:

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

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.

62. Review of the Scottish Executive MMR Expert Group, Edinburgh, April 2002

This Expert Group was set up by the Scottish Executive (Parliament) in 2001 to:

(a) describe the consequences of an alternative vaccination policy to MMR

(b) review evidence on the apparent rise in autism

(c) describe the process of vaccine testing and monitoring of adverse effects

(d) have regard to the role and remit of the Joint Committee on Vaccination and Immunisation, the Committee on Safety of Medicines and the Medicines Control Agency (all in London)

The Expert Group's report made a number of useful suggestions:

A number of members of the Scottish Expert Group declared financial interests in relation to the manufacturers of MMR. These included Prof. Johnstone (major shareholder of Glaxo SmithKline), Dr. Bramley (non-personal research funding), the Very Rev Graham Forbes, Chairman (non-personal shareholding), Dr Goldblatt (is appearing as an expert witness on behalf of the manufacturers of MMR in the forthcoming High Court action, plus consultancy and other work, including for GlaxoSmithKline), Prof. Ritchie (lectures, seminars and trials sponsored by pharmaceuticals industry), Prof. Weaver (shares in GlaxoSmithKline) and Dr. Riley (shares in GlaxoSmithKline). The number of members with declared interests appears very high, and their nature surprising, given the sensitivity of the issues involved.

PART G

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.)

63. 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:

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.

64. 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:

65. 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:

66. 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:

67. 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.

Other "facts" quoted by Watson in "Aventis Pasteur MSD - Vaccines For Life" paper:

68. 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 (which are taken from the paper by the MCA and the DoH) are set out below, with the DoH's text in italics, and with my own responses following.

Overall comment - 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 at all.

PART H

STUDIES THAT POINT TOWARDS THE PLAUSIBILITY OF AN MMR/GUT/AUTISM LINK

69. 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?).

70. 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:

71. US paper, by Drs. Delgiudice-Asch (clinical instructor in psychiatry, Mount Sinai School of Medicine) and Hollander (Seaver Autism Research Centre)

This includes:

72. 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:

Fudenberg states that:

73. Dr. Reed Warren, Professor of Biology at Utah State University in Logan, set out a pathogen-autoimmune hypothesis for autism (source details not known):

Dr. Warren outlined the possibility of several key factors, which included:

74. 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:

It was also noted that:

It was further noted there was a link between genetic background and frequency of infections:

75. 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:

76. Paper by Dr. Vijendra Singh, College of Pharmacy, University of Michigan, Ann Arbor, joint with 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:

The features above included genetic predisposition, gender imbalance (four or five times higher frequency in boys than girls), major histocompatibility association, and immune activation.

77. Unpublished US paper, by Dr. Oleske and Assistant Professor Zecca, New Jersey Medical School

This found that:

78. US paper by Theresa C. Binstock, Researcher in Developmental and Behavioural Neuroanatomy, IMI, Denver

This found that

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

This letter reported:

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

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

80. Paper by Thompson, Montgomery, Pounder & Wakefield, Is Measles Vaccination A Risk Factor for Inflammatory Bowel Disease, The Lancet, April 1995, 345: 1071-74

The summary of this paper was as follows:

81. 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.

82. 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:

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.

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.

83. Paper by P. G. Auwaerter and Diane Griffin, (source: Clinical Immunolgy and Immunopathology, 79(2): 163-70, May 1996):

This found that:

84. 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:

85. Paper by Diane E. Griffin, D. E. Hussy et al, Johns Hopkins University, US, Journal of Infectious Diseases, 173 (6), 1320-26, June 1996)

This found that:

These researchers found that:

86. Paper by Martinez et al, Proceedings of the National Academy of Sciences, 94.8726-31 1997:

This found that:

87. 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:

88. 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.

89. 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:

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.

90. 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 (full details of date and journal of publication not available)

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:

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

91. 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:

92. 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, 89: 105-108

This paper suggested that:

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.

93. 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:

94. 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.

95. 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:

In his studies, he reported two important observations:

Also:

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:

96. 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?

97. 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:

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

98. 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:

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

99. 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.

100. 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:

101. 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:

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.

102. 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:

The study also assessed T1/T2 responses:

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

103. 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:

The study team also observed:

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".

104. 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:

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".

105. 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:

106. 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.

107. 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:

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".

108. 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.

The results of the study were:

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.

109. 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:

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.

110. Review, The Concept of Enterocolonic Encepalopathy, Autism and Opioid Receptor Ligands, Wakefield, Pulestone, Montgomery et al, Inflammatory Bowel Disease Study Group Royal Free and University College Medical School London and Department of Pathology, Coombe Women's Hospital and Trinity College Dublin, Aliment Pharmacological Ther., 2002: 16: 663-674.

This review paper set out some of the background to the relevance of the gut-brain axis in understanding the pathogenesis of autism:

111. Report of Study by Comi et al, Johns Hopkins Hospital, Baltimore, US

This study looked at the background history of families of children with autism. It found that families of children with autism had an unusually high incidence of diseases of the immune system, in particular rheumatoid arthritis.

Comi and colleagues sent questionnaires to the families of 61 children with autism, and to 46 children without autism. The families were asked if they suffered from autoimmune diseases, such as rheumatoid arthritis, lupus, early-onset diabetes, multiple sclerosis and thyroid disorders.

The results showed that

Dr. Comi urged that larger studies should be undertaken

112. Paper, Small Intestinal Enteropathy With Epithelial IgG and Complement Deposition in Children with Regressive Autism, by Torrente, Ashwood, Day et al, Lancet, May 2002

This study compared duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation, and 18 histologically normal controls. The study was part of a continuing investigation into a novel gastrointestinal pathology in children with regressive autism. Inflammatory pathology had already been confirmed in these children in the large intestine and upper gastrointestinal tract.

Routine staining showed only minor differences between autistic children and controls, but immunochemistry highlighted striking abnormalities in the group with autism. The density of CD8 intraepithelial lymphocytes was significantly greater in autistic children than in normal controls or children with cerebral palsy, but was not as high as in children with coeliac disease.

This study:

This study adds a very important piece to the emerging jigsaw of autistic regression, intestinal disease and the presence of measles virus in many affected children. Dr. Simon Murch, one of the authors, commenting on the study, stated that "the big question is whether such unexpected gut involvement either causes or exacerbates the cognitive abnormalities that typify autism. If the answer is yes, then this may point towards the logical use of immune-based therapy in future children at the time of their first regression".

113. Paper, Abnormal Measles Serology and Autoimmunity in Autistic Children, by Singh, Nelson (Utah State University), Jensen and Bradstreet, published in the Journal of Allergy and Clinical Immunology 109 (1) S232, January 2002 and also presented to the 102nd General Meeting of the American Society for Microbiology, Salt Lake City, Utah, May 19th-23rd 2002

Autoimmunity to brain myelin protein (MBP) secondary to a measles infection may cause autistic regression in some children with this neurodevelopmental disorder.

The authors hypothesised that MMR immunisation is a source of measles infection, hence the serological link between MMR and MBP antibodies might exist in autistic children. To test the hypothesis, the authors conducted a serological study of MBP, MMR and neuro-axon filament protein (NAFP) in serum and cerebral spinal fluid (CSF) of autistic children. Antibodies were assayed by immunoblotting with MBP, NAFP and MMR as antigens.

The authors found that:

In the light of this new evidence, the authors suggest that in some cases of autism, the MMR vaccine might cause autoimmunity, and it might do so by bringing on an atypical measles infection that does not produce a typical measles rash but instead manifests neurological symptoms upon immunisation.

The authors add that the MMR antibody has been previously reported to be the hemagglutinin protein of the vaccine measles virus (MV-HA). Immunoblotting analysis showed the presence of an unusual MMR antibody in 60% (75 out of 125) of autistic children, but none of the 92 normal children had this antibody. Moreover, by using MMR blots and monoclonal antibodies, the authors had found that the specific increase of MV antibodies or "MMR" antibodies was related to measles hemagglutinin antigen (MV-HA).

114. Paper by O'Leary et al, Coombe Women's Hospital and Trinity College Dublin, presented July 2002 to a conference of the Pathological Society of Great Britain and Ireland

(these brief details are based upon reports in June 2002 in the UK press)

115. Paper by Dr Andrew Wakefield to US Committee on Government Reform Hearing, The Status of Research into Vaccine Safety and Autism, Washington DC, June 2002

Dr Wakefield updated the Committee with the state of his research into the causes of autistic enterocolitis:

Dr Wakefield also gave details of "re-challenge" deterioration, where children had experienced a double-hit from MMR or measles-containing vaccine, with acquisition of autistic symptoms first time around and then worsening of these symptoms after a second, later, immunisation. The researchers had observed that some children receiving the second dose had deteriorated, and this decline was referred to as "biological gradient" (i.e. Downhill).

He also noted that in its review of April 2001, the Vaccine Safety Committee of the US Institute of Medicine had stated, in the context of MMR, that "challenge/re-challenge" would constitute strong evidence of an associated" (in other words, to degenerate once might be coincidence, but to worsen after a second vaccination was much stronger proof of an underlying causal association).

The researchers how now undertaken a systematic evaluation of the re-challenge and biological gradient effects in children with regressive autism. "Exposed" children with normal early development and regressive autism who had received more than one MMR/MR vaccination were compared with age- and sex-matched "unexposed" children who had normal early development, and also with children who had regressive autism but only one MMR (but otherwise similar baseline characteristics to the exposed group).

In a preliminary analysis, exposed children scored significantly higher than unexposed children for:

The preliminary study had also found that no measures of disease were worse in unexposed than exposed children. The data had identified a "re-challenge effect" on symptoms and a "biological gradient effect" on severity of intestinal inflammation.

Dr. Wakefield also stated that he had repeatedly requested a meeting with the UK Chief Medical Officer for England and Wales, Professor Liam Donaldson, to discuss this. The response had been a refusal to meet, and a demand for the children's samples. However, no scientific protocol had been offered indicating how these samples would be analysed. In any event, independent sample analysis was offered to the defendants' scientists as part of the forthcoming UK High Court cases.

116. Paper by Dr. Arthur Krigsman to US Committee on Government Reform Hearing, The Status of Research into Vaccine Safety and Autism, Washington DC, June 2002

Dr. Krigsman set out his findings from data drawn from his evaluation of gastro-intestinal symptoms of children with autism. He had observed that a large proportion of his autistic patients suffered from chronic unexplained gastrointestinal symptoms. His experience covered 43 consecutive children aged 2-10 years. Most had been referred by private practitioners, but others were self-referred. Some 42 patients had received a diagnosis of either autistic disorder or ASD, one was Aspergers.

Features were:

Dr. Krigsman's findings were as follows:

The lymphoid nodules of the terminal ileum were found to be markedly enlarged. This is in agreement with the previously published findings of Dr. Wakefield, in which a similar proportion of patients were found to have abnormal lymphonodular hyperplasia of the terminal ileum.

The second significant finding was the histologic evaluation of the biopsy specimens:

In regard to the last-mentioned group of patients listed earlier, the majority of these patients were found to have a heavy and diffuse lymphoid hyperplasia of the colon (macroscopic and microscopic), signifying an activation of the colon's internal immune system.

Krigsman's overall conclusion:

Krigsman posed four questions for further debate:

117. Unpublished Research by Dr Paul Shattock, University of Sunderland Autism Research Unit, June 2002

This research is continuing, but some details were released to the UK media at the end of June 2002. The basic details were:

Shattock commented that "In the group where parents stress that MMR caused the problem, we do not get abnormal levels of IAG and the researchers suspect that a different mechanism causes the autism. We believe it may be measles in the intestine which causes inflammation and permeability of the intestines. The numbers here are quite small, so any connection does not show up in epidemiological studies".

Shattock added that the latest reliable figures (for the UK) showed that 1 in every 150 children suffer from ASD. If his ARU's findings remained at the 10% mark, then 1 in every 1,500 MMR vaccinations will trigger autism.

118. Paper by Sheils, Smyth, Martin and O'Leary, Development of an Allelic-Discrimination Type Assay to Differentiate between the Strain Origins of Measles Virus Detected in Intestinal Tissue of Children with Ileocolonic Lymphonodular Hyperplasia and Concomitant Developmental Disorder, Department of Histopathology, Trinity College, Dublin, Ireland (full publication details not known)

The authors noted that in a recent study, their research group had described the presence of measles-virus RNA genes in a new form of inflammatory bowel disease with concomitant developmental disorder.

One of the many questions raised by that study was whether the measles virus detected was wild or vaccine type in origin.

The objective of this pilot study was to address this point. Several conserved amino acid coding changes have been identified in measles virus strains in the Edmonston Vaccine lineage, and it has been suggested that these represent a vaccine "strain signature".

One such site (nucleic acid position 7901, amino acid position 211) displays a consistent A-G mutation in Edmonston derived vaccines, compared with wild type strains. The site is reportedly located in the H gene region of the measles genome, and is associated with cellular CD46 interaction.

This single base mutation was used as the basis for the design of an allelic discrimination assay, using TaqMan MG8 probes (FAM labelled for wild type and VIC labelled for vaccine type). The assay was run on an ABI 7000 sequence detection system using total RNA extracted from intestinal biopsies amplified with TaqMan one-step PCR kit.

Synthetic oligonucleotides representing wild and vaccine strains were designed using published sequences from the NCBI database, and used as controls in the assay system.

The study found that:

119. Paper by Dr. Vijendra Singh, Utah State University, Journal of Biomedical Science, 2002; 9: 359-364

This was a further paper following the examination of blood samples from 125 autistic children and 92 controls. Singh's team had found an unusual MMR antibody in serum samples from 75 autistic children, but not in any of the normal controls.

The paper by Dr. Singh was attacked by Dr. Mary Ramsay, an epidemiologist at the UK Public Health Laboratory Service (and a colleague of Dr. Elizabeth Miller). Dr. Ramsay stated: We have problems with the methodology of the study. I find it a strange technique to use the vaccine as a combined antigen. The internationally-validated technique is to look at the vaccine as a combined antigen".

However, Dr. Singh's paper explained his reasoning for choosing this approach: "Antibodies to MMR will be a true measure of seroconversion for this triple or polyvalent vaccine, instead of antibodies to measles, mumps or rubella viral proteins that are individually used for measuring virus serology in routine practice".

Dr. Ramsay was reported to have later privately admitted that she had not actually read Dr. Singh's paper.

120. Paper, Gastrointestinal Microflora Studies in Late-Onset Autism, Finegold, Molotoris, Song et al, Infectious Diseases Section, Veterans Affairs Medical Center, West Los Angeles, California US, published Journal of Clinical Infectious Diseases, 2002, Sept. 1: 35 (Supl 1): S6-S16.

The authors noted that:

121, Paper, Innate Immunity Associated with Inflammatory Responses and Cytokine Production against Common Dietary Proteins in Patients with Autism Spectrum Disorder, by Jyonouchi, Sun and Itokuzu, Department of Paediatrics, University of Minnesota, Minneapolis, US (full publication details not known)

The objective of this study was to examine the proposition that children with ASD frequently reveal various gastrointestinal symptoms that may resolve with an elimination diet, along with apparent improvement of some of the behavioural problems. The evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses.

The study measured IFN-gamma, IL-5 and TNF-alpha production against representative dietary proteins (DPs) such as gliadin, cow's milk protein and soy by peripheral blood mononuclear cells (PBMCs) from ASD children and controls (those with dietary protein intolerance, ASD siblings and healthy unrelated children.

The study evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses.

The results of this study were:

122. Paper, Treatment of Late Onset Autism As A Consequence of Probable Autoimmune Processes Related to Chronic Bacterial Infection, E. B. Matarazzo, Dept. Of Psychiatry, School of Medicine, University of Sao Paulo, Brazil, November 2002

Two cases were described, of children who first developed normally but before the age of three developed autistic symptoms following the reactivation of a chronic oto-rhinolaryngologic infection. The clinical and laboratory data of the cases supported the aetiological hypothesis of an autoimmune process.

Adrenocorticotrophic hormone (ACTH) was prescribed in one case within the first months, and the child was cured.

The other patient was two years old when autism presented, but was only treated six years later, showed a partial but definite improvement with immunosuppressive treatment.

The study report proposed that re-activation of a chronic bacterial infection be included among the aetiologies of late-onset autism. It also demonstrated that, when the aetiological hypothesis of an autoimmune process based on clinical and laboratory data was considered, an immunosuppressive treatment could be effective and safe.

123. Unpublished letter by Dr. Wakefield to the New England Journal of Medicine, November 2002

In late 2002, in response to the Madsen et al (Denmark) study, Dr. Andrew Wakefield wrote to the New England Journal of Medicine. His letter included the following key points:

Wakefield asked, in his letter, if a synergistic adverse interaction between mercury and a live viral vaccine was biologically plausible. He commented that the immunosuppressive and immunomodulatory effects associated with mercury exposure were accompanied by increased susceptibility to challenge with infectious agents.

He noted that in previously-resistant animals, sub-toxic doses of mercury chloride had induced an autoimmune syndrome characterised by the expansion of TH2 cells, IL-4 production by splenocytes and IgG1 and IgE production. This had been accompanied by a non-healing phenotype with increased footpad swelling and parasite burden. Methyl mercury enhanced the immune damage and chronicity of coxsackie B3 myocarditis in mice, compared with mice infected without prior mercury exposure (the study he quoted was Ilback et al, Effects of Methyl Mercury on Cytokines, Inflammation and Virus Clearance in a Common Infection, Toxicology Letters, 1996 89: 19-28). And mercury was only one of several exposures to infants that might potentially influence the immune response to live viral vaccines.

124. Study by Croonenberghs, Wauters, Devreese, Verherk et al, In Autism - Increased Serum Albumin, Gamma Globulin, Immunoglobulin IgG and IgG2 and IgG4, University Center of Child & Adult Psychiatry and Department of Medical Biochemistry, University of Antwerp

This study noted that research on the biological pathophysiology of autism had found some evidence that immune alterations might play a role in the pathophysiology of the illness. The study team consequently expected to find that autism was accompanied by abnormalities in the pattern obtained in serum protein electrophoresis and in the serum immunoglobulin (Ig) and IgG subclass profile.

The team examined whether subjects with autism showed changes in total serum protein (TSP) and the serum concentrations of albumin, alphal globulin, alpha2 globulin, beta globulin and gamma globulins, IgA, IgM and IgG and the IgG subclasses IgG1, IgG2, IgG3 and IgG4, compared with normal controls.

The study found:

The study concluded that:

PART H

OTHER RELEVANT PAPERS

125. 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:

126. 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".

127. 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:

Study progress on molecular markers of neurotoxicity:

On animal models of CNS diseases following childhood virus infection:

128. 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.

129. 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:

130. Statement by Dr. Tom Jefferson, Head of Vaccine Division, Cochrane Collaboration, Oxford, UK, October 2002

The repeated assurances of the medical establishment that there was strong evidence against any MMR/autism link were undermined by a statement by Dr. Tom Jefferson in late 2002. Dr. Jefferson has been funded to investigate vaccine safety by the European Commission. He is also a Board Member of the European Programme for Improved Vaccine Safety Surveillance, which has been set up by the European Commission.

Press reports quoted Dr. Jefferson as stating:

He also offered the comment that Governments were "reluctant" to accept this, but that they owed it to future generations to back this idea. He was especially concerned because future vaccination programmes were likely to give children five, six or even seven vaccines all at once. He commented: "We have to think very carefully about how we will monitor these vaccines.......It is no use having a situation where someone suggests a possible harm and then everyone runs around frantically trying to find bits of evidence. What is required is good-quality information that has been systematically collated and assessed."

PART K

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:

131. 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, 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).

132. 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, 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:

The study is funded by the Wellcome Trust (£461724).

133. 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 was originally 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:

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).

134. 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:

135. Study, Role of Maternal Immunity in Susceptibility to Measles Virus Infection and Disease, Glenn F. Rall, Fox Chase Cancer Center, US

The proposer of this study noted in early 2002 that it was increasingly apparent that the development of a child's immune response was strongly influenced by maternal immunity, both during gestation and postnatally through the transfer of antibodies in breast milk. Thus, if vaccines were involved in the etiology of autism, the possibility that altered immunity might contribute to increased risk seemed tenable. The study proposed:

136. Studies Commissioned by the US Center for Disease Control

At the hearing in June 2002 by the US House of Representatives Committee on Government Reform (see elsewhere in the document), Dr. Roger Bernier, Associate Director for Science, National Immunization Program, CDC, outlined five studies planned or underway to investigate the causes of autism:

The CDC also discussed studies to look at possible links with thimerosal - this is dealt with in the next section.

137. Study by the UK National Institute for Biological Standards and Control (NIBSC)

This is a £300,000 study funded by the UK Department of Health. Work commenced in September 2002. Virologists at NIBSC will work in collaboration with the Paediatric Gastroenterology Department at the Royal free Hospital, London (the department where Dr. Andrew Wakefield formerly worked). The hospital retains samples of bowel tissue from the autistic children used in the original 1998 Wakefield et al study.

In addition to these samples of bowel tissue, the study will also use other samples. The study is being led by Dr. Muhammed Afzal, principal scientist at NIBSC, and Dr. Phil Minor. Dr. Minor also criticised the study by Dr. Vijendra Singh (reported elsewhere in this note) as "fundamentally flawed".

On 23rd August 2002, the London Evening Standard newspaper reported that Dr. Minor was also being paid by Glaxo SmithKline, manufacturers of MMR, to act as an expert witness in the impending UK High Court MMR/autism cases. GSK is one of three UK companies that are the subject of this litigation, the other two being Aventis Pasteur MSD and Merck & Co. Campaigners described Dr. Minor's dual role as "disgraceful". The Conservative Member of Parliament, Julie Kirkbride MP, who had unsuccessfully attempted to sponsor a private Parliamentary Bill to allow single-antigen vaccines, commented "This news will hardly inspire public confidence".

The London Evening Standard report also confirmed that Dr. Minor had also sat on the 2001 Medical Research Council review into the MMR/autism issue (reported elsewhere in this Briefing Note). In documents seen by the Evening Standard, covering declaring interests as part of the MRC Review, Dr. Minor had stated that he had no commercial or academic interests to declare, but that he was "an expert adviser on molecular virology in MMR/autism cases".

Dr. Minor had previously authored a paper in the "Mill Hill Essays" series, in 1998, published by the National Institute for Medical Research. This review paper concluded: "There is no evidence currently available that stands up to examination that measles virus is present in tissue from Crohn's Disease.........Autism occurred before MMR vaccine was introduced, and it would be surprising if it did not occur after. To find out........needs a large carefully-designed study, but.........there is no scientific reason to believe that there is a connection based on the knowledge that is available now..........At the moment, the scientific consensus is that there is nothing in it."

138. Study by the University of California at Davis into Environmental Factors

This study was ready to be launched at the start of 2003. The study will be the first-ever major epidemiological case-control study of US autism, and will:

The study is one of three projects within the University of California at Davis Center for Children's Environmental Health and Disease Prevention. The Center was created in autumn 2001 with grants from the National Institute of Environmental Health Sciences, the US Environmental Protection Agency, and the MIND Institute at UC Davis.

Researchers will review regional-center records for children with autism and children with mental retardation or developmental delay. Families will complete questionnaires and their children will give specimens, and the research team will examine exposure to toxins, diet, genetic background, chemical and cellular markers from tissue samples and other information relating to both before-birth and after-birth periods.

139. Other UK Studies Funded By the Medical Research Council, London

A number of studies into autism are currently funded by the UK Medical Research Council. It is instructive to note that not one of these involves the clinical examination of children affected by autism following vaccination, nor explores the alleged MMR/autism link in any way, nor examines the potential role of viral infections.

Current (as at July 2002) studies are:

140. Study by Autism Center, University of Medicine & Dentistry, New Jersey, US

This is a study researching the physical symptoms common to many autistic children, including allergy, asthma, eczema, epilepsy, sleep problems and gastrointestinal disorders. Total value $1.5m. No further details are available.

141. Study by Center for Disease Control, New Jersey, US

This CDC study is assessing autism prevalence in New Jersey, and will seek to identify every autistic child born between 1992 and 1998 in four counties, Ocean, Essex, Union and Hudson. Total value $1m. No other details are available.

142. Study by Robert Wood Johnson Medical School, New Brunswick, US

This study is being undertaken at the Center for Neurotoxicology and Exposure Assessment at the Robert Wood Johnson Medical School. Researchers are examining neurological toxins amongst autistic children aged 24 months to 36 months. No further details available.

143. Survey by New Jersey Answers for Autism

This is a study seeking information from all families in the area with autism, to identify patterns common to child developmental backgrounds including immunisation, medication during pregnancy, viruses and toxins. No other information is to hand, but the value of the study is $160,000.

PART L

THE THIOMERSAL ISSUE

144. Thiomersal's Possible Role

An obvious feature of the current litigation situation regarding autism and vaccination is that the UK cases are proceeding on the basis of autism following MMR (or MR) vaccination, whereas the US cases are over the link between autism and thiomersal.

However, the two suspected causes are not mutually exclusive. It has never been suggested that MMR causes all autism, and the two factors may in any case be working in concert.

145. 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:

Key action agreed was:

146. UK Vaccines With Thiomersal

Vaccines in the UK that are believed to still contain, or until recently contained, thiomersal are:

In January 2003, a detailed report in The Scotsman newspaper listed four influenza vaccines in use in the UK (out of a total of seven) that still used thiomersal:

The UK Department of Health was quoted in the report, "There is no evidence of long-term adverse effects due to the exposure levels of thiomersal in vaccines".

It is also 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?

147. 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:

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:

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.

There was an interesting postscript to the Simpsonwood review above. In a letter to the US National Law Journal, following earlier coverage in its issue of 20th March 2002 of this subject, Mike Weathersby, a lawyer involved in the US thiomersal lawsuits, pointed out that:

148. 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:

In July 2002, the Indianapolis Star newspaper quoted the lawyers Waters and Kraus as saying that "Lilly flim-flammed scientists for years with a 1931 study that concluded thiomersal wasn't harmful to humans". The Star went on: "The study, published in the American Journal of Hygiene, reported that merthiolate has a very low order of toxicity......for man".

Digging further, Waters found out that the study's toxicity data came from experimental use of thiomersal by doctors from Lilly and Indianapolis City Hospital on meningitis patients during a severe outbreak in 1929-30. 'The 1931 study on a cohort of severely ill people (who all died) ended up being quoted in Lilly brochures into the 1980s', Waters said. 'It very clearly demonstrates an effort to do an unethical study and then paint the results in a certain way that helps them sell this product'. Lilly ignored or covered up later evidence that thiomersal, which contains 50 per cent mercury by weight, can be dangerous to humans", Waters said.

The detailed sequence uncovered by Waters (the wording is taken directly from their press release) is as follows:

149. UK Medicines Control Agency Position On Thiomersal

150. US Center for Disease Control Thiomersal Studies

At the hearing of the US House of Representatives Committee on Government Reform in June 2002 (see elsewhere for further details), several studies on the thiomersal issue were outlined by the US CDC representative, Dr. Roger Bernier:

(study one) This is the thiomersal Screening Analysis in the US Vaccine Safety Datalink (VSD) Project, which commenced Autumn 1999. Data from two health management organisations (HMOs) with automated outpatient data is screened. The CDC and VSD researchers found statistically significant associations between thiomersal and neurodevelopmental disorders such as language and speech delays, attention deficit hyperactivity disorder, stuttering and tics. No association was found with autism. The associations were weak and varied between HMOs. A third HMO has since been examined. This did not confirm the results of the first study phase. These results require further examination.

(study two) This is the Thiomersal Follow-Up Study. This will be designed to assess whether preliminary results from automated data used in study one can be confirmed using objective neuropsychological testing. The study will focus on the same developmental disorders as study one. Results are expected by the end of 2003.

Three other studies are planned, with results not available until 2005 or later.

The US CDC has been heavily criticised by parents' groups over its stance on access to the Vaccine Safety Datalink (VSD) database. The US group Safe Minds openly challenged the CDC to open VSD data to all qualified university-based researchers, but the CDC refused. The current position is that:

151. Study, Mercury Concentrations and Metabolism in Infants Receiving Vaccines Containing Thiomersal - A Descriptive Study, by Pichichero, Cernichiari, Lopreiato and Treanor, University of Rochester Medical Center, US, published in The Lancet, November 30th 2002.

Review by Helen Tucker
 Review by Sallie Bernard at Safeminds.org
 Review by Sandy Mintz at Vaccinationnews.com

This was a study published in The Lancet, conducted by Michael Pichichero and colleagues. Its appearance was hailed with relief by the medical community as "proof" that there was not a potential thiomersal role in the vaccine/autism debate, and that thiomersal-containing vaccines were safe.

Dr. Pichichero was interviewed by Dr. Laurie Barclay for Medscape. He summarised his study as follows:

The study was critically reviewed by Sally Bernard of the US parents' group Safe Minds. Bernard's comments were as follows:

In concluding, Sally Bernard also makes a number of other profound criticisms of this study:

Her conclusion is that the Pichichero study does not offer the reassurance on thiomersal safety that is so widely claimed of it by the medical establishment. It is a small-scale descriptive study with many methodological limitations. It has little or no vale regarding thiomersal safety.

PART M

FLAWED REGULATION AND MONITORING

152. 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:

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.

The problem should be seen in the wider context of lack of comprehensive monitoring of adverse outcomes from medical care in the UK National Health Service. In June 2002, it was reported that the newly-created National Patient Safety Agency had received 27,000 confidential reports from staff concerning minor or major incidents of medical error in a pilot study of 28 health trusts. However, the data system was so poor that no fewer than 62% of incidents could not be classified. Some 2% of errors were described as "catastrophic". It is not known whether any involved MMR or other vaccines, or degeneration into autism.

153. 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).

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.

154. UK Department of Health Re-Launch of MMR, 22nd January 2001

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:

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.

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:

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.

PART N

UK AND US POLITICAL INITIATIVES

155. House of Commons Health Committee, Westminster

The thiomersal issue does not appear to have been formally considered by the Select Committee. The possible link with autism had not surfaced publicly at the time of my evidence to the Committee.

156. UK All Party Parliamentary Group On Autism (APPGA), Westminster

157. Scottish Parliament, Edinburgh

158. UK Liberal Democrats

159. UK Conservatives

160. US House of Representatives Committee on Government Reform

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)

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".

In a hearing on 19th June 2002. In his opening address, Rep. Dan Burton stated:

Some of the evidence to this hearing has been outlined earlier in this document.

Further hearings by the Government Reform Committee are planned. Other relevant points are:

On 30th December 2002, Rep. Dan Burton wrote to the Indianapolis Star, setting out some key points in response to an editorial in the newspaper on 11th December. Samples of Burton's key arguments included:

Some of the evidence submitted to the Committee has been summarised in earlier sections. Evidence can also be read on the Committee on Government Reform's website.

PART P

SOME BROAD CONCLUSIONS AND QUESTIONS

161. Some Broad Conclusions

The above puts "under one roof" a considerable amount of information on the MMR/autism and the thiomersal/autism issues (which are likely to prove to be interlinked), though it cannot possibly be an exhaustive coverage, given the many issue involved and the ongoing scientific debate. However, it demonstrates that:

162. Some Unanswered Questions

Some outstanding questions, which the media may find useful to bear in mind, are offered here...

David Thrower, UK tel. 01925-264156, non-UK 44 1925 264156

email david@throwerwarrington.freeserve.co.uk  

Overland postal address 49, Ackers Road, Warrington, Cheshire, WA4 2DZ, England

10th January 2003