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Letter
to NEJM from Dr Andrew J Wakefield MB.,BS FRCS FRCPath
Sir,
Population-based studies (1), in contrast with molecular and immunological
studies (2-6), have not found an association between MMR vaccination
and autism. As pointed out by Madsen et al (NEJM
2002;347:1478-1482 (1)) and endorsed by others (7), epidemiological
studies that have examined this relationship have been inadequate.
Have Madsen et al fared better?
I have no doubt
that other correspondents will deal with a principal limitation
of their study, that is, the failure to disaggregate the relevant
autism subset - one which they attempt to describe in the introduction
to their paper - from the overall autism population. This is equivalent
to looking at the totality of hepatitis, irrespective of aetiology,
in a study designed to examine a possible causal relationship with
a single, specific exposure that may account for a minority hepatitis
subtype only.
My purpose is
to try and help clarify the hypothesis of my group, and to dissociate
this from the many proxy hypotheses generously, if erroneously tested
in our name. Our studies have been concerned with examining the
aetiology and pathogenesis of autism in a subset of children who
became encephalopathic after a period of normal development and
suffer an immune-mediated gastrointestinal pathology (2-4,8-14).
Within the relevant subset of children we have observed frequent
atopy (especially food allergy), antibiotic use, ear infection,
multiple concurrent vaccine exposure and a strong family history
of atopic and autoimmune disease, as reported by others (15). Consistent
with these clinical observations, there appears to be, in many affected
children, a TH2 mucosal and systemic immune bias; this is evident
in lymphocyte cytokine profiles (14,16), eosinophil infiltration
of the intestinal mucosa, and up-regulation of class II antigen
within the intestinal lamina propria that is not seen on the adjacent
epithelium (8-10). Dysregulated mucosal immunity in affected children
is accompanied by an excess of TNFa-positive lymphocytes, to an
extent that distinguishes the autistic lesional mucosa from both
inflammatory and non-inflammatory paediatric controls (14) that
is consistent with the findings of others (17). There is a profound
expansion of CD19+ lymphocytes in the lamina propria, mirroring
the associated hyperplastic lymphoid response that, at the macroscopic
level, is particularly evident in the ileum and colon (13). In controlled,
systematic studies intestinal lymphoid hyperplasia of the degree
seen in affected children is clearly not, as anecdotal impression
would have it, a normal variant (9,18). While the TH1-TH2 model
is an oversimplification, its serves as a useful template for our
working model.
Early on in
the current debate, in a paper that sought to articulate the hypothetical
relationship between MMR and regressive autism, we wrote, "At
the level of the immune response, the newborn
tends towards a TH2 response to pathogens and gradually shifts towards
a TH1 response with age. If this transition does not take place
appropriately, the infant is likely to be at greater risk of mounting
aberrant immune responses in later life, as seen in patients with
allergies. Given that, under normal circumstances the age of this
transition will be different for different children, it seems inevitable
that a ubiquitous viral exposure [MMR] of all 15-month-old children
could induce an immune response that is consistent with the individual
dynamics of this TH2-TH1 transition." (19).
A precursor to an adverse reaction to MMR may be a congential or
acquired aberrant TH2 immune programming. This would increase the
likelihood of an inadequate antiviral immune response in
the face of a live viral vaccine and may facilitate viral persistence
and immunopathology, as described for measles virus in affected
children (2,4).
The key to defining
the "child at risk", therefore, is an examination of the
co-factors that may interfere with the appropriate TH2-TH1 transition
prior to, or concomitant with, MMR exposure. One such
factor may be mercury, for which the immuno-toxicity (putting aside
for now the associated neurotoxicity) of organic and inorganic derivatives
is qualitatively similar. Is a synergistic adverse interaction between
mercury and a live viral vaccine biologically plausible? The immunosuppressive
and immunomodulatory effects associated with mercury exposure are
accompanied by increased susceptibility to challenge with infectious
agents. One of the best-characterised examples of T-helper
cell phenotypic polarity in response to infection is the murine
model of Leishmania major. Murine susceptibility to L. major infection
is dependent upon induction of a genetically restricted TH2 response.
Resistant animals, that exhibit a genetically restricted TH1 response
to L.major, are rendered susceptible by prior exposure to mercury
(20). In previously resistant animals, sub-toxic doses of mercuric
chloride induced an autoimmune syndrome characterised by the expansion
of TH2
cells, IL-4 production by splenocytes and IgG1 and IgE production.
This was 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 (21). Similarly,
mercuric chloride exposure significantly impaired macrophage-mediated
resistance to generalised infection with herpes simplex type-2 in
a murine model (22).
Mercury is only
one of several exposures to infants that may potentially influence
the immune response to live viral vaccines. In testing the correct
hypothesis at the population level, these factors
will need to be taken into account and appropriate adjustments made.
It may be, for example, that the rapidly changing pattern of infant
mercury exposure - as thimerosal in bacterial and subunit vaccines
- will with the necessary adjustments, reduce statistical power
to the extent that such studies fail to offer any convincing evidence
either way. It is my personal opinion that the answer will be found
in the detailed analysis of each individual child - from clinical
history to molecular idiosyncrasy.
The foundations
of our hypothesis have not shifted. Failure to take it into account
has served merely to polarise the debate, confuse the consumer,
and allow the polemic of Public Health to soar a little closer to
the sun.
References
1. Madsen MK., Hviid A., Vestergaard M., Schendel D., Wohlfarht
J.,
Thorsen P., Olsen J., Melbeye M. A population-based study of measles
mumps rubella vaccination and autism. NEJM 2002;347:1478-1482
2. Uhlmann V., Martin CM., Shiels O., Pilkington L., Silva I.,
Lillalea A. Murch SH., Wakefield AJ., O'Leary JJ. Potential viral
pathogenic mechanism for new variant inflammatory bowel disease.
Molecular Pathology. 2002;55:1-6
3. Wakefield AJ. Enterocolitis, autism and measles virus. Molecular
Psychiatry. 2002;7 Suppl 2:S44-46
4. Shiels O., Smyth P., Martin C., O'Leary JJ. Development of an
allelic discrimination type assay to differentiate between strain
origins of measles virus detected in intestinal tissue of children
with
ileocolonic lymphonodular hyperplasia and concomitant developmental
disorder. Journal of Pathology. 2002 .A20
5. Singh V., Lin S., Yang V. Serological association of measles
virus and human herpesvirus-6 with brain autoantibodies in autism.
Clinical Immunology and Immunopathology. 1998:89;105-108
6. Singh VK, Lin SX., Newell E., Nelson C. Abnormal
measles-mumps-rubella antibodies and CNS autoimmunity in children
with
autism. J Biomed. Sci. 2002;9:359-364
7. Spitzer WO., Aitken KJ., Dell'Aniello S., Davis MW The natural
history of autistic syndrome in British children exposed to MMR.
Adverse
Drug reactions and Toxicol. Rev. 2001:20;160-163
8. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik
M, et al. Ileal LNH, non-specific colitis and pervasive developmental
disorder in children. Lancet 1997; 351: 637-641
9. Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM,
Davies S, et al. Enterocolitis in children with developmental disorder.
American Journal of Gastroenterology 2000; 95:2285-2295
10. Furlano RI, Anthony A, Day R, Brown A, McGavery L, Thomson MA,
et al. Colonic CD8 and ?d T cell infiltration with epithelial damage
in
children with autism. Journal of Pediatrics 2001;138:366-372
11. Torrente F, Machado N, Ashwood P, et al. Enteropathy with T
cell
infiltration and epithelial IgG deposition in autism. Molecular
Psychiatry 2002;7:375-382
12. Wakefield AJ, Puleston J., Montgomery SM., Anthony A., O'Leary
JJ., Murch SH. Review article: the concept of entero-colonic
encephalopathy, autism and opioid receptor ligands. Alimentary
Pharmacology and Therapeutics 2002; 16: 663-674
13. Ashwood P., Murch SH., Anthony A., Pellicer AA., Torrente F.,
Thomson M., Walker-Smith JA., Wakefield AJ. Intestinal lymphocyte
populations in children with regressive autistic spectrum disorder
and
entero-colitis. Gastroenterology 2002;122: Suppl. A1004
14. Ashwood P., Walker-Smith J., Murch S., Wakefield A.
Pro-inflammatory cytokine production in the duodenal and colonic
mucosa
of children with autistic spectrum disorder (ASD) and a novel
entero-colitis; Gastroenterology 2002;122: Suppl. A617
15. Comi AM, Zimmerman AW., Frye VH., Law PA., Peeden JH. Familial
clustering of autoimmune disorders and evaluation of medical risks
in
autism. J. Child Neurol 1999; 14;388-394
16. Gupta S., Aggarwal S., Rashanravan B., Lee T. Th1- and Th2-like
cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol 1998;
85:106-109
17. Jyonouchi H., Sun S., Le H. Pro-inflammatory and regulatory
cytokine production associated with innate and adaptive immune responses
in children with autism spectrum disorders and developmental regression.
18. Kokkonen J., Ruuska T., Kartunen TJ., Maki M. Lymphonodular
hyperplasia of the terminal ileum associated with colitis shows
an
increased gd+ T-cell density in children. Am J Gastroenterol.
2002;97:667-672
19. Wakefield AJ.and Montgomery SM. Autism, viral infection,
measles-mumps-rubella vaccination. Israeli Med Assn J. 1999;1:183-187
20. Bagenstose LM., Mentink-Kane MM., Britingham A., Mosser DM.,
Monestier M. Mercury enhances susceptibility to murine Leishaniasis.
Parastite Immunology 2001;23:633-640
21. Ilback NG., Wesslen L., Fohlman Friman G. Effects of methyl
mercury on cytokines, inflammation and virus clearance in a common
infection (Coxsackie B3 myocarditis) Toxicol. Lett. 1996;89:19-28
22. Christensen MM., Ellermann-Eriksen S., Rungby J., Mogensen SC.
Influence of mercuric chloride on resistance to generalized infection
with herpes simplex virus type 2 in mice. Toxicology 1996;114:57-66
W. John Martin, M.D., Ph.D. testimony about the Polio Vaccine.
This issue really came back into focus, my focus, when we were looking
for viral causes of what appears to be an ever increasing prevalence
of neuropsychiatric, neurobiological dysfunctional brain syndromes,
and so forth. Over the last several years, I have sought evidence
of viral infections in patients both in terms of patients with the
chronic fatigue syndrome, autism, neurobiological disorders, comas
of unknown origin, and so forth, major psychiatric illness. The
one virus which we were able to isolate and characterize is unmistakably
African green monkey cytomegalovirus.
I had notified centers for disease control by way of a manuscript
and a request to transfer some of this information when I first
had it, which was back in 1994, without any real success, but when
the data was unequivocal, which was in 1995, we contacted the Bureau.
At that stage, we were really just trying to get some reassurance
that they no longer used monkey kidneys to make polio vaccines and
were told that unfortunately they still did...
I was given
some reassurance in March 1995, that something would happen, a lot
of correspondence back and forth... I was advised in June that I
should come to a meeting on cell substrate safety that was being
sponsored by the FDA and the pharmaceutical industry... I presented
our concerns with this use of African green monkey vaccines. Questions
were raised as to whether it would be a problem with live vaccine
or killed vaccine. I said it's probably more likely a problem with
live vaccines. I gave them a proposal that said that it would be
prudent to test the monkeys used in vaccine production for cytomegalovirus,
particularly the derivatives of cytomegaloviruses. It would be worthwhile
to test current vaccine lots as well as past vaccine lots and it
would be important to do a prevalent study to see how many people
may be infected with simian African green monkey cytomegalovirus,
a fairly straightforward proposal... The issue was straightforward,
that people know that there are cytomegaloviruses in the monkeys.
People are not testing for them, and people should be testing for
them...
The formal response
came back from FDA in January 1996, which was essentially: thank
you.. our budgets are tight... we can't afford any outside money...
Indirectly, what that was saying to me was that they're under great
constraints to deal with anything that might be considered a proprietary
interest of the vaccine manufacturers."
He also submitted
a proposal to the CDC and the Advisory Committee on Immunization
Practices that advises CDC, with similar results.
"What I've
tried to picture is that, if one had the choice, again, of making
a vaccine, one would be unwise to go to Africa, to take monkeys
straight out of Africa, take out their kidneys, grow their kidneys
for two weeks, add another virus that could allow for a combination
type event, and 48 hours later, take it, a crude gamish mixture,
and give it to every child in the country... You could say, that
there is enough experience that that's being safe and not a hazard.
The problem with that is that people are in full agreement that
there has never been any instrument in place to look for longterm
complications of vaccines. There are instruments to look for acute
ill effects. In 24 hours, 48 hours, within the first week, people
have that instrument, and they can quantify that, but the prospect
of having an insidious disease of delayed onset, which would overlap
and mesh with existing diagnoses that could be viral induced and
could account for illnesses, has not been in place. People are very
reluctant to put that in place now because of obvious political
as well as financial implications...
Vaccine Safety
Dr. John Martin
One of society's highest obligations is the protection of its children.
Vaccine programs provide a proven method for childhood disease prevention.
The safety of such programs has been entrusted to vaccine manufacturers
and to government. regulatory agencies. Although widely touted as
the major medical triumph of the 20th century, the development of
viral vaccines has elements of less than stellar performance. The
discovery in 1960 of live SV-40 virus contamination in formalin-treated
poliovirus vaccine, produced in kidney cells cultures from rhesus
monkeys, did not lead to an immediate recall of the contaminated
vaccines. Rather the production method was switched to the use of
kidney cells from the much less well characterized African green
monkeys. This switch in monkey species was soon followed by the
decision to forgo formalin inactivation by using a weakened (attenuated)
live strain of poliovirus. Persisting concerns regarding contaminating
viruses in the live poliovaccine led in 1972 to a joint study between
the vaccine manufacturer and the United States Food and Drug Administration
(FDA). Kidney cultures from all 12 monkeys tested grew African green
monkey simian cytomegalovirus (SCMV). Only 4 of the SCMV isolates
were detectable using the regular methods for virus detection. No
changes in testing methodology were imposed, nor was the scientific
community alerted to the findings. An excuse that was subsequently
offered was that all such information about the study was deemed
to be proprietary. The results of this earlier study were, however,
not conveyed to me in 1977 when, as an FDA scientist, I notified
the Director of the FDA's Bureau of Biologics that certain poliovaccine
lots contained unexplained non-cellular DNA; and were therefore
potentially viral contaminated.
The issue of SCMV contamination of poliovirus vaccines was again
raised with the FDA in May 1995. I was then working as a virologist
at the University of Southern California. I had developed tissue
culture methods which indicated the presence of atypical viruses
in patients with complex neurological diseases. The viruses were
striking in that they failed to evoke an inflammatory reaction in
the patients from whom they were isolated. They were termed stealth
viruses on this basis and seemingly they lacked target antigens
for recognition by the body's cellular immune system. Sequencing
studies on a stealth virus indicated it had originated from SCMV.
Several meetings with FDA and Center for Disease Control and Prevention
(CDC) officials clearly pointed to their unwillingness to allow
any outside review of vaccine safety procedures. For example, a
simple request to review histological slides of neurological tissue
of monkeys inoculated with poliovaccine was refused, again on the
basis that it was proprietary information. Noteworthy was the admission
that the vaccines were routinely tested in rhesus monkeys because
African green monkeys commonly show evidence of neurological disease.
Moreover, even in rhesus monkeys, the vaccine was said to induce
considerable damage, although less than that induced by non-attenuated
poliovirus.
The actual sequence data were published in a respected virology
journal in July 1995. The article aroused the interest of anti-vaccine
consumer groups. Through the efforts of one of these groups, I was
invited to attend a vaccine safety meeting of the Institute of Medicine,
National Academy of Sciences. The open meeting held on November
6, 1995 was followed the next day by an "executive session."
I was informed that several individuals at this meeting were "furious"
that I was allowed to speak. A very much watered down account of
what I said subsequently appeared in the official report of the
meeting.
Some insight into the lack luster nature of the existing system
was provided by several brief interchanges with Government and other
officials during the last several years. For example, I was asked
whether formalin treatment would inactivate stealth viruses. My
response was that I did not know. The chairman of the National Immunization
Advisory Committee suggested his advocacy of a split protocol in
which both formalin inactivated and live attenuated poliovaccine
would provide the necessary time window for the manufacturer of
the inactivated vaccine to develop the stocks required for a complete
switch. True to his suggestion, the official switch to inactivated
vaccine is scheduled for January 2000. Of course, those "in
the know" would have already switched to the inactivated vaccine.
An FDA reform bill was being considered by Congress in 1997. I suggested
that the bill include the provision that "If a safety issue
is identified in the regulation of a biological product, then Industry
will waive its proprietary protection so that the information could
be made available to the scientific community." The suggestion
was well received by the counsel for the House Commerce Committee.
It was soon dropped, however, when support was not forthcoming from
Industry, FDA or the American Medical Association (AMA). In speaking
with an AMA lobbyist, I understood they "would not want the
public to know that their doctors were not in the knowledge loop."
I once asked industry personnel involved in poliovaccine production
whether they were still encountering SCMV in poliovaccine production
lots. After some hesitation that disappeared as we all identified
ourselves as parents, the straightforward answer was "not infrequently."
Armed with this information I again requested of an FDA official
to please use modern techniques such as the polymerase chain reaction
(PCR) to screen poliovaccine lots for SCMV. "We would not know
what to do with a positive result" was his answer.
Continued sequencing of the prototype SCMV-derived stealth virus
have helped substantiate the original suggestion that stealth adapted
viruses simply lack the critical target antigens for cellular immune
recognition. More impressively, the virus has the capacity to assimilate
genes from infected cells and from bacteria. The cellular genes
identified within the stealth virus include a gene with potential
oncogenic (cancer causing) activity. The bacterial genes serve a
wide range of metabolic functions that could enhance bacterial growth.
Human and animal viruses with bacterial sequences represent a novel
life form that has been christened viteria. The recombination of
viral, bacterial and cellular genes within broadly infectious viteria
is clearly of major medical and Public Health significance. For
instance, it could provide a viral explanation for positive findings
in clinical assays designed to detect various bacteria including
the Borrelia burgdorferi (the agent for Lyme disease), mycoplasma,
and chlamydia. FDA and CDC were informed of the publication of the
results. It was disheartening, yet challenging, that neither organization
responded. NIH was also notified but merely acknowledged that research
is supportable by grants.
During the last decade, I have written several clinical articles
describing stealth virus infected patients with complex illnesses.
The patients have included children with autism, adults with psychotic
disease and several individuals with chronic fatigue/fibromyalgia
syndrome. An additional recent publication described a stealth virus
infected child whose illness began in 1997 as a behavioral problem.
It took over seven months before the illness was attributed to brain
damage, as confirmed by magnetic resonance imaging (MRI). Even then
the neurologist was unable to detect impaired motor or sensory functions.
A brain biopsy performed shortly after the essentially normal clinical
examination showed marked vacuolating/spongiform change. The child's
clinical condition progressively deteriorated. He was examined at
several major medical centers where it was wrongly concluded that
he had a genetic disease from which he would soon die. He was shown
to be stealth virus infected by tissue culture and significantly
improved with anti-viral therapy, although he still has major residual
deficits.
Where is the Public Health concern that a childhood viral infection
was not recognized at major medical centers. Where is the interest
in the many other children who have tested positive for stealth
viruses. Why the lack of discussion about possible brain damage
causing national tragedies such as school shootings, and the increasing
prevalence of autism, attention deficit, asthma and sudden infant
death syndrome. Are stealth virus infected patients populating our
psychiatric institutions, allergy clinics and even our cancer wards.
The world and, in particular, its children appear to be at risk
for stealth adapted viruses. The contribution of vaccines to the
formation and dissemination of these viruses should be an open topic
for scientific discussion. This is not occurring with those presently
in charge of overseeing the safety of the Nation's immunization
program.
W. John Martin, M.D., Ph.D.
Center for Complex Infectious Diseases
Rosemead CA 91770
More
on vaccines:
Aseptic meningitis as a complication
of mumps vaccination
Hepatitis A
Hepatitis
B
Infant Rotovirus
The Meningococcal Vaccine - Public Policy and Individual Choices
Pneumococcal
disease and vaccine
Whooping Cough or Pertussis
Adverse
effects of adjuvants in vaccines
First International Public Conference on Vaccination
Letter
to NEJM from Dr Andrew J Wakefield MB.,BS FRCS
Quotes: Medical Doctors Speak out on Vaccinations
Study Attempts Cover Up of Autism-Mercury
Link
CDC Plans For Mass Vaccination Of All
Children With AIDS Vaccine
Top Ten Vaccine Information Sources Recommended
by the National
Workshop on simian virus-40
Vaccines fueling autism epidemic?
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