Measles, Mumps, Rubella Vaccine: Through a Glass, Darkly.
January 23, 2001
(Adverse Drug Reactions 2000,19(4) 1-19. Authors: Andrew J Wakefield FRCS, Scott M Montgomery PhD.)
Confidence in vaccine safety is essential for the success of vaccination programmes.
There is growing parental and professional concern about the safety of the trivalent MMR vaccine.
Suspected long-term adverse events from MMR include some forms of regressive autism and inflammatory bowel disease (Crohn's disease and ulcerative colitis).
Some doctors and scientists suspect that the combination of the three live viruses in one vaccine increases the risk of these adverse events. In 1999 we reported data - endorsed by the Medical Research Council, peer reviewed and published - showing that concurrent exposure to natural (or vaccine) measles and natural mumps infections is a significant risk factor for inflammatory bowel disease.
Vaccine manufacturers and departments of public health unanimously assert the safety of the trivalent measles, mumps and rubella vaccine, citing extensive safety testing. Moreover, the public is assured that there is nothing in the safety studies to provide a basis for any anxiety over possible delayed adverse effects.
This important new article examines the safety trials of MMR and finds no grounds for complacency. Instead the adverse autistic and gastrointestinal side-effects now asserted by tens of thousands of parents in the US, UK and elsewhere are foreshadowed in the results of medical research and of the safety trials even before the vaccine was introduced.
* Pre-licensing trials of MMR revealed gastrointestinal events that persisted to the end of the trial period in significant numbers of children from developed countries. Despite this, the follow up period for subsequent trials was reduced from 28 days to 21 days.
Furthermore, in subsequent trials the data from contrasting populations (developed and developing countries) was aggregated, masking the potential significance of gastrointestinal side effects in children from developed countries.
* The decision to combine the three vaccines in one (undoubtedly atypical) exposure was taken without specific consideration of the known associations between concurrent exposures to common childhood infections and later consequences. By 1979, atypical patterns of exposure to measles, mumps, rubella and chickenpox were identified as possible risks for autism.
* In addition to the above, the very first pilot studies of MMR revealed that the component viruses of MMR could interfere with one another.
Despite evidence of potential dose and strain-dependent interactions affecting immune responses to the vaccine viruses and therefore possible adverse events, the question was never investigated further.
* The import of the article is enhanced by the publication of the comments of four reviewers. Taken as a body, the reviews are highly supportive of this new paper. Two reviewers, in particular, concur that, on the evidence presented by Wakefield and Montgomery, the safety trials of MMR were at best weak and at worst inadequate.
Clearly in the context of MMR one plus one plus one never did equal three.
In summary, the authors suggest that until such time as the question of MMR safety is resolved, the public must, at the very least, be offered a choice.
As the last Minister for Health, the Hon Frank Dobson said, in another medical context, "If there is even a hypothetical risk (of harm) and a safer alternative exists, we should use it".
In the current circumstances, given the significant index of suspicion that now exists in relation to the safety of MMR, regressive autism and inflammatory bowel disease (Crohn's disease and ulcerative colitis), then it is surely right to allow parents to use the monovalent vaccines where they are, rightly or wrongly, concerned.
Perhaps the strongest endorsement of the value of this paper comes from one of the reviewers, Dr A Peter Fletcher, MB BS PhD, a former Principal Medical Officer in the Medicines Division, now MCA, of the Department of Health who served as Medical Assessor to the Committee on Safety of Medicines.
"With all the benefits of hindsight, what may now be said about the decision to grant a Product Licence (as they were then called) to MMR 10 or so years ago? Evidence on quality and efficacy was probably adequate so a decision had to be made on grounds of safety.
Being extremely generous, evidence on safety was very thin. Being realistic there were too few patients followed up for insufficient time. Three weeks is not enough, even for RCT's, neither is 4 weeks. By 1988-89 we knew from experience with pertussis vaccination that longer duration was essential- how much longer it is difficult to say but as long as humanly possible.
We also knew that numbers, big numbers were equally necessary. Additionally we knew that observational cohort studies could be conducted on 10,000 or more patients for up to 18 months. Primary care computerised databases (GPRD for example) were already up and running which would permit prospective record surveillance on several million patients. There was insufficient information on the immunological effects of a trivalent vaccine compared to monovalent vaccines.
Was there detectable immunosuppression with trivalent vaccine versus monovalent? From known clinical experience with measles mumps and rubella infections we could make an estimate of the incidence of serious disease outcomes which would be prevented by effective vaccination. From these figures we could make an informed guess of ADR levels that could be tolerated.
Did the available evidence on the trivalent vaccine support the belief that benefit would outweigh risk? On the basis that effective monovalent vaccines were available the CSM could be confident that delay in granting a licence would not result in a catastrophic epidemic of measles, mumps and rubella.
Caution should have ruled the day, answers to some important questions should have been demanded and strong encouragement should have been given to conduct a 12-month observational study on 10-15,000 patients and a prospective monitoring programme set up with a computerised primary care database. The granting of a Product Licence was premature."
One of the authors of the paper, Andy Wakefield FRCS, makes the following additional comments.
"This paper is a summary of a detailed analysis of safety trials for measles containing vaccines that I began in 1994."
"The Department of Health (in the United Kingdom) were in receipt of an earlier draft version of this paper, which was sent to them some months ago in order to permit adequate time to prepare sufficient stocks of monovalent vaccine pending publication of the paper."
"I am a firm believer in the protection of children against serious infectious diseases and their consequences. This paper advocates vaccination against measles, but the issues of vaccine safety are vitally important and must be of paramount concern".
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