(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".
Commentary by Barbara Loe Fisher
Co-founder & President
National Vaccine Information Center
COVERING UP THE LOOKING GLASS
The response by the Medicines Control Agency (MCA) and Department of Health in the UK to the publication of the critique of MMR pre-licensure studies by Andrew Wakefield, M.D. and Scott Montgomery, Ph.D. ("Measles, Mumps, Rubella Vaccine: Through a Glass, Darkly" in Adverse Drug Reactions and Toxicological Reviews, volume 19 no 4, 2000) is unfortunately distinguished by its hysterical tone and arrogance rather than intellectual honesty andbalance. http://www.doh.gov.uk/mmrresponse.htm
Throughout, the reader gets the familiar feeling that physician public health officials defending their turf "doth protest too much." You can almost see their collective teeth grind as they issue categorical denials like "The MCA totally refutes any suggestion that MMR vaccines were licensed prematurely" and (my favorite) "It is not that there is no evidence [to support an association between combined measles, mumps, and rubella vaccine and inflammation of the bowel or autism] but that there is evidence and it does not show an association."
Even so, there are small nuggets buried in the rhetoric that leave the door open for future wiggle room such as "The Committee on Safety of Vaccines has concluded that, based on the data available at the time of licensing, combined measles, mumps and rubella vaccines were licensed appropriately."
Most significantly, this MCA rebuttal of Wakefield and Montgomery's suggestion that MMR vaccine was prematurely licensed without adequate proof of safety, never states precisely how many children were enrolled in placebo controlled MMR pre-licensure trials. One would expect the MCA to proudly broadcast the total numbers of children studied - if the numbers were high in the many thousands. However, at no time during the MCA's feverish defense of itself, is there any mention of the total numbers of children enrolled in controlled MMR pre-licensure studies in the U.S. or the U.K.
Was it 300 or 3,000 or 30,000 children? Perhaps the answer to that question lies in the Merck product manufacturer insert on MMR, in which the only mention of numbers of studied children is: "Clinical studies of 279 triple seronegative children, 11 months to 7 years of age, demonstrated that MMR is highly immunogenic and generally well tolerated."
Not a very good sign. It is difficult to have confidence in any vaccine safety and efficacy study, controlled or uncontrolled, that only includes 279 children. Such small numbers effectively prevent systematic analysis of the vaccine's effects in genetically diverse populations.
In addition, MCA issues a de facto admission that prelicensure trials are too small by dismissing Wakefield and Montgomery's criticism that there was inadequate long term follow-up of children in MMR pre-licensure trials for evidence of chronic illness following vaccination. MCA asserts "The numbers included in the trials, even if they were all followed up long term, would not be sufficient to detect rare problems." Of course, it depends upon what the definition of "rare" is, and post-MMR vaccine chronic neuroimmune dysfunction may not be so very rare if acknowledged as vaccine-relatedrather than dismissed as "coincidental."
MCA cannot resist overreaching in its crude, hyperactive attack on Wakefield and Montgomery's elegant paper, as the following MCA statement demonstrates:
"Overall, the value of measles vaccines, including high titre vaccines in developing countries, has been to reduce morbidity and mortality wherever they are used."
Tell that to the mothers and fathers of girl babies in Africa who died of broad based immune suppression in the 1980's after being injected with a high titre experimental Edmonston Zagreb measles vaccine that was up to 500 times more potent than licensed measles vaccines. If it hadn't been for a brave French researcher, who risked his career by insisting the trials be halted in 1990 after he discovered the excess deaths, that experimental measles vaccine would have been licensed for routine use in babies around the world. Instead, former Centers for Disease Control Director and US Surgeon General David Satcher had to publicly apologize in 1996 to the parents of African American and Hispanic babies in inner city Los Angeles because the principal investigators in the US arm of that high titre measles vaccine trial had failed to inform the parents that their children were being injected with an experimental vaccine.
It is no wonder informed parents are losing faith in what vaccine policymakers in the US and UK say and do. Self serving denials, rather than calls for credible research, only reinforce public perception that cover-up is the only game these apologists know how to play.
Landrigan, P.J., Witte, J.J., (26/3/73), Neurologic Disorders Following Live Measles Virus Vaccination, The Journal of the American Medical Association, Vol 223, No. 13:pp 1459-1462 Abstract: From 1963 through 1971, eighty four cases of neurologic disorders with onset less than 30 days after live measles-virus vaccination were reported in the United states. Thirteen could be adequately accounted for by cases other than vaccine, and another 11 were uncomplicated febrile convulsions probably related to vaccination. One case met diagnostic criteria for subacute sclerosing panencephalitis. The remaining 59 showed clinical features of encephalitis or encephalopathy. Causes of these cases could not be established, but 45 (76%) had onset between 6 and 15 days after vaccination; this clustering suggests that some may have been caused by vaccine. From 1963 through 1971, 50.9 million doses of measles vaccine were distributed, and, therefore, incidence of the reported neurologic disorders was 1.16 per million doses. Risk of encephalitis following measles infection is one per thousand cases. (my note - the vast majority of vaccine complications go unreported making the figure inaccurate and the figure for encephalitis complications following measles infection is grossly overstated.)
Keep in mind when reading the following abstract that the Australian recommendation has recently been altered to say that simple colds and febrile conditions are no longer contraindications to vaccination. Keep in mind also, the case of David Bonello who went to the doctor to be treated for a cold at 4 months old, was vaccinated against his mother's wishes, and is now permanently brain damaged.
Krober, MS, Stracener, CE, Bass, JW; Decreased Measles Antibody Response After Measles-Mumps-Rubella Vaccine in Infants with Colds; JAMA, April 24, 1991-Vol 265., No 16 Abstract: We examined the possibility that the common cold or afebrile upper respiratory tract infection might interfere with successful immunization in children who receive standard measles-mumps-rubella vaccine. Infants 15 to 18 months of age presenting at our well-child clinics for routine examination and immunizations were divided into two groups. Thos infants with a history and physical findings of upper respiratory tract infection were compared with healthy control group infants who did not have upper respiratory tract infections; and who did not have a history of upper respiratory tract infection symptoms within the previous month. Both groups were studied for their serological response to measles-mumps-rubella vaccination. Prevaccination serum samples were obtained prior to vaccine administration and postvaccination serum samples were obtained 6 to 8 weeks later. Measles antibody was measured in these serum samples by an indirect fluorescein-tagged antibody test. Ten (21%) of 47 infants with colds failed to develop measles antibody, while only one (2%) of 51 well infants failed to develop antibody. We conclude that infants with colds have a significant sero-conversion failure rate associated with measles vaccine administration and that this may be the cause of some primary measles vaccine failures.
Farrington P Pugh S Colville A Flower A Nash J Morgan-Capner P Rush M Miller E, A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines, Lancet 1995 May 27;345(8961):1369 Abstract: We describe a new method for active post-marketing surveillance of vaccine safety based on patient records. We studied the association between diphtheria/tetetanus/pertussis (DPT) vaccination and febrile convulsion, and between measles/mumps/rubella (MMR) vaccination and febrile convulsion and idiopathic thrombocytpoenic purpura (ITP) in five district health authorities in England by linking vaccination records with computerised hospital admission records. We found an increased relative incidence for convulsions 0-3 days after DPT vaccination. The effect was limited to the third dose of vaccine for which the attributable risk (all ages) was 1 in 12,500 doses. Completion of vaccination by 4 months instead of 10 months after the change in the UK to and accelerated immunisation schedule may have resulted in a 4-fold decrease in febrile convulsions attributable to DPT vaccine. 67% of admissions for a convulsion 6-11 days after MMR vaccination were attributable to the measles component of the vaccine (risk 1 in 3,000 doses). An excess of admissions for a convulsion 15-35 days subsequently; there was no evidence of a mumps strain-specific effect. The estimated absolute risk of 1 in 24,000 doses was 5 times that calculated from cases passively reported by clinicians. This finding emphasises the need for active surveillance of adverse events. The record linkage method that we used is an effective way to identify vaccine-attributable adverse events.
Herceg, A., An outbreak of measles in a highly immunised population: immunisation status and vaccine efficacy, Australian Journal of Public Health, 1994 Vol 18, No 3 Abstract: An outbreak of 18 cases of measles in a primary school in the Australian Capital Territory n August and September 1993 provided the opportunity to study measles immunisation status and measles vaccine efficacy. Parents of 384 (78 %) of 491 children answered a questionnaire on recent illness consistent with measles and measles immunisation. Parents transcribed details of measles immunisation from the personal health record of the child to the questionnaire. Thirty-three percent of cases and 3.4 percent of the other children had not been immunised. Overall, 95% of children had been immunised. The efficacy for all measles vaccines was estimated to be 90 percent (95% confidence interval (CI) 75 to 96) and for measles-mumps vaccine 87 percent (CI 70 to 95). All of the immunised cases had received measles-mumps vaccine. There was no incrased risk of measles infection in those who had been immunised at under 15 months of age compared with those immunised at 15 months or older, or in thos who could not provide a date of immunisation compared with those who could. None of the children who had received two doses of vaccine caught measles. The date of immunisation was provided by 65% of the respondents who said their children had been immunised. Asking parents to provide this date instead of viewing the health record is a less expensive way of assessing immunisation status but this method needs to be evaluated. Measles outbreaks still occur in highly immunised populations when vaccine efficacy appears to be acceptable.
I received a copy of a 35 page MMR fact sheet from Richard Barr of Dawbarns Solicitors, Bank House, King's Staithe Square, King's Lynn, Norfolk PE30 1RD, UK. I will give some excerpts and those interested will have to contact the above mentioned address for a copy. Dr. Andrew Wakefield of the UK who did work on Crohn's disease and measles is looking into autism and measles
- The Japanese findings indicate that adverse reactions to these types of MMR vaccine were up to 78 times as frequent as our Government's Chief Medical Officer of Health has Admitted ( 7.1/1000 = 78.1/1000 ). (1) If those figures are correct , then the vaccine is more dangerous than the illness; and it does not give a great deal of confidence that the government has got its figures ( or information about safety or side effects ) right.
There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of natural measles but did receive measles vaccine.
Clients ( and those who have contacted us ) have reported to us a number of problems with the vaccine. To date we are aware of more than 600 instances of side effects following the MMR and MR vaccines. The figures in ( brackets )...side effects as of January 1997.
Autism (202) Crohn's disease and other serious chronic stomach problems (110) Epilepsy (97) Hearing and vision problems (40) Arthritis and arthralgia ( including juvenile rheumatoid arthritis ) (42) Behavior and learning problems ( in older children ) (41) Myalgic encephalomyelitis (ME) and chronic fatigue (24) Diabetes (9) Guillain - Barre syndrome (9) Idiopathic thrombocytopaenic purpura ( and other purpuras ) (5) Subacute sclerosing Panencephalitis (SSPE) (3) Wegener's Granulamatosis (2) Multiple Sclerosis (1) Death (14)
Our investigations indicate that there are biological mechanisms by which the components of MMR vaccine can cause encephalopathy which leads to autism. It may be caused by immune complexes ( molecules of antigens and antibodies linked together ) blocking small blood vessels in the brain. (2)
The distinguished neurologist Dr. Charles M. Poser has drawn the link between the vaccines and demyelination. Almost any...vaccination can lead to a non infectious inflammatory reaction involving the nervous system.... The common denominator consists of a vasculopathy that is often.... associated with demyelination. (3)
We know of experts who believe that there is a connection between autism and peptides leaking through the gut wall. damage to the gut wall is caused by inflammatory bowel disease, and it looks likely that we will be able to show that the vaccine causes that condition. Therefore, through this route alone, it follows that there is a clear possible link with the vaccine. - Dr. Andrew Wakefield has a fact sheet on children with persistent stomach problems ( pains, constipation or diarrhea ) following the vaccination.
(1) A prefecture-wide survey of mumps meningitis associated with measles, mumps and rubella vaccine. Takashi Fujinaga, MD , Youichi Motegi, MD, Hiroshi Tamura, MD and Takayoshi Kuroume , MD. Pediatric Infectious Disease Journal, March 1991 Vol. 10 , No. 3.
(2) The Biology of Autistic Syndromes: Christopher Gilberg and Mary Coleman: MacKeith Press 2nd Ed. pg 22.
(3) Posner CM. Neurological syndromes that arise unpredictably. Consultant January 1987 pp. 45-46.