Wakefield Responds To Japan Study


Honda H, Shimizu Y and Rutter M.

No effect of MMR withdrawal on the incidence of autism: a total population study

Journal of Child Psychology and Psychiatry 2005


Commentary

Andrew J Wakefield FRCS FRCPath and Carol Stott PhD

Honda and colleagues present a fascinating report on the cumulative incidence (numbers of new cases with time) of autistic spectrum disorders (ASDs) in the Kohoku Ward, Yokohama, Japan, for children born 1988 to 1996. The study seeks to examine the relationship between ASD and MMR vaccination. Japan is unique since MMR was introduced in 1989 and discontinued in April 1993. Honda et. al. see this as providing an ideal opportunity to test whether there is a causal association between MMR exposure and incidence of ASDs. They predict that, if MMR causes autism,  stopping MMR should result in a subsequent decline in incidence. This was not seen.  In fact, there was a striking rise in the incidence of ASDs in this population over time, with a marked rise postdating the removal of MMR. The authors state that their finding 'implies that MMR could not cause a substantial proportion of cases of autism'.

In conducting a study of this kind it is important to consider the background against which earlier hypotheses relating to the possible association between measles containing vaccines such as MMR, bowel disease and childhood developmental disorders were formulated, and according to which any relevant data should be interpreted.

The above notwithstanding, the authors of the Japanese study are confident in the completeness of ascertainment of ASD cases, the accuracy and precision of their screening, and the quality of diagnostic services for developmental disorders. Given this level of confidence in the incidence figures, the data merit further scrutiny in light of Japan's unique experience with the vaccines of interest.

Background

In 1998 one of us (AJW) made a recommendation in relation to how parents might wish to protect their child from the relevant infections - measles, mumps and rubella - by vaccination. This recommendation was based upon published scientific studies from my own laboratory together with an extensive examination of safety studies conducted in relation to measles vaccine either given alone or in combination with the other viral vaccines. The recommendations were that consideration should be given to (i) having M, M and R separately as the individual component vaccines and (ii) allowing an interval of one year between the vaccines.

The basis for these recommendations came from the following observations.

? First, that the safety studies of MMR vaccine were inadequate, a conclusion subsequently endorsed by independent scientific review  .

? Second, that there was clear evidence from the early clinical trials of MMR, of 'interference' between the component viruses in the combined vaccine, an influence apparently mediated through an altered immune response to the vaccines when given together.  The safety consequences of this 'interference' are completely unknown since they have not been investigated as they should have been.

? Third, that children that had experienced concurrent natural measles (or single measles vaccine) and natural mumps infections within the same year were at significantly greater risk of later inflammatory bowel disease . The latter finding is consistent with a natural 'interference' phenomenon that potentially increases the risk of long term measles virus infection and delayed disease. It is quite possible that this effect could operate for an interval of one year or more between exposure to two different viruses.  Measles virus and measles vaccines can suppress the immune system for a prolonged period after exposure . This effect is exemplified by the excess mortality and immunosuppression associated with potent measles vaccines, observed in developing countries, which led to these vaccines being abandoned3. 

Having established this background, one can examine the relevant events in Japan.

Vaccination policy and policy change in Japan

Monovalent measles vaccine was introduced in Japan in 1978 and was recommended to be given at 12 - 72 months of age.  Rubella vaccine was introduced in 1977 and was recommended for junior high school female students. An MMR vaccination programme was launched in April 1989 for children aged between 12 and 72 months with the majority receiving the vaccine by 18 months of age. There was no mumps vaccine used in Japan before the introduction of MMR.

It is notable that various brands of MMR vaccine were licensed in Japan, some of them containing the mumps Urabe AM9 strain. Due to increasing public and professional concern about reported incidences of meningitis following MMR, public confidence declined over the years following its introduction and MMR vaccine uptake fell. Subsequent studies confirmed that the Urabe AM9 mumps vaccine was causally associated with meningitis. This resulted in the termination of the MMR programme in April 1993, and no child in the current study received MMR from 1992 onwards. The Urabe AM9 mumps vaccine was discontinued and replaced with a strain of mumps vaccine which did not cause meningitis.  Single measles, mumps, and rubella vaccines replaced the combined vaccine in 1993 in a new immunisation schedule, which was formalised the following year. The recommendation was for Japanese children to receive monovalent measles, mumps and rubella vaccines to be given to infants spaced by a period of not less than four weeks.

Against the background of this changing vaccination policy the cumulative incidence curve of ASD in this population is very interesting (see Figure One).

The Japanese study does not tell us anything about the incidence of ASD prior to 1988; this can be estimated (overestimated) from prevalence data shown in Figure 1. Following the introduction of MMR there was a rise in annual incidence of ASDs from less that 25 per 10,000 population before MMR to 85.9 (95% Confidence Intervals 55.3 - 116.5) for children born in 1990. The incidence subsequently declined to 55.8 (32.0 - 79.6) for children born in 1991.

The incidence then rose again sharply, to a level of 161 (121.8-200.8) in 1994. During these years the single vaccine policy gained further acceptance as public and professional confidence was restored following the removal of the Urabe mumps vaccine. The authors note that beyond 1994 the Kohuku Ward was redistricted but claim no effect of this on interpretation of the data. It is interesting to note, however, that the confidence intervals on the point estimates of ASD incidence increase in parallel with this demographic change. A result of this is that the precision of the point estimates appears to have been compromised after this time. ASD incidence beyond 1994 is, therefore, is not as accurate as preceding years.

The multiphasic shape of the incidence curve is strikingly different from that seen in the UK  (fig 2) and the US  (fig 3) where distributions are primarily monophasic (i.e. a continuous rise). The shape of the Japanese graph would be consistent with an influence of an additional factor(s) on the evolution of an environmentally induced disease where, overall, exposure to the cause was increasing over time.

In light of the biological nature of viral interactions and the protracted effects on the immune system of measles exposure in particular (either as natural infection or vaccination) it is evident that, although MMR vaccine itself was discontinued in this infant population beyond 1993, for all practical purposes, because of the behaviour of these viruses, children vaccinated according to the recommended schedule were still receiving 'M-M-R' at age one year. In other words the administration of the separate vaccines in close temporal proximity amounts, in biological terms, to overlapping exposure. Such close proximity of exposure is clearly atypical and something that would have been very rare with natural infection to measles, mumps and rubella viruses. The Japanese data are therefore not at odds with the original interpretation and the subsequent recommendations referred to earlier. They are entirely consistent with what is known about the behaviour of these viruses. The authors of the Japanese study make the error of examining MMR as an isolated exposure without giving any consideration to the arguments that have been put forward or the data upon which those arguments were based.

In light of these observations the data could be interpreted as indicating a major influence of the pattern of exposure to these vaccine viruses on ASD incidence in this Japanese population. Moreover, it suggests a possible re-challenge effect of close temporal exposure to these vaccine viruses on ASD incidence at the population level, whereby the exposure has been introduced, removed and then re-introduced. Nonetheless the interpretation by Public Health authorities that this is the 'last word on the subject' and that these data prove that MMR is safe is misleading and suggests a very limited perspective of the issues and a misunderstanding of the previously published concerns that have guided the research of those involved with the examining the safety of measles vaccines. Enthusiasm to exonerate the MMR vaccine is no excuse for misrepresenting the published basis for the safety concerns.

Regressive autism: methodological flaws

It is also worth commenting on one major methodological flaw in the paper. The original description by Wakefield et al and subsequent studies others indicate that any potentially causal relationship between MMR and ASD relates to a regressive form of autism, in which the child developed normally prior to exposure.

In the study of Honda et al, children underwent routine developmental assessment at 3 months and 18 months of age, while the recommended schedule for MMR vaccination was 12 months of age. The authors define regression as demonstrable loss of skills after 18 months of age. Therefore children who have developed normally for the first year of life, who then receive an MMR at 12 months of age and who subsequently regress over the course of the next 6 months, will be misclassified as non-regressive cases when in fact quite the opposite may be the case. Misclassification of the children's autism of this kind will render meaningless, the authors sub-analysis in relation to regression. This is supported to the extent that the shape of the respective incidence curves in the sub-groups is similar. Therefore, the regression data do not merit further consideration.
 
The authors conclusion that their '.findings indicate that simply terminating MMR vaccination programs will not lead to a reduction in the incidence of ASD' is self-evident. The original recommendation however made no such na´ve claim. The recommendations were based on empirical data, which indicated a serious adverse effect of close temporal exposure to two or more of these vaccines. The Japanese data give no reason to change theses recommendations.

 
Legend to Figure 1.  * The published prevalence of ASD did not exceed 25 cases per 10,000 population at any time in Japan before the introduction of MMR. This prevalence figure is therefore an overestimate of incidence in this population. M-M-R = separate measles, mumps and rubella vaccines.
  


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