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

Hideo Honda¹, Yasuo Shimizu, Michael Rutter

J Child Psychol Psychiatry. 2005 Jun;46(6):572-9.

doi: 10.1111/j.1469-7610.2005.01425.x.

AAP: In a study of all children born between 1988 and 1996 in Yokohama, Japan, the number of new cases of autism spectrum disorder (ASD) increased significantly even though MMR vaccination decreased and ended in 1993.. In addition, there was a steep increase in ASD that started with the 1993 birth cohort. Authors concluded that the withdrawal of MMR vaccine cannot be expected to lead to a reduction in the incidence of ASD and the vaccine cannot explain the rise over time in the incidence of ASD.

Abstract

Background: A causal relationship between the measles, mumps, and rubella (MMR) vaccine and occurrence of autism spectrum disorders (ASD) has been claimed, based on an increase in ASD in the USA and the UK after introduction of the MMR vaccine. However, the possibility that this increase is coincidental has not been eliminated. The unique circumstances of a Japanese MMR vaccination program provide an opportunity for comparison of ASD incidence before and after termination of the program.

Methods: This study examined cumulative incidence of ASD up to age seven for children born from 1988 to 1996 in Kohoku Ward (population approximately 300,000), Yokohama, Japan. ASD cases included all cases of pervasive developmental disorders according to ICD-10 guidelines.

Results: The MMR vaccination rate in the city of Yokohama declined significantly in the birth cohorts of years 1988 through 1992, and not a single vaccination was administered in 1993 or thereafter. In contrast, cumulative incidence of ASD up to age seven increased significantly in the birth cohorts of years 1988 through 1996 and most notably rose dramatically beginning with the birth cohort of 1993.

Conclusions: The significance of this finding is that MMR vaccination is most unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD, and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD.

An egregious omission given what is known about Dr. Michael Rutter of the UK: Not only is Dr. Rutter a paid expert witness for vaccine makers facing litigation regarding the MMR vaccine, he was also a board member of the Wellcome Foundation, a front foundation for Glaxo Smithkline, a vaccine maker. Dr. Rutter is also a primary witness in the case against Dr. Andrew Wakefiled, a British doctor who published a paper implicating MMR vaccine in autism.

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

Honda H, Shimizu Y and Rutter M.
Journal of Child Psychology and Psychiatry. February 2005

Commentary: Japanese study is the strongest evidence yet for a link between MMR and autism

Andrew J Wakefield FRCS FRCPath and Carol M 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 his 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 review¹.
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 together². 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 disease³. 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 exposure⁴. 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 abandoned (reviewed in³).

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 program 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 program 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 immunization schedule, which was formalized 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; prevalence data are used as an estimate of the upper limit (Figure 1). Following the introduction of MMR there was a rise in annual incidence of ASDs to 85.9 for children born in 1990. The incidence subsequently declined to 55.8 for children born in 1991.

The incidence then rose again sharply, to a level of 161 (121.8-200.8) in 1994. During this time the single vaccine option 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, not as accurate as preceding years.

The multiphasic shape of the incidence curve is strikingly different from that seen in the UK¹ (Figure 2) and the US² (Figure 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 (‘interference’) 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 children vaccinated according to the recommended schedule were still receiving ‘M-M-R’ at age one. 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 due 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 behavior of these viruses. The authors of the Japanese study make the error of examining MMR as the single exposure of interest 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 (MMR) has been introduced, removed (voluntarily through lack of public confidence), and then re-introduced (as M, M, and R close together). 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 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 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 in this way will render meaningless the authors’ sub-analysis comparing regression and non-regression. This is supported by the fact that the shape of the respective incidence curves in the regression and non-regression sub-groups is similar. The regression data, therefore, 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 naļve claim. The recommendations were that the vaccines should be given separately and spaced by one year; this was 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 these recommendations.

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

¹ Jefferson et al Vaccine 2003;21:3954-3960
² Buynak EB et al JAMA 1969;207:2259-2262. Minekawa Y, et al.. Biken Journal 1974;17:161-167
³ Montgomery SM et al. Gastroenterology 1999; 116: 796-803
⁴ Wakefield AJ & Montgomery SM. Adverse Drug Reactions and Toxicological Reviews 2000;19:265-283
⁵ Jick H et al Epidemiology 2003;14:630-631
⁶ Barbaresi WJ Archives of Ped Adolescent Med 2005;159:37-44

CRITIQUES OF THE STUDY

■ The study tells us little about ASD incidence of ASD prior to 1988, when MMR was introduced. But we do know that the published prevalence of ASD did not exceed 25-per-10,000 at any time in Japan prior to 1988.

■ Annual incidence of ASDs for children born in 1987 was 20-per-10,000, but after MMR was introduced, in 1988, annual incidence more than quadrupled, to 85.9-per-10,000 for children born in 1990.

■ But then, MMR coverage began to decline dramatically, as concerns over the mumps viral component grew. ASD incidence likewise declined during this period, to 55.8 for children born in 1991 – representing a drop of 35%.

■ Following complete discontinuation of MMR in 1993, ASD incidence rose again, this time quite dramatically, to 161-per-10,000 for children born in 1994. However, during this time the recommended schedule was changed to include three single vaccines (M-M-R, given four weeks apart), which gained widespread acceptance, causing coverage to increase significantly.

■ For all practical purposes, children vaccinated according to the new schedule were still receiving ‘M-M-R’ at around age one. Giving the three separate vaccines in such close proximity amounts to overlapping exposure, in biological terms.

■ Early MMR trials showed clear evidence of ‘interference’ between the viruses in the combined vaccine, mediated through an altered immune response. The safety consequences of this ‘interference’ are completely unknown.

■ Children who have natural measles (or single measles vaccine) and natural mumps infections within the same year are at significantly greater risk of later inflammatory bowel disease,[19]which is consistent with an ‘interference’ phenomenon that could increase the risk of long-term measles virus infection and delayed disease.

■ The authors are wrong to examine MMR as the single exposure of interest, when in biological terms, exposure to M-M-R through three consecutive monovalent vaccines actually increased after 1993 when MMR was discontinued.

■ The data, therefore, could be interpreted as indicating a major influence of the pattern of exposure to these vaccine viruses on ASD incidence in this Japanese population.

■ More importantly, the data suggest a possible re-challenge effect of close temporal exposure to these three vaccine viruses on ASD incidence at the population level, whereby the exposure (MMR) has been introduced, removed (voluntarily through lack of public confidence), and then re-introduced (as M, M, and R close together).

■ ASD numbers increased and decreased in direct proportion to the total number of children vaccinated with the three live viruses. There is evidence of an effect not only from de-challenges and re-challenges, but there is also a “dose-response” relationship on a population level.

■ Such a dose-response relationship on a population level is rare; and is evidence of a possible causal association.

■ The interpretation by Public Health officials 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 published concerns on viral interference in a trivalent live-virus vaccine.

Undisclosed Conflict of Interest: Co-author Michael Rutter has close associations with the drug industry, including GlaxoSmithKline. He was a paid expert witness on their behalf in the UK MMR vaccine damage litigation. That was not declared in the Honda/Rutter paper.

SUMMARY:

Despite the methodological problems in Honda et al., and quite apart from the fact that an ecological study of this kind cannot be used to make attributions about causality, the unrecognized challenge-rechallenge effect of vaccination on autism rates in Japan provide yet another piece of support for the MMR-autism link. Because this study failed to clearly interpret the true population risk in the exposure of interest–assuming the removal of an exposure that in reality had remained– the conclusions drawn by the authors are based on erroneous reasoning. Although drawing overly strong conclusions about an association between MMR-type exposures and autism would be premature in light of the study’s ecological design constraints, the data clearly indicate that further scrutiny of the data is required.