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# 8.5 MMR safety

Fitzpatrick, M. (2004) Chapter 8 ‘The Lancet Paper’ taken from MMR and Autism: What Parents Need to Know, London, Routledge. Copyright © 2004 Michael Fitzpatrick.

In January 2001 Dr Wakefield adopted a radically different tack in the campaign against MMR. He now turned to the field of public health and vaccination policy, questioning whether appropriate safety procedures had been followed when MMR was introduced into Britain in the late 1980s. In a paper written with his Royal Free colleague, epidemiologist Scott Montgomery, Dr Wakefield claimed that the trials carried out on MMR before it was licensed in Britain involved monitoring children for side effects for only 28 days (Wakefield, Montgomery 2000). They also claimed that the authorities had not taken account of the problems of ‘viral interference’ arising from using the combined MMR vaccine and that early studies had missed or ignored evidence of gastro-intestinal side effects of MMR.

Entitled ‘MMR vaccine: through a glass, darkly’2 the Wakefield and Montgomery paper provoked a storm of controversy.

It was published in the Adverse Drug Reactions and Toxicological Reviews, a highly specialist (and now defunct) journal with a regular readership estimated at around 300. The editors of this journal, anticipating a critical response to the article, published it together with the comments of four reviewers. (Critics subsequently pointed out that, although the reviewers were distinguished in their own fields, they did not include a vaccine specialist.) The most significant comment came from Dr Peter Fletcher, a former head of the Committee on Safety of Medicines, who substantially endorsed the case made by Wakefield and Montgomery and concluded with the damning judgement that ‘the granting of a produce licence [for MMR] was premature’ (Fletcher 2001: 289). In the subsequent discussion, another supporter of the anti-MMR campaign emerged: Dr Stephen Dealler, consultant microbiologist at Burnley General Hospital in Lancashire (Dealler 2001). A veteran of the BSE/CJD controversy, in which he emerged as a protege of Professor Richard Lacey (whose maverick reputation appeared to be enhanced when the nightmare scenario he had long predicted came, at least in part, to pass), Dr Dealler had now become a supporter of Dr Wakefield's theory of autism (see Fitzpatrick 1998: 45–8). He had already published a comprehensive endorsement of unorthodox biomedical approaches to autism on the Internet (Dealler 1999).

Recognising that his most recent paper might not otherwise attract public attention, Dr Wakefield launched the article at a press conference and released copies of the paper to the mainstream media before either public health authorities or doctors involved in giving vaccinations had a chance to read it. Another stormy press conference guaranteed a blaze of publicity (Abbasi 2001).

The Wakefield/Montgomery paper prompted forceful rebuttals from vaccine authorities. On behalf of the Medicines Control Agency, Arlett and Bryan insisted that the MMR trials had followed up children for between six and nine weeks (and, in some studies, for longer) (Arlett, Bryan 2001). They accused Wakefield and Montgomery of errors of statistics and interpretation of key surveys, and claimed that they had missed or ignored other important studies. A scathing review from the Public Health Laboratory Service (now the Health Protection Agency) concluded that ‘overall, we find this paper lacking in a coherent scientific rationale, selective in the reporting and interpretation of other work and statistically invalid’ (Miller, Andrews 2001). Paediatric vaccine specialists dismissed the concerns raised by Wakefield and Montgomery as ‘idiosyncratic’ and questioned the authors' tactics in presenting their paper to the popular press before most clinicians had a chance to read it in a peer-reviewed journal (Elliman, Bedford, 2001).

Two distinct issues were confused in the discussion of ‘interference’ (Arlett, Bryan 2001, Wakefield, Montgomery 2001). One is the question of whether there is a higher incidence of adverse reactions with the combined vaccine, compared with vaccines given separately. Contrary to Dr Wakefield's claims, the consensus emerging from a number of studies is that there is not (Halsey 2001). For the MCA, Arlett and Bryan insisted that there was no convincing evidence of either chronic gastro-intestinal problems or autism resulting from MMR (Arlett, Bryan 2001). The second is the question of ‘immuno-logical interference’: does giving three antigens together lead to a diminished antibody response to each one? According to the review by the American Academy of Pediatrics, ‘although early studies showed the potential for some interference between these vaccine viruses as indicated by reduction in the mean antibody response to one or more of the components in the combined vaccines, adjusting the titres of the vaccine viruses resulted in similar responses for the combined and separate administration of these vaccines’ (Halsey 2001: 25). Arlett and Bryan pointed out that, in 30 studies of the combined MMR vaccine before its Introduction in Britain, no problems of interference had been identified. Furthermore, the effectiveness of post-licensing surveillance had been confirmed by its success in identifying, as a rare adverse reaction, ITP (idiopathic thrombo-cytopenic purpura – a rash associated with a blood abnormality, which usually resolves spontaneously) at a rate of one in 24,000 cases (Miller 2001).

In the subsequent discussion about the safety of MMR a number of issues arose (although none shed much light on the MMR-autism hypothesis). One set of concerns – promoted at first by the wider anti-immunisation movement – focused on the withdrawal in Britain in 1992 of two brands of MMR that used a mumps component derived from the Urabe strain of the virus. In 1988, before the Introduction of MMR in Britain, a study in Canada and the UK reported the occurrence of aseptic meningitis following immunisation with the Urabe strain mumps vaccine, at a rate of between one in 100,000 to one in 250,000. Given that this rate of meningitis was much lower than that occurring with natural mumps (which MMR had been shown to prevent) it was preferable to proceed with the Introduction of MMR. Furthermore, it was not, at that time, clear that any alternative vaccine was safer. However, although passive surveillance procedures showed a very low risk, a more intensive study in 1992 in the Nottingham area revealed a higher incidence of aseptic meningitis at a rate of one in 3,000 – following MMR (Miller et al 1993). Accordingly, the vaccine authorities decided to switch to using only brands of MMR containing the Jeryl Lynn strain of mumps (which had not been linked to cases of meningitis). In response to continuing claims of government perfidy in introducing MMR including Urabe (on the grounds that it was known to cause aseptic meningitis in rare cases), it has been pointed out that, if Jeryl Lynn had not been available, it would still have been preferable to carry on with MMR include Urabe as the benefit from reducing the risk of mumps far exceeded the risk of vaccine-related meningitis.

Another controversy arose from official attempts to promote studies of MMR safety in general as evidence against claims that it caused autism. The most popular study in this regard comes from Finland – a country that introduced a two-dose MMR programme in 1982 and now claims to have virtually eradicated these three diseases. Long-term population-based passive surveillance studies found that no cases of developmental regression had been reported as resulting from MMR in 1.8 million children (Peltola et al 1998, Patja et al 2000). It is true, however, that because people in Finland had no reason to suspect that MMR might be associated with autism, they would be unlikely to report it as an adverse reaction. Dr Fletcher, among many others, was critical of the government's use of such ‘negative studies as absolute evidence of safety’. Nevertheless, the large-scale, long-term, comprehensive and prospective character of these studies make them strong evidence for the safety of MMR in general (Bandolier 2002).

In response to studies of this type, which failed to substantiate the claims of anti-MMR campaigners, they retorted that ‘absence of evidence is not the same as evidence of absence’ (Aitken 2001b) – meaning that just because a particular study does not turn up evidence for the MMR-autism link does not prove that there is no link. (This epithet became something of a mantra.) But two things may be said in response to this. The first is that, as stated in the MCA reply to Wakefield's paper, ‘it is not that there is no evidence, but that there is evidence and it does not show an association’ (Arlett, Bryan 2001: 44). The second is that, if you have looked hard enough for a particular sort of evidence and have failed to find it, the sensible conclusion must be that it is not there and that it is time to think again and look elsewhere. This is how Professor Vivian Moses responded to similar demands for absolute assurances of the safety of genetically modified food products:

> Since we can judge present and future safety only on the basis of past experience, an absence of evidence of harm is precisely the only evidence we can ever expect to accumulate for the absence of harm.

> (Moses 2002: 2)

Alternatively, one can continue to demand that the rest of the world proves that there is no link, or one can delude oneself that the evidence really is there, if only the rest of the world could see it.

The most curious feature of the ‘through a glass, darkly’ paper is that it has no direct relevance to the MMR-autism link. Even if it were true that pre-licensing surveillance of MMR had been inadequate, this would not advance Dr Wakefield's claim that MMR was causing ‘autistic enterocolitis’ and thus contributing to an epidemic of autism. It is strange that, at a time when he was under intense pressure to substantiate this hypothesis, Dr Wakefield chose to turn aside from his own sphere of expertise (gastroenterology) to enter fields (public health and vaccination policy) in which he had no previous experience. However, a close reading of the concluding section of the paper suggests that Dr Wakefield's strategy was that, if the safety of MMR in general could be put in doubt, the credibility of any particular risk attributed to the vaccine would be raised.

Confident of finding a resonance in an increasingly risk-averse climate, Dr Wakefield invoked the ‘precautionary principle’ popularised by the environmentalist movement:

> Surely, when a medical intervention is intended for universal use, particularly in healthy infants, there is almost no limit to the vigilance that should be exercised.

> (Wakefield, Montgomery 2000: 277)

With a reference to ‘healthy infants’ that was guaranteed to appeal to the popular press, Dr Wakefield proposed an extreme level of caution that would deter any preventive or therapeutic intervention. In truth, there must always be a limit to vigilance: otherwise we allow the danger against which we are vigilant to become oppressive.

Despite this, at a time when the nation was in the grip of a multiplicity of millennial anxieties, Dr Wakefield readily found the highest authority for his precautionary approach:

> As the last Minister for Health, the Hon. Frank Dobson said recently, in the context of another medical intervention, ‘if there is even a hypothetical risk [of harm] and a safer alternative exists, we should use it’

> (Wakefield, Montgomery 2000: 279)

As a ‘precautionary measure’ to prevent possible transmission of variant CJD in February 1998, Mr Dobson had insisted that albumen (derived from blood products) used as a stabiliser in some vaccines should be imported from countries not affected by BSE. If the Minister for Health himself could use a hypothetical risk to justify introducing an alternative, then so could Dr Wakefield. He argued, ‘for MMR’, in relation to autism and inflammatory bowel disease, ‘a significant index of suspicion exists without adequate evidence of safety’ (Wakefield, Montgomery 2000: 279).

Although Dr Wakefield had not clearly established either that there was ‘a significant index of suspicion’ about MMR or that its safety record was inadequate, his case appeared to be strengthened by coupling these two dubious propositions together. ‘If the risk of chronic immune-mediated disease is increased by concurrent exposure to the component viruses of MMR, either in their natural or vaccine form’ (a conditional clause that remained unvalidated), then, Dr Wakefield triumphantly concluded, by giving the vaccines separately ‘we have the ability to artificially dissociate these exposures, and the possible associated risks’ (Wakefield, Montgomery 2000: 279). By disparaging the safety record of MMR and inflating unsubstantiated risks, Dr Wakefield may not have advanced the MMR-autism thesis, but he had given a powerful boost to the demand for separate vaccines.

2 The title is derived from the epistles of St Paul: ‘For now we see through a glass, darkly; but then face to face: now I know in part; but then shall I know even as I am known’ (Corinthians I; 13:12).

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