Effect of Pentavac and measles-mumps-rubella (MMR) vaccination on the intestine
- 1Department of Medicine, University Hospital, Hringbraut, Reykjavík, Iceland
- 2Center for Children Health Services, Reykjavík, Iceland
- 3Center for Children Health Services, Reykjavík, and Sudurnes Health Institute, Keflavik, Iceland
- 4Department of Medicine, GKT Medical School, London, UK
- Correspondence to:
Professor I Bjarnason, Department of Medicine, Guy’s, King’s, St Thomas’ Medical School, Denmark Hill Campus, Bessemer Road, London SE5 9PJ, UK;
- Accepted 15 May 2002
Background: The safety of infant vaccination has been questioned in recent years. In particular it has been suggested that the measles, mumps, and rubella (MMR) vaccination leads to brain damage manifesting as autism consequent to the development of an “enterocolitis” in the immediate post-vaccination period.
Aim: To assess if MMR vaccination is associated with subclinical intestinal inflammation, which is central to the autistic “enterocolitis” theory.
Methods: We studied 109/58 infants, before and two and four weeks after immunisation with Pentavac and MMR vaccines, for the presence of intestinal inflammation (faecal calprotectin).
Results: Neither vaccination was associated with any significant increase in faecal calprotectin concentrations.
Conclusions: The failure of the MMR vaccination to cause an intestinal inflammatory response provides evidence against the proposed gut-brain interaction that is central to the autistic “enterocolitis” hypothesis.
The presence of lymphoid nodular hyperplasia and colitis in autistic children, termed autistic “enterocolitis”, with various gastrointestinal symptoms investigated a number of years after immunisation is not in doubt.1,2 However, the aetiology and pathogenesis of the intestinal inflammation is controversial3 as is the possible role of the intestine in the development of the central nervous system dysfunction that may manifest in mental health disorders.4,5
One hypothesis of the pathophysiology of autistic “enterocolitis” postulates that the measles vaccination virus of the measles, mumps, and rubella (MMR) vaccine escapes initial detection by the immune system3 and disseminates to the intestinal lymphoid tissue. Here, it is suggested, it leads to an “enterocolitis” with increased permeation of neurotoxic luminal substances during a vulnerable part of brain development, leading to regressive autism.3,6 Central to this hypothesis is the development of intestinal inflammation in the immediate period following vaccination.
We tested this hypothesis by assessing intestinal inflammation (faecal calprotectin) before and after Pentavac and MMR vaccination in a group of infants.
SUBJECTS AND METHODS
Iceland has a developed health service with a centralised vaccination programme that results in infant vaccination rates approaching 100%. Pentavac (Pasteur Mérieux, France) vaccination (against diphtheria, tetanus, pertussis, polio, Haemophilus influenza type b) is performed at three, five, and 12 months of age and MMR (Priorix; SmithKline Beecham) vaccination at 18 months. One hundred and nine infants attending two of the vaccination centres of Southwest Iceland participated. These were consecutive infants where the parents had been sent a pre-attendance information leaflet explaining the nature and aims of the research. All of those approached participated. No infant met the predetermined specific exclusion criteria to this study which included those specified by the makers of the vaccines, the presence of intestinal diseases, or ingestion of medications that are associated with intestinal permeability-inflammation.7
The infants were studied by measuring faecal calprotectin (Calprest, Calprotech Ltd, London, UK) one week before Pentavac (at 12 months of age) and MMR (at 18 months) vaccination, and two and four weeks later, respectively. Pentavac does not contain mercury, which has been proposed to predispose to the toxicity of MMR.8 The pre-Pentavac measurement served as the normal reference range. The faecal calprotectin assay differs somewhat from many of the published ones,9–12 mainly in the extraction procedure and amount of stool required for assay (200 mg rather than 5 g). The Calprest method gives calprotectin values that are approximately five times higher than the older method,13 with improved sensitivity14 for the detection of intestinal inflammation in adults.
All parents provided written informed consent and the studies were approved by the National University Hospital Ethics Committee.
Table 1 shows the median (range) values for faecal calprotectin concentrations in infants. There were no statistically significant differences in faecal calprotectin concentrations at any time points (p>0.25) (Friedman’s two way analyses of variance) or when assessed in subjects studied before and after Pentavac (p>0.2) or MMR (p>0.3) vaccination (paired Student’s t test on logarithmically transformed data which were normally distributed).
Naturally occurring measles viral infection has a predilection for the intestinal lymphoid tissue and may cause intestinal inflammation, which on occasions may resemble Crohn’s disease.15,16 The measles virus has controversially17 been implicated in the pathogenesis of Crohn’s disease18–20 and other diseases, including multiple sclerosis.21 The suggestion that the live attenuated measles vaccine might lead to ileocolonic inflammation with autistic features1,2 has caused equal interest. This hypothesis was formulated in an attempt to explain the high prevalence of “enterocolitis” in autistic children with gastrointestinal symptoms.1,6 Consequent to the measles vaccine virus induced ileocolonic inflammation, it is suggested, there is increased intestinal permeation of a variety of intestinally derived neuroactive peptides that interfere with brain development.6,22–24 In support of this hypothesis are reports of intestinal pathology1,2 and abnormal intestinal function in children with autism25–27 when examined a number of years after the vaccination. These data are not particularly controversial but rather highlight the possible role and effect of the measles vaccination virus in the development of this inflammation in the immediate post-vaccination period and the postulated consequential effect on brain function.
In this study we specifically assessed the possibility that MMR vaccination leads to subclinical intestinal inflammation in infants undergoing immunisation. The upper limit of faecal concentrations of calprotectin (110 mg/l; 95% confidence limits (2 SD) calculated from logarithmically transformed mean data) before vaccinations at 12 and 18 months of age are comparable with published data in normal infants of the same age28–30 and are twice as high as those reported in healthy adults. Pathological intestinal inflammation is easily differentiated from normal as faecal calprotectin values are usually well in excess of 1000 mg/l28,29 under these circumstances.
There was no evidence that either Pentavac or MMR vaccination provoked subclinical intestinal inflammation in any of our apparently healthy children during the four week post-vaccination period. This lack of a detectable intestinal inflammatory response suggests that the measles vaccine virus itself is not enterotoxic in healthy infants which argues against the MMR induced autistic “enterocolitis” theory. This does not however rule out the possibility that vaccination might have an adverse effect on susceptible infants that are perhaps immune compromised or with an immunological makeup that predisposes them to autoimmune disease.31
The study was supported by the Science Fund of the University Hospital Hringbraut Reykjavik and by Wyeth Lederle