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Commentary on the paper by Bremner et al (see page 567)
Parents of children at heightened risk for atopy are frequently concerned about early immunisations. Apart from concerns about rare allergic reactions to the vaccine antigens or contaminants themselves (reviewed in Grüber and colleagues1), there exists a fear that immunisations may promote the development of atopic disease, leading to delayed or incomplete vaccination of these children. Some reports about an association of immunisation and atopic disease have fuelled this fear.
Moreover, the rising prevalence of allergic diseases in many industrialised countries has been associated with improvement in hygiene standards. It is thought that a lack of microbial stimuli delays the maturation from the fetal Th2 skewed immune system towards the more Th1 balanced immune system of the school child, and thus renders children more susceptible to Th2 dependent allergic disease. In this context, early childhood vaccinations have been viewed as a promoter of atopy development, either directly by the administration of agents which induce a Th2-type immune response or indirectly by the prevention of infections which otherwise would induce a preferential Th1-type immune response, and would thus skew the cytokine balance away from atopy.2
What is the currently available evidence for an atopy promoting effect of early childhood immunisations? An IgE response to vaccine antigens is commonly detectable in the sera of vaccinated children. About 50% of infants have detectable IgE against diphtheria/tetanus after primary vaccination,3 and after booster vaccination later in life more than 90% of vaccinees have detectable IgE against the vaccine antigens.4 The IgE response to vaccine antigens seems to be more pronounced among atopic individuals,3,5 but the correlation of IgE and protective IgG against the vaccine antigens is poor.6,7 IgE formation against vaccine antigens should thus be regarded as a regular component of the immune response, although exaggerated in atopics. It should be noted that an IgE response to vaccine antigens is not predictive of allergic side effects to the vaccine.
By contrast, there is no convincing evidence that IgE formation against nutritive or inhalant allergens is enhanced by routine vaccinations. Longitudinal data from infants in a Swedish controlled pertussis vaccine trial and from a German observational birth cohort show no increased sensitisation rate following pertussis vaccination.6,8 In fact, better general vaccination coverage in the latter cohort was dose dependently associated with a transient reduction of the risk for allergic sensitisation to allergens up to age 5 years.9 Two cross-sectional studies, however, suggested an association of vaccination and allergic sensitisation against environmental allergens by deprivation of natural infections. Among pupils from a Swedish anthroposophic school, likely to follow a more traditional lifestyle, including diet and healthcare, measles/mumps/rubella vaccination (MMR) was less common than in regular schools (18% v 93%), as was allergic sensitisation (24% v 34%, respectively), but a history of measles was more common (61% v 1%, respectively).10 In Guinea-Bissau, surviving measles cases from a devastating measles epidemic were less frequently sensitised to environmental allergens than children who were vaccinated against measles.11 It is unclear, however, to what extent a selection bias due to a loss of children with a less efficient Th1 immune response to the measles infection has flawed the results.
Does routine immunisation promote the development of allergic disease? In many cases, atopic dermatitis is the earliest clinical manifestation of the “atopic march”. Parents frequently report an onset of atopic dermatitis after primary immunisation, but this is generally what would be expected with regard to the peak incidence of the disease. A recent longitudinal survey with 9744 children followed up from birth to 3–15 years reported an almost twofold incidence ratio of atopic dermatitis among measles, mumps, and rubella vaccinated children versus non-vaccinated children; the incidence ratio for measles infected children, however, was similar.12 For pertussis vaccination, no effect was seen in the Swedish trial.13 In the German cohort, measles/mumps vaccinated children with a family history of atopic disease were less likely to experience atopic dermatitis up to age 5 years than non-vaccinated children (OR 0.50, 95% CI 0.29 to 0.86), and a dose dependent inverse association of atopic dermatitis and better vaccination coverage in general was noted.9 A large international cross-sectional study involving more than 100 000 children (ISAAC) showed a weak negative association of atopic dermatitis and better diphtheria-tetanus-pertussis or measles vaccination coverage.14
Some cross-sectional studies suggested an association of asthma symptoms and vaccination. In a retrospective, non-randomised study, 11% of 243 children vaccinated against diphtheria, tetanus, and pertussis but only 2% of 203 non-vaccinated children developed subsequent asthma.15 In New Zealand, none of 23 children without documented vaccination against diphtheria, tetanus, pertussis, and polio developed asthma, but 23% of 1242 vaccinated children had asthma episodes.16 The Swedish pertussis trial showed no association of pertussis vaccination and asthma symptoms.13 In ISAAC, there was a weak negative association of asthma symptoms with local birth-year immunisation rates for DTP and measles,14 and in the German birth cohort study, again a dose dependent reduction of asthma with better vaccination coverage was seen.9
Allergic rhinitis is a relatively late event of the “atopic march”. In ISAAC, a negative association of allergic rhinitis and DTP or measles vaccination was found among adolescents.14 In the pertussis trial, no association was found except a higher prevalence of allergic rhinitis at 7 years for children initially immunised with the two component pertussis vaccine and who received a booster dose with an acellular vaccine compared with those who received no booster vaccination (relative risk 3.6; 95% CI 1.1 to 12.0).13 In this issue, Bremner et al show no risk reduction of hay fever among children who received DTP and MMR vaccination on time; among those with delayed completion of these vaccinations, however, a reduced risk for hay fever is reported.17 The authors hypothesise that intercurrent infections account for the delay in vaccination and for the hay fever risk reduction.
By contrast to allegedly Th2 promoting vaccines, BCG has gained recent interest as an antagonist of exaggerated effector T-cell immune responses. Numerous experimental studies show the capacity of mycobacterial preparations to down-regulate allergic sensitisation and allergen induced airway hyperreactivity.18–20 Following the observation that tuberculin reactions among BCG vaccinated children from a region with a high mycobacterial burden was inversely associated with total IgE, allergic sensitisation, and allergic symptoms,21 a large series of epidemiological studies investigating mainly children from low tuberculosis incidence countries have mostly failed to confirm this inverse association (reviewed in Grüber and Paul22). Accordingly, Bremner et al report in this issue no protective effect of BCG vaccination against hay fever in British children.17 Results of attempts to employ mycobacterial vaccines as a therapeutic agent in allergic disease have been inconsistent so far.23–27 Prospective prevention trials are lacking. Neonatal BCG vaccination has been abandoned in many countries with a low tuberculosis incidence because of its limited efficacy against tuberculous infection and potentially severe side effects. Reintroduction of BCG vaccination as an atopy preventing measure is clearly not justified.
Other bacterial antigens such as cellular pertussis seem to down-regulate IgE to co-administered antigens.6 In an experimental model, pertussis also down-regulates hyperresponsiveness to a model allergen (personal observation). Theoretically, it seems to be possible to simultaneously induce immunity against infectious agents and tolerance against allergens.28 In the light of recent advances in the understanding of relatively harmless infectious agents as adjuvants for regulatory T-cell induction,29 vaccines may be considered for atopy prevention as a vehicle with an extensive safety record in children.
How can we understand the findings regarding early immunisation and atopy with regard to the hygiene hypothesis? Routine immunisations effectively protect our children from potentially harmful disease which thus leads to a reduction in microbial stimulation. Considering experimental data, it seems biologically plausible that vaccines may serve as a surrogate stimulus for the developing immune system. A possible atopy inhibiting effect by better vaccination coverage as suggested by some epidemiological data might be more relevant to the development of atopic disease than vaccine induced Th2-type phenomena.
Parents of children about to be vaccinated should be reassured that common childhood vaccines are unlikely to promote atopic disease, and be informed that possible future development of atopic symptoms is most likely not causally related to vaccination but a coincidence. It remains to be elucidated whether vaccines specifically designed to down-regulate Th-2 type immunity are safe and effective in preventing the development of atopic disease. In the meantime, effective protection against potentially life threatening or disabling infectious diseases should be offered to every child—atopic or not.
Commentary on the paper by Bremner et al (see page 567)
Competing interests: none declared
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