BCG has profound immunomodulatory effects that may reduce the risk of food allergy in children
The prevalence of allergic disease in developed countries has risen dramatically since the mid 20th century and Australia now has the highest documented prevalence of childhood food allergy in the world.1 Theories to explain this rise include changes in the timing of food introduction, epigenetic changes related to environmental factors, and alterations in micronutrient status (particularly of vitamin D). Interactions between the human microbiome, microbial exposures during infancy and the developing immune system are particularly important. According to this model, termed the “hygiene hypothesis” or, more recently, “biome depletion”,2 immune system development may be influenced not only by infections, but also by exposures to animals and antibiotics, and through birth by Caesarean section.
There are currently no interventions to combat the epidemic of food allergy. However, vaccination with live attenuated Mycobacterium bovis, also called bacille Calmette-Guérin (BCG), might offer a strategy to reduce the risk of allergic disease at the population level or in high-risk groups. Administered shortly after birth to protect against tuberculosis, BCG is the oldest vaccine still in routine use (since 1921), and is one of the most widely used vaccines in newborns and young infants worldwide. It has a long-established safety profile: with correct intradermal administration, local adverse effects occur in fewer than 1% of vaccinees. Disseminated BCG disease is rare, usually occurring only in the context of HIV infection or rare inherited immunodeficiencies. The ability of BCG to influence the immune response to diseases unrelated to tuberculosis has become a topic of great interest with broad, global implications.3 It is these immunomodulatory effects, distinct from the protection it provides against tuberculosis, that underlie the possibility that BCG might be useful in reducing the risk of allergic disease.
T-helper cells, atopy and heterologous immunity
For more than half a century, it has been recognised that natural infections can affect the immune response to unrelated pathogens by, for example, altering the balance in T-helper cells. T-helper 1 (Th1) and T-helper 2 (Th2) cells are subsets of adaptive T-lymphocytes that are distinguished on the basis of the cytokines they produce. In simple terms, Th1-mediated responses are associated with protection against intracellular pathogens (and also some autoimmune diseases), while Th2-mediated responses are linked to IgE production, atopy (elevated sensitivity to certain allergens), and protection against extracellular parasites. A balance between these two cell types is maintained by reciprocal inhibition and through regulation by T-helper 17 and regulatory T-cells.
Recent evidence suggests that BCG vaccination can alter T-helper cell polarisation in a similar manner to natural infection.4 In particular, after a natural infection or BCG vaccination, T-cells can cross-protect against other, unrelated pathogens in a process known as heterologous T-cell immunity.3,5 Further, the innate immune system, like the adaptive immune system, has the ability to learn from past experience in a phenomenon termed “trained immunity”.6 BCG vaccination enhances or trains the innate immune response to subsequent infection through epigenetic reprogramming of monocytes.5
It has been proposed that these immunological mechanisms explain the remarkable finding that, in high-mortality settings, certain infant vaccinations have an effect on child mortality that is not explained by their effect on the targeted disease (the concept of heterologous or non-specific effects of vaccines).3,7 There is evidence that live attenuated vaccines, such as BCG and the measles vaccine, reduce all-cause infant mortality in high-mortality settings, primarily by protecting against neonatal sepsis and respiratory infections caused by pathogens other than Mycobacterium tuberculosis and the measles virus.3,7 Further, recent evidence from Denmark suggests that the measles–mumps–rubella (MMR) vaccine reduces the risk of hospitalisation for infectious diseases caused by unrelated (non-targeted) pathogens for at least 6 months after vaccination,8 showing that there is also a direct relevance to high-income, low-mortality settings such as Australia.
The impact of childhood vaccinations on heterologous immunological development raises the question of whether other immune-mediated conditions might be affected by childhood vaccinations. Atopic disease is characterised by dysregulation of the immune system, particularly by Th2 cell polarisation, partly due to epigenetic changes related to exposure during early life to microorganisms, micronutrients and other modulators of the immune system.9
The first randomised trials of BCG in at-risk infants
Food allergy, in particular, is one of the earliest manifestations of the atopic phenotype and has been described as the “second wave” of the allergy epidemic.9 Its prevalence is rising at a time when the prevalence of other atopic diseases has plateaued, and it now affects about 10% of 12-month-old infants in Melbourne.1 As Th2 cell polarisation in these cases probably occurs very early in infancy, possibly in utero, neonatal BCG vaccination could potentially divert immune system development toward a less atopic phenotype and prevent subsequent clinical food allergy because of its marked Th1 cell polarising effect. Importantly, BCG is suitable for administration immediately after birth.4
Recent reviews suggest that vaccination with BCG protects against childhood asthma and eczema, but there have been few randomised controlled trials and the data from observational studies are inconsistent.10,11
Although the two randomised trials of BCG and atopic disease that have been reported had shortcomings, and neither was designed to specifically investigate food allergy, their results are nevertheless interesting. In the first study, 121 6-week-old infants at high risk of allergic disease (having a close relative with allergic disease) in the Netherlands were randomised to vaccination with BCG or placebo to determine whether BCG vaccination reduced the rate of subsequent allergic disease. At 18 months of age, BCG vaccination was associated with reduced prevalence of eczema (relative risk [RR], 0.72; 95% CI, 0.5–1.0; P = 0.07) and reduced use of eczema medication (RR, 0.58; 95% CI, 0.3–1.0; P = 0.04), but there was no effect on other allergic diseases.12 However, the study was stopped well before the target number of infants had been enrolled, so that it was underpowered and unable to definitively determine whether BCG vaccination had an overall effect on atopic disease. Further, infants were vaccinated at 6 weeks of age, but there is evidence that the protective effects against atopic sensitisation are greatest when BCG is given during the first week of life.13
The second randomised trial compared early (median age: 2 days) versus late (median age: 42 days) BCG vaccination in 281 low-birthweight infants in Guinea-Bissau, West Africa.There was no overall effect on atopic sensitisation (assessed by skin-prick testing) 3 to 9 years later. However, when children who had been given a vitamin A supplement (a potential effect modifier) were excluded from the analysis, early BCG appeared to have been protective (odds ratio [OR], 0.40; 95% CI, 0.15–1.06; P = 0.07). Interestingly, among all children, those who had responded to BCG vaccination by developing a scar had a diminished risk of sensitisation (OR, 0.42; 95% CI, 0.19–0.94; P = 0.03). However, the small size of the study made it impossible to determine a general effect of BCG vaccination on atopic sensitisation. The study was also limited by the absence of an unvaccinated control group. Finally, the high burden of infectious disease in the treated population and the low prevalence of atopic disease in Africa limit its relevance to children in Australia.13
The next steps
Neither of these studies investigated food allergy adequately, but definitive trials are underway elsewhere. In Melbourne, more than 1400 infants are being enrolled in a randomised controlled trial to investigate whether BCG at birth reduces allergy and infection during the first year of life (ClinicalTrials.gov identifier: NCT01906853). Extensive immunological studies as well as investigation of the gut and respiratory microbiome will help unravel the mechanisms underlying any observed effects.14 In Denmark, 4300 infants have been enrolled in a randomised controlled trial of BCG vaccination at birth, with the primary outcome being hospitalisations by 15 months of age (ClinicalTrials.gov identifier: NCT01694108). Secondary outcomes include allergic disease in general and food allergy in particular; immunological studies will complement the epidemiological investigation.15 Each study also includes the prevalence of non-tuberculosis infectious diseases as outcomes, based on the ability of BCG to confer protection against unrelated infections.
The World Health Organization has recently highlighted the potential importance of the heterologous effects of BCG vaccination and advocated that more studies be undertaken to identify the underlying immunological mechanisms.16 In addition to BCG, the possible heterologous effects of other vaccinations need further exploration, both in relation to doses and timing.13 If routine childhood vaccinations in younger infants leave profound, long-lasting impressions on the immune system that influence susceptibility to non-targeted infections,7,17,18 it is not inconceivable that other immune-mediated diseases, including food allergy and other atopic diseases, may also be affected. The possibility of using currently available vaccinations to alter the immune system in this beneficial manner is an exciting prospect in the battle against the epidemic of allergic disease.