Saving lives by training innate immunity with bacille Calmette-Guerin vaccine.

F or many years, public health practitioners have been puzzled by the fact that vaccines developed to fight specific diseases also have nonspecific effects that alter the host response to unrelated infections. In PNAS, Kleinnijenhuis et al. (1) describe part of the immunological mechanism for the nonspecific effects of vaccines: Bacillus Calmette–Guérin vaccine (bacille Calmette–Guérin), which is used to protect against tuberculosis (TB), induces nonspecific protection against unrelated pathogens via epigenetic reprogramming of monocytes. When the Swedish Tuberculosis Society introduced bacille Calmette–Guérin to protect against TB in the northernmost province of Sweden in 1927, Carl Näslund, the physician in charge, noted that children who received bacille Calmette–Guérin at birth had a mortality rate that was almost threefold lower than the very high rate of 10% among unvaccinated children. Most of the reduction in mortality was seen in the first year of life, whereas TB killed mainly older children. Näslund concluded, “One is tempted to explain this very low mortality among vaccinated children by the idea that BCG vaccine provokes a nonspecific immunity” (2) (translated from the French). Subsequent controlled trials have confirmed that bacille Calmette–Guérin may do more than protect against TB. In several controlled trials among children and teenagers in the United States and United Kingdom in the 1940s and 1950s, bacille Calmette– Guérin reduced nonaccidental deaths from causes other than TB by 25% (95% confidence interval 6–41%) (3). Nonetheless, as the incidence of TB declined, virtually all European countries opted for the specific interpretation and removed bacille Calmette–Guérin from their vaccination schedule or restricted it to high-risk groups. Subsequent studies have suggested that this may have increased the incidence of a wide variety of conditions, such as atopic dermatitis (4), malignant melanoma (5), and lymphoma (6). However, bacille Calmette–Guérin remains one of the most widely used vaccines because it is given routinely in lowincome countries, where TB is endemic. In these countries, the World Health Organization (WHO) recommends that bacille Calmette–Guérin be given at birth to normal-birth-weight neonates. Low-birthweight neonates are often considered to be immunologically immature; thus, they are given bacille Calmette–Guérin only when they have reached normal birth weight. This has provided an opportunity to test the effect of giving bacille Calmette– Guérin at birth in randomized trials in low-birth-weight neonates. In West Africa, these trials have shown that bacille Calmette–Guérin reduces neonatal mortality by more than 40%, mainly by preventing neonatal sepsis and respiratory infections (Fig. 1) (7, 8). There are major public health implications if BCG given at birth reduces neonatal mortality by more than 40%. Neonatal infections kill millions of children every year in low-income countries, and high neonatal mortality remains one of the main stumbling blocks for reaching the Millennium Development Goal 4 of reducing child mortality by twothirds between 1990 and 2015. Although the WHO recommends that bacille Calmette–Guérin be given at birth to normal-birth-weight children, it is very often given much later for logistic reasons; thus, the median age of bacille Calmette– Guérin vaccination is more than 4 wk in African countries (9). It may prove extremely cost-effective to ensure that all neonates, both those with normal and low birth weights, receive bacille Calmette– Guérin on time at birth. However, these potentially very important findings have so far been largely ignored, mainly because they seemed biologically implausible when judged by our previous model of immunity and the effect of vaccines (10). The work of Kleinnijenhuis et al. (1) is therefore extremely important because it offers an immunological explanation for the beneficial nonspecific effects of bacille Calmette–Guérin that have been observed in epidemiological studies. In a series of convincing human, animal, and in vitro studies, Kleinnijenhuis et al. (1) document that bacille Calmette–Guérin can induce long-lasting epigenetic changes that lead to increased proinflammatory cytokine production on subsequent challenge with unrelated antigens. In mice, bacille Calmette–Guérin led to a 70% reduction in mortality from an unrelated infection when challenged 2 wk later with Candida albicans. It is very likely that this explains why bacille Calmette–Guérin has been consistently observed to reduce mortality and morbidity to a far greater extent than can be explained by the prevention of TB. It is rare that epidemiological and immunological data support each other to such an extent, telling a completely coherent and plausible story. It is to be hoped that the authors of the present study and others will pursue these results and examine the role of potential effect modifiers, such as age at vaccination, sex, timing of response, boosting of training responses, and interaction with other vaccines. The epidemiological studies suggest that the training effects are stronger in very young individuals (11), and it would therefore be important to examine the mechanisms not only in adult volunteers but in newborns. Many studies have suggested that the beneficial nonspecific effects of vaccines are stronger for females (12), and it is important to investigate whether the training process of the innate immune system differs by sex. In the present study, the first samples were collected after 2 wk (1). However, in the West African trials in low-birth-weight neonates, a significant reduction in mortality was observed within 3 d of bacille Calmette–Guérin vaccination (8). In animals, bacille Calmette–Guérin has an effect after only 1–2 d (13); it is therefore important to establish how quickly the training process becomes effective. Other issues of major interest are the duration of the training effects, the extent to which they are modified by subsequent exposure Fig. 1. Newborn in Guinea-Bissau receives the first training of innate immunity with bacille Calmette–Guérin.