TY - JOUR T1 - Making sense of emerging evidence on the non-specific effects of the BCG vaccine on malaria risk and neonatal mortality JF - BMJ Global Health JO - BMJ Global Health DO - 10.1136/bmjgh-2020-002301 VL - 5 IS - 3 SP - e002301 AU - Quique Bassat AU - Gemma Moncunill AU - Carlota Dobaño Y1 - 2020/03/01 UR - http://gh.bmj.com/content/5/3/e002301.abstract N2 - Vaccines are, indisputably, one of the greatest public health interventions, with a substantial positive impact on child survival. The remarkable declines in child mortality observed during the last quarter of a century, whereby global under 5 deaths were essentially halved, go hand in hand with the estimated 2–3 million child deaths prevented by vaccines annually.1 The premise for this is clear: vaccines directly prevent a variety of life-threatening diseases. Vaccines can also be held directly responsible for the eradication of smallpox, the first and only infectious disease extinguished by the action of humans and are paving the way for the disappearance of other terrible infections such as polio, measles or rubella.In recent years, however, it has become increasingly clear that the impact of vaccines is achieved by their direct prevention against specific pathogens, and through a series of non-specific effects.2 These non-specific effects, also termed ‘heterologous’ effects, appear to be more common as a result of the vaccination with certain live-attenuated antigens (eg, the Bacillus Calmette-Guérin (BCG), measles or polio), and have been proposed for a wide variety of existing vaccines. Observational studies have pointed out to a longer-term all-cause mortality decrease attributable to having received those vaccines, independent of the target disease. Non-specific effects are understandably less tangible and less well-characterised than the direct ones, and therefore, remain a matter of significant debate and controversy.3To date, the nature of non-specific effects has not been fully elucidated, although the current thinking points to trained innate immunity as the main underlying mechanism.4 Trained immunity refers to an immunological memory of the innate response, a process in which certain stimuli induce epigenetic changes in the innate immune cells,5 increasing the response to the same and different subsequent stimuli. Vaccines with non-specific effects would induce reprogramming of … ER -