Newborn BCG vaccination complemented by boosting correlates better with reduced juvenile diabetes in females, than vaccination alone

•Retrospective birth cohorts and national vaccination history show BCG effect on T1D.•Newborn BCG vaccination and boosting prevents T1D in female but not in male youth.•BCG mitigates murine and human T1D glycaemia by induction of aerobic glycolysis.•BCG prevents T1D in female NOD mice by suppression of diabetogenic immune cells.•BCG may prevent T1D in human females by a similar mechanism as in NOD mice. Type 1 diabetes (T1D), like other autoimmune diseases, is on the rise since the second half of the 20th century. Hypothetically this has been ascribed to restricted exposure to microbial diversity due to advanced hygienic practices accompanying modernization, and increasing prosperity in urban versus rural habitats. The autoimmune animal model of T1D, inhibited by Bacillus Calmette Guerine (BCG), motivated testing the impact of BCG on T1D incidence in humans. Several epidemiological analyses, short of one, failed to demonstrate a protective effect of BCG against T1D. The present retrospective analysis of two data sets reevaluates the hypothetic inhibitory effect of BCG on human T1D. Reassessment of data from a Swedish study reveals that a single BCG vaccination provided a small but significant protection against T1D. A second data set of T1D prevalence/1000 Israeli military conscripts, from a doctoral thesis presenting 17 birth cohorts at age 17 is evaluated against the national schedule of vaccination related to years of birth. To correct for the annual increasing T1D trend the mean urbanization (census) rate was set as an annual moving average and factored into the prevalence (T1D/1000) of respective birth cohorts. Three groups of cohorts corresponding to BCG vaccination are presently identified; Group A corresponds to the years in which newborns were vaccinated and boosted if necessary, at age 12. Group B corresponds to the period when boosting was discontinued. Group C corresponds to years when newborn BCG vaccination was discontinued. T1D (only in females) was slightly but significantly lower in group B (n = 5 cohorts) versus C (n = 8 cohorts, p = 0.0475, by Mann Whitney U test). T1D in group A (n = 4 cohorts) was lower than in group B (p = 0.02). This analysis supports the hypothesis that in human females postnatal BCG vaccination, reinforced by boosting, has a protective impact on T1D being superior to omitted boosting, which in its turn is still better than stopping vaccination altogether. This analysis further suggests that upon advanced modernizat