"Trained Immunity" from Mycobacterium spp. exposure (BCG vaccination and environmental) may have an impact on the incidence of early childhood leukemia

Abstract

Preventive variables for childhood leukemia incidence (LI) remain unknown. Past assertions that childhood vaccinations, especially BCG, may be potentially protective have remained disputed for over five decades because of the lack of a unifying framework to explain variable outcomes in different studies. An examination of the early childhood LI for 2020 in European Region countries with supposedly similar underlying confounders but differential childhood vaccination coverage displays negative covariation with prevailing Mycobacterium spp. exposure in BCG-vaccinated children. The childhood LI in 0-4-year-old populations with >90% childhood BCG vaccination coverage is found to be strongly but negatively correlated with prevailing tuberculin immunoreactivity [r(24): -0.7868, p-value: < 0.0001]. No such correlation existed for the LI in 0-4-year-old populations without BCG vaccinations, though weak associations are hinted at by the available data for MCV2, PCV3, and DTP3 vaccinations. We hypothesize that early childhood BCG vaccination "priming" and subsequent "trained immunity" augmentation by "natural" boosting from Mycobacterium spp. exposure play a preventive and protective role in childhood LI. The non-consideration of prevailing "trained immunity" could have been a cause behind the conflicting outcomes in past studies. Exploratory studies, preferably performed in high-burden countries and controlling for the trained-immunity correlate and other potential confounders, would be warranted in order to establish a role for BCG vaccination and early-life immune training (or lack thereof) in childhood LI and help put the current controversy to rest.

Keywords: BCG vaccine; DTP3; MCV2; Mycobacterium spp.; PCV3; childhood leukemia; childhood vaccinations; trained immunity.

Figure 1

Early childhood leukemia incidence (LI) in 2020 negatively correlated with “Trained Immunity” prevalence in BCG-vaccinating countries. (A) The prevalence of tuberculin sensitivity test (TST) positivity – a measure of BCG vaccination or environmental Mycobacterium spp. exposure conferred “trained immunity” in children/individuals without active tuberculosis, is negatively correlated with leukemia incidence (LI) in 0-4Y-olds (<5Y-olds) [r(50): - 0.4772, p-value: <0.0005]. (B) The early childhood (0-4Y-olds) LI rates are found to be more strongly negatively correlated with the populations’ TI correlate (TST positivity) in BCG-vaccinating countries (BCG) with >90% BCG vaccination coverage in 1-Year-olds, unlike that observed for the non-vaccinating countries (No-BCG). The LI in 0-4Y-old children population that had been differentially vaccinated with DTP3 (C), MCV2 (D), PCV3 (E), and BCG (F) also negatively correlated with the TI correlate (TST positivity) of the population. Note: The negative association of populations’ TI correlate (TST positivity) with the early childhood LI with regard to coverage of other childhood vaccinations (e.g., DTP3, MCV2, PCV3) is substantially weaker than that for BCG (R²-values ranged from 0.1173 to 0.2997 for DTP3, MCV2, PCV3, as compared to 0.6191 for BCG). The inclusion of partially BCG-vaccinated countries in the non-vaccinated or vaccinated group did not affect the overall relationship/correlation. [n = number of countries; *average vaccination coverage (%) in 1-Year-olds for 2016–2020; R²: coefficient of determination; regression line is solid for p-values <0.05, while it is dashed/broken for p-values >0.05].