'Trained immunity' from Mycobacterium spp. (environmental or BCG) exposure predicts protection from Coronavirus disease 2019 (COVID-19)

Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their bacillus Calmette-Guerin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous ′trained immunity′ (TI) conferred by exposure to Mycobacterium spp. ( i.e. , environmental and BCG), it is argued that the estimates of the prevalence of TI of populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (twenty-four), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences ( r (24): -0.79 to -0.57; p-value: <0.004), mortality ( r (24): -0.63 to -0.45; p-value: <0.03), and interim case fatality rates(i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing/planned randomized controlled trials should consciously consider including measures of TI as - a) all individuals immunized do not respond equally, b) small study groups from higher background TI could fail to indicate any protective effect.