"Trained immunity" from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes

Protective variables for Coronavirus Disease 2019 (COVID-19) are unknown. "Trained immunity" of the populace as a result of Bacille Calmette-Guérin (BCG) vaccination policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of "trained immunity" or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 epidemiological data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity-a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations-is found consistently negatively correlated with COVID-19 infections and mortality. We seek to draw attention toward the inclusion of controls for underlying "trained immunity" and heterologous cell-mediated immunity prevalence that may be preexisting or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning potential benefit from them.