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

ABSTRACT Protective variables for COVID-19 are unknown. ‘Trained immunity’ of the populace as a result of BCG immunization 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 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 per million population, at all the time points evaluated. We propose that on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes may actively consider, if not already, the inclusion of controls for underlying ‘trained immunity’ and heterologous cell-mediated immunity prevalence that may be pre-existing or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning their potential benefit.