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

Singh, S.; Maurya, R. P.; Singh, R. K.

Protective variables for COVID-19 are unknown. 'Trained immunity' of the populace as a result of BCG 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 'trained immunity' has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any correlation. Whereas, when we analyze the COVID-19 data of European countries without any mandatory BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of Mycobacterium spp.(including BCG vaccine) exposure of the populations is consistently negatively correlated with COVID-19 infections per million population at all the time points evaluated [r(20): -0.5511 to -0.6338; p-value: 0.0118 to 0.0027]. The results indicate that the on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes should consider the inclusion of 'controls' for underlying 'trained immunity' prevalence or that resulting from the intervention (BCG vaccine) in such trials to arrive at more dependable conclusions.