The complex coincidence of several immunopathological, socio-cultural, and health infrastructure factors may affect the COVID-19 related mortality among different populations. The impact of the age on disease progression has been confirmed in several studies. Recently limited ecological and clinical studies have sparked controversy among researchers about the protective impact of the non-specific effect of routinely used Bacille Calmette-Guerin (BCG), Hepatitis A virus (HAV), and influenza (Flu) vaccines or their natural infections against COVID-19. In the present study, variables, including BCG vaccination coverage, HAV prevalence, and population age distributions, from 59 countries were analyzed to examine their potential association with COVID-19 infection and related mortality rate. Concerning COVID-19 cases/million population (1MP) and mortality, there are significant differences between countries with and without BCG vaccination programs (p-value <0.001). A significant negative correlation between both BCG coverage and HAV prevalence with COVID-19 related mortality was also found (r (59)=-0.4, p-value <0.05), (r (59) =-0.3, p-value <0.01). Based on the results of the present study, previous ecological analyses and available epidemiological evidence, along with knowledge of the immune response to BCG, HAV and influenza vaccination, as well as COVID-19 infection progression, the current study suggest a hypothesis that IFN-γ induced immune response which could be triggered by BCG, HAV, and flu vaccination or natural infections may have a protective effect against COVID-19 related mortality.Keywords: COVID-19, Interferon γ,,, mortality, BCG, HAV.