BCG vaccination provides protection against IAV but not SARS-CoV-2

Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism. [Display omitted] •BCG vaccination provides significant protection against IAV in mice and hamsters•BCG provides no protection against SARS-CoV-2 in mice and hamsters•SARS-CoV-2 induces pulmonary hemorrhage and disseminates to the bone marrow•Monocytes from BCG-vaccinated humans induce more cytokines to IAV than SARS-CoV-2 Kaufmann et al. show that BCG vaccination protects mice and hamsters against influenza, but not SARS-CoV-2. The distinct tropism of SARS-CoV-2 for pulmonary endothelial cells may lead to lung hemorrhage and systemic viral dissemination. Thus, the protection of BCG against viral pathogens is mainly determined by pathogenesis of infections.