Vertebrate host defense against infection is mediated by the combined functions of the innate and adaptive arms of the immune system. Vaccination typically targets the adaptive immune response promoting long-lived antibody and T cell responses specific to the pathogen in question. However, an alternative strategy would be to boost the non-specific effector functions of the innate immune system thereby promoting host resistance against multiple infectious agents. BCG (Bacille Calmette Guerin) is a century old vaccine that utilizes an attenuated strain of Mycobacterium bovis to prevent tuberculosis (TB). While now recognized to provide inconsistent protection against adult pulmonary TB, BCG is still employed to protect infants and children against disseminated, extra-pulmonary forms of the disease. Interestingly, BCG vaccination has been known for over 60 years to have non-specific beneficial effects reducing all-cause mortality in infants as well as promoting tumor regression and is a widely used therapy for bladder cancer. The basis of these off- target effects of BCG is poorly understood but lately has received a lot of investigation as a possible manifestation of a phenomenon called “trained immunity”.

Exciting new research in the TB field has indicated that when administered to non-human primates intravenously (iv) instead of by the conventional intradermal/subcutaneous (sc) route, BCG can induce sterilizing immunity against aerosol Mycobacterium tuberculosis challenge. Our group has studied the possible contribution of innate immune mechanisms to this unusual protection and in the process discovered that when given iv (but not sc ) BCG also induces striking resistance against intranasally administered SARS-CoV-2 in mouse models. My talk will focus on the immunological mechanisms underlying this non-specific protection and more generally on how innate immune stimulation could be used to promote host resistance against respiratory pathogens.