BCG vaccination provides cross-protection against influenza infection through trained adaptive immunity.

Abstract The ongoing COVID-19 pandemic highlights the threat emerging viruses pose to the world. While the development of a new vaccine can take at least 1–2 years, alternative approaches are urgently needed to alleviate the burden of rapid transmission. The Bacillus Calmette-Guerin (BCG) vaccine is currently used worldwide to prevent tuberculosis but has also been shown to protect against a wide range of infections. Several studies have attributed this broad protection to trained immunity. While innate immune cells usually act in a non-specific manner, in the context of trained immunity, these cells acquire an enhanced capacity to protect against different pathogens. However, preliminary work suggests that BCG may be mediating trained immunity by enhancing the adaptive immune system as well. Before the current pandemic, Influenza A virus (IAV) was responsible for the most devastating pandemic in history and remains the cause of yearly epidemics. Thus, investigating the cross-protection of BCG against IAV could determine whether BCG vaccination could offer an alternative preventive strategy against viruses with pandemic potential. To determine the protective effects of BCG against IAV infection, C57BL/6 mice were vaccinated intravenously (-iv) or subcutaneously (-sc) with BCG then infected with H1N1. We showed that BCG-iv vaccinated mice exhibited increased survival against IAV and a decreased viral load. Interestingly, BCG-iv uniquely induces the enrichment of CX3CR1+ αβ memory T cell populations which may be contributing to protective immunity against IAV infection. Overall, the present study evaluates whether beneficial effects from a widely distributed vaccine could provide some protection against emerging pulmonary pathogens.