COVID-19 continues to exact a toll on human health despite the availability of several
vaccines. Bacillus Calmette Guérin (BCG) has been shown to confer heterologous immune protection against
viral infections including
COVID-19 and has been proposed as
vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against
COVID-19 using the golden Syrian hamster model together with immune profiling and single cell
RNA sequencing (scRNAseq). We observed that BCG reduced both lung SCV2 viral load and
bronchopneumonia. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell
lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits
immunoglobulin-producing plasma cells to the lung suggesting accelerated antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung
immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.