BCG-Based Vaccines Elicit Antigen-Specific Adaptive and Trained Immunity against SARS-CoV-2 and <i>Andes orthohantavirus</i>

Background: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis ( M. tb ). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb , other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus . Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 10 8 CFU or one dose of 1 × 10 5 CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4 + and CD8 + T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response.