OR21

1:Faculty of Medicine, Universidade Católica Portuguesa, 2635-631 Rio de Mouro, Portugal; 2:Center for Interdisciplinary Research in Health, Universidade Católica Portuguesa, 2635-631 Rio de Mouro, Portugal

Mycobacterium tuberculosis (M.tb) causes active tuberculosis (TB) leading to death in most cases if left untreated, latent infection, or can be cleared by the host leaving no trace. Protection against TB is strongly dependent on CD4⁺ T-cells, and to some extent CD8⁺ T-cells, as is demonstrated by the absence of protection in immunocompromised individuals with CD4⁺ T-cell lymphopenia. The identification of mycobacterial-specific peptides presented by MHC-I and MHC-II to T-lymphocytes is paramount to understanding the mechanisms of protection against TB.

Using immunopeptidomics in human macrophages infected with Bacillus Calmette-Guérin (BCG) (Bettencourt et al, NPJ vaccines 2020), or M.tb (Almujri et al, in review), 112 BCG and 81 M.tb antigens were identified, respectively. Strikingly, 12 antigens were presented by both BCG and Mtb-infected cells. In the first study, five antigens were expressed in viral vectors, and evaluated as vaccine candidates in a murine aerosol M.tb challenge model. Vaccines containing combinations of three (glfT2, iniB, fas) or five antigens (glfT2, iniB, fas, PPE15, ag85A), as BCG booster, conferred significant protection in mice compared to BCG alone. In the second study three antigens were formulated as protein-in-adjuvant, or DNA vaccines, and one antigen (metE) conferred significant protection in mice. These results constitute a proof-of-concept for this unbiased strategy to identify novel candidate antigens for vaccines against TB.

Finally, the antigens presented by both BCG and Mtb-infected cells, represent the most promising antigen candidates for vaccines to boost BCG. I will describe the selection of combinations of antigens for vaccine design and development.