BCG Delta BCG1419c increased memory CD8(+) T cell-associated immunogenicity and mitigated pulmonary inflammation compared with BCG in a model of chronic tuberculosis

Abstract

Previously, we reported that a hygromycin resistant version of the BCG Delta BCG1419c vaccine candidate reduced tuberculosis (TB) disease in BALB/c, C57BL/6, and B6D2F1 mice infected with Mycobacterium tuberculosis (Mtb) H37Rv. Here, the second-generation version of BCG Delta BCG1419c (based on BCG Pasteur ATCC 35734, without antibiotic resistance markers, and a complete deletion of BCG1419c) was compared to its parental BCG for immunogenicity and protective efficacy against the Mtb clinical isolate M2 in C57BL/6 mice. Both BCG and BCG Delta BCG1419c induced production of IFN-gamma, TNF-alpha, and/or IL-2 by effector memory (CD44(+)CD62L(-)), PPD-specific, CD4(+) T cells, and only BCG Delta BCG1419c increased effector memory, PPD-specific CD8(+) T cell responses in the lungs and spleens compared with unvaccinated mice before challenge. BCG Delta BCG1419c increased levels of central memory (CD62L(+)CD44(+)) T CD4(+) and CD8(+) cells compared to those of BCG-vaccinated mice. Both BCG strains elicited Th1-biased antigen-specific polyfunctional effector memory CD4(+)/CD8(+) T cell responses at 10 weeks post-infection, and both vaccines controlled Mtb M2 growth in the lung and spleen. Only BCG Delta BCG1419c significantly ameliorated pulmonary inflammation and decreased neutrophil infiltration into the lung compared to BCG-vaccinated and unvaccinated mice. Both BCG strains reduced pulmonary TNF-alpha, IFN-gamma, and IL-10 levels. Taken together, BCG Delta BCG1419c increased memory CD8+T cell-associated immunogenicity and mitigated pulmonary inflammation compared with BCG.