Systematic evaluation of Mycobacterium tuberculosis proteins for antigenic properties identifies Rv1485 and Rv1705c as potential protective subunit vaccine candidates

ABSTRACT

Lack of efficacious vaccines against Mycobacterium tuberculosis (MTB) infection is a limiting factor in the prevention and control of tuberculosis (TB), the leading cause of death from an infectious agent. Improvement or replacement of the BCG vaccine with one that reliably protects all age-groups is urgent. Concerns exist that antigens currently being evaluated are too homogeneous. To identify new protective antigens, we screened 1781 proteins from a high-throughput proteome-wide protein purification study for antigenic activity. Forty-nine antigens (34 previously unreported) induced antigen-specific IFN-γ release from peripheral blood mononuclear cells (PBMCs) derived from 4452 TB and suspected TB patients and 167 healthy donors. Three (Rv1485, Rv1705c and Rv1802) of the 20 antigens evaluated in a BALB/c mouse challenge model showed protective efficacy, reducing lung CFU counts by 66.2%, 75.8%, and 60%, respectively. Evaluation of IgG2a:IgG1 ratios and cytokine release indicated that Rv1485 and Rv1705c induce a protective Th1 immune response. Epitope analysis of PE/PPE protein Rv1705c, the strongest candidate, identified a dominant epitope in its extreme N-terminal domain accounting for 90% of its immune response. Systematic pre-clinical assessment of antigens Rv1485 and Rv1705c is warranted.