A Mycobacterium tuberculosis rare variable antigen vaccine reduces lung pathology without affecting bacterial burdens

Mycobacterium tuberculosis is the leading cause of death globally due to a single infectious agent. Currently, no reliable vaccine against pulmonary tuberculosis, the primary adult disease caused by Mtb infection, exists. CD4 T cells are essential in protection against Mtb infection and inducing a protective CD4 T cell response remains the goal of most Mtb vaccines currently in testing. However, most Mtb T cell antigens do not exhibit antigenic variation, suggesting that T cell recognition does not drive selection of escape mutants. We utilized a set of antigens that do exhibit sequence diversity within human T cell epitopes and tested the impact of vaccination with these rare variable antigens (RVMA) using a DNA vaccine platform. We found vaccination with RVMA significantly alters the immune response to Mtb infection in both C57BL/6 and hypersusceptible SP140-/- mice without reducing bacterial burdens. RVMA vaccination of hypersusceptible SP140-/- animals prevented necrosis and altered the lesion composition reducing tissue damage and increasing CD4 T cell distribution. Reductions in pathology were associated with increases in RORγt-expressing CD4 T cells and decreases in monocyte-derived cells in the lungs prior to the development of necrotic lesions. These results suggest T cell responses to certain antigens may be involved in preventing pathology without significantly changing bacterial burdens.