A Mycobacterium tuberculosis rare variable antigen vaccine reduces lung pathology in hypersusceptible SP140^-/- mice

Mycobacterium tuberculosis is the leading cause of death globally due to a single infectious agent. Currently, no licensed vaccine protects against pulmonary tuberculosis, the primary adult disease caused by Mtb infection. 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, in contrast to other pathogens, most Mtb T cell epitopes do not exhibit sequence variation, suggesting that T cell recognition does not drive selection of escape mutants. We discovered hypothetical Mtb 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 lung 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, and were independent of B cells. These results suggest T cell responses to certain antigens may be involved in preventing pathology without significantly changing bacterial burdens and indicate that these antigens can be efficacious in Prevention of Disease TB vaccines.