bioRxiv2025
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 ROR{gamma}t-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. SignificanceMtb is the leading cause of death worldwide due to an infectious agent, a title it has held for most of human history. Despite significant efforts, an effective vaccine that prevents the morbidity associated with pulmonary tuberculosis, the most prevalent form of adult TB disease, has yet to be developed. A lack of correlates of protection and ideal antigen targets have hampered the development of a subunit vaccine. Mtb is unique in that the CD4 T cell epitope sequences of Mtb are predominantly under purifying selection. Targeting antigens that are an exception to this T cell epitope sequence conservation can inform our understanding of what the most optimal antigens are for inclusion in an effective vaccine against Mtb. Our study describes the effects of a vaccine consisting solely of antigens that exhibit epitope sequence diversity on the outcome of infection and identifies possible benefits to lung pathology. Given the ongoing interest in prevention of disease (POD) vaccines for TB, these results can inform future vaccine design and the search for correlates of protection.