Vaccine reduces TB lung damage without lowering bacteria

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading infectious killer worldwide and an effective vaccine for the common adult lung disease has not been found. CD4 T cells are known to be essential for protection against Mtb, and most vaccine efforts aim to induce protective CD4 T cell responses. A puzzle for TB vaccinology is that most Mtb T cell antigens show very little sequence change over time, suggesting that T cell recognition does not usually drive the bacterium to make escape mutants. In the work reported by J. Ernst and colleagues, researchers took a different approach: they focused on a small set of antigens that are exceptions to this rule and do show sequence diversity within human T cell epitopes. These antigens, called rare variable antigens (RVMA), were delivered using a DNA vaccine platform to see whether stimulating T cell responses to these less-conserved targets would change the course of infection. The team tested this RVMA DNA vaccine in standard laboratory mice and in a genetically hypersusceptible mouse model to observe how the immune response and disease in the lung would be affected.

The study used a DNA vaccine platform encoding the rare variable antigens (RVMA) and examined outcomes after Mtb infection in both C57BL/6 mice and hypersusceptible SP140 -/- mice. Vaccination with RVMA significantly altered the immune response to infection in both mouse strains but did not reduce bacterial burdens in the lungs. In the SP140 -/- animals, which normally develop severe disease, RVMA vaccination prevented necrosis and changed the composition of lung lesions: tissue damage was reduced and CD4 T cell distribution within lesions increased. These improvements in pathology were linked to measurable shifts in immune cell populations before the onset of necrotic lesions, specifically increases in RORγt-expressing CD4 T cells and decreases in monocyte-derived cells in the lungs. In short, RVMA vaccination changed how the immune system responded and limited lung damage, even though the number of bacteria in the lung (bacterial burdens) remained unchanged.

These findings suggest a new angle for TB vaccine development: it may be possible to prevent the damaging lung pathology that causes illness and death without necessarily lowering bacterial counts. Because most Mtb CD4 T cell epitopes are conserved, the choice of antigens for a subunit vaccine has been uncertain. Targeting the small group of antigens that do show epitope sequence diversity—the RVMA—helped reduce tissue damage in a susceptible model, indicating that some T cell responses can protect against disease manifestations rather than directly controlling bacterial numbers. For researchers and vaccine designers, this points toward including antigen types that influence pathology in addition to those that might control bacterial growth. Given strong interest in prevention of disease (POD) vaccines for TB, these results from J. Ernst’s team can help guide which antigens to test next and inform the search for correlates of protection that predict reduced illness, not just lower bacterial loads.