A new study led by the Bryson Lab at the Ragon Institute and published in Science Translational Medicine lays out a practical roadmap for making better tuberculosis (TB) vaccines by starting from what infected human immune cells actually show to CD4 T cells. The team used a technique called immunopeptidomics to see which TB proteins infected human immune cells actually put on their MHC class II “display” for CD4 T cells. This being the information T cells need to help fight TB.

TB still kills over a million people each year. The current BCG vaccine protects young children from the worst forms of TB, but it doesn’t protect most adults from lung TB. One big reason is that many vaccine targets were chosen because they were easy to find in lab cultures or worked in animals—not because we knew human cells really show them after TB infection.

The Bryson Lab’s method in this study infected real human immune cells, isolated the MHC-II molecules, and identified the TB pieces sitting on them. They found a smaller, clearer set of TB proteins (many secreted or on the surface, including ESX family proteins) that human cells truly present. Helpfully, these pieces were very similar across more than 51,000 TB genomes, so a vaccine based on them would work against TB strains from many parts of the world.

The next step was to consider whether a vaccine could be developed that forces human cells to present those same peptides. The team built mRNA constructs encoding the Mtb antigens and sent them to different parts of the cell. When they sent the TB antigens to acidic compartments in the cell (lysosomes) — the same pathway used during real infection — the cells showed far more of the TB pieces on MHC-II. In some cases, two TB proteins that normally go together in the bacterium (like EsxA and EsxB) had to be delivered together to get strong display. This creates a simple design rule for future vaccine designs.

They also found that cells infected with BCG showed several of the same TB pieces, which means these targets could be added on top of BCG to make it stronger, not replace it.

Put together, the study gives TB researchers two key things: a set of TB antigens that human cells are known to actually present and that are common across many TB strains, and a proven mRNA method to make human cells present them well. That directly addresses one of the current bottlenecks in building a better TB vaccine and reflects significant progress in fighting the disease.