Immunotherapy combined with BCG vaccine drastically lowers tuberculosis relapse risk

Tuberculosis (TB) remains one of the world’s leading causes of death, and preventing post-treatment relapse continues to be a major worldwide health challenge. But a new study led by scientists at the Hackensack Meridian Center for Discovery and Innovation (CDI) reveals that combining an immunotherapy with the traditional Bacille Calmette-Guérin (BCG) vaccine drastically lowers the risk of TB relapse in preclinical models.

The findings outline a promising avenue for strengthening long-term immune control against TB recurrence, in the latest issue of The Journal of Infectious Diseases. The research was led by corresponding author Martin Gengenbacher, Ph.D., associate member of the CDI and faculty member at the Hackensack Meridian School of Medicine, alongside lead author Chen-Yu Tsai, Ph.D., and collaborator Sabine Ehrt, Ph.D., professor for immunology and microbiology at Weill Cornell Medicine.

“These findings support further investigation of B-cell-targeted immunomodulation to improve durable immune control and reduce tuberculosis relapse,” the authors report.

Bacille Calmette-Guérin (BCG) is currently the only approved TB vaccine used clinically, but it has drawbacks. It protects children effectively against severe disease, but its ability to prevent pulmonary TB in adults and stop relapse following treatment is limited. Recurrent infection after treatment accounts for a big part of the global TB burden. 

Building on recent discoveries that specialized splenic B cells help restrict TB infection, the research team set out to determine whether immunotherapy designed to boost B-cell survival and activation could improve BCG-mediated protection against disease reactivation.

Using an established preclinical model of latent TB and spontaneous relapse, the investigators tested a combination of BCG vaccination and B-cell-targeting immunotherapy with recombinant A proliferation-inducing ligand (rAPRIL, a protein cytokine known to regulate B-cell survival and differentiation).

The preclinical studies demonstrated promising results: a relapse rate of 26 percent for the combined immunotherapy and vaccine therapy, compared with 60 percent for the vaccine alone, and 78 percent with a saline control.

To better understand how the treatment worked, flow cytometry was used to analyze immune cell populations in the lungs and spleens. They discovered that adjunctive rAPRIL immunotherapy selectively remodeled and activated marginal-zone B (MZB) cell compartments, significantly increasing markers associated with cellular activation and tissue retention (CD69 and CD86). In contrast, T-cell populations were only modestly affected across treatment groups, demonstrating that the enhanced protection was primarily driven by the modulation of B-cell compartments.

By demonstrating this method of preventing TB recurrence, the CDI team’s work provides a pathway for potential therapeutic and vaccine strategies aiming at durable, lifelong immunity against TB.

This study was supported by awards from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).