BAFF and APRIL immunotherapy following Bacille Calmette-Guérin vaccination enhances protection against pulmonary tuberculosis in mice

Min Xie ¹ Chen-Yu Tsai ¹ Joshua Woo ¹ Frank Nuritdinov ¹ Melissa Cristaldo ¹ Narineh Michelle Odjourian ¹ Rosleine Antilus-Sainte ¹ Maureen Dougher ¹ Martin Gengenbacher ^1,2*

• ¹ Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States
• ² Hackensack Meridian School of Medicine, Nutley, United States

Bacille Calmette-Guérin (BCG), the only tuberculosis vaccine currently in clinical use, provides inadequate long-term protection. Administered at birth, BCG induces broad immune responses against a large number of antigens shared with Mycobacterium tuberculosis (Mtb), but protection wanes over time. We have previously shown that unconventional B cell subsets play a role in tuberculosis control. In this study, we investigate the potential of recombinant cytokines targeting B cells -B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) -to modulate BCG immunity and improve protection in mice. Both cytokines play overlapping roles in B cell development and peripheral survival. Following subcutaneous BCG vaccination, immunotherapy with BAFF or APRIL resulted in an increased frequency of unconventional B cells potentially transitioning into antibody-producing plasma cells. Concurrently, we observed an increased frequency of central memory T cells, a subset critical for protective immunity. Changes in cellular immune responses were accompanied by reduced pro-inflammatory cytokine profiles and a contraction of the leukocyte population in lungs. Importantly, mice receiving BCG vaccination followed by BAFF or APRIL immunotherapy exhibited superior long-term protection against pulmonary tuberculosis relative to controls that received only BCG. In summary, our findings demonstrate that combining BCG vaccination with B cell targeted immunomodulatory therapies can improve long-term protection against pulmonary tuberculosis, highlighting the continued relevance and underutilized potential of BCG as a vaccine platform.