The role of B cells in respiratory mucosal AdHu5Ag85A vaccine-induced immunity against tuberculosis

Abstract

Background: Mycobacterium tuberculosis (M.tb) is the causative pathogen of tuberculosis (TB) that is currently the leading cause of death from a bacterial infection. The only licensed vaccine against tuberculosis is the Bacille Calmette-Guérin (BCG) vaccine which fails to effectively protect against adult pulmonary TB. For this reason, efforts have focused on developing novel vaccine platforms to boost BCG-induced immunity. In this regard, a human adenovirus serotype 5 expressing the mycobacterial secreted antigen Ag85A (AdHu5Ag85A) vaccine developed in our lab has been evaluated in a phase I clinical trial. It was shown to boost and elicit lasting T cell responses in BCG-vaccinated volunteers. Although inducing a strong type I T cell mediated immunity by this vaccine is crucial for protection, the role of vaccine-induced B cell responses in protecting against M.tb infection remains poorly understood. Recent studies have shown B cells to contribute to protection by modulating T cell immunity during intracellular bacterial infections. Therefore, we hypothesize that AdHu5Ag85A vaccination also induces antigen-specific B cell responses and such B cells have an immunomodulatory effect on vaccine-induced T cell immunity. Methods: We compared antigen specific T cell and antibody responses in wild type (WT) Balb/c mice with B cell deficient (Jh-/-) mice after intranasal AdHu5Ag85A vaccination. Results: Interim data has demonstrated that AdHu5Ag85A induces antigen specific antibodies. In the absence of B cells, AdHu5Ag85A vaccination resulted in reduced Ag85A CD8+ T cells within the BAL compared to WT. Importantly, this correlated with impaired protection against pulmonary M.tb infection. The study is ongoing to examine the mechanisms by which B cells modulate these T cell responses. Conclusion: These data suggest that B cells are required for optimal protective T cell responses following AdHu5Ag85A respiratory mucosal vaccination against M.tb infection.