Abstract
Current tuberculosis (TB) control in the presence or absence of human immunodeficiency virus (HIV) infection
is suboptimal: Bacillus Calmette-Guérin (BCG), the sole TB vaccine in clinical use, provides only limited
protection during childhood and multi-drug chemotherapy faces challenges due to the alarming spread of drug
resistance. An integrated approach combining chemotherapy with a therapeutic vaccine given after exposure to
Mycobacterium tuberculosis (Mtb) could be a way forward. TB vaccine research mostly focused on prophylactic
candidates aiming to prevent infection. Therapeutic TB vaccines with novel mechanisms of action are needed
(i) to complement existing chemotherapy and prevent relapse thereafter, and (ii) to cure latent TB infection (LTBI)
or prevent reactivation. T lymphocytes are critical for the control of TB infection and the specific T cell response
elicited by a vaccine has been used as a key correlate of immunogenicity. In contrast, B cells are understudied
in all areas of TB research. Using a deep immunophenotyping approach, our preliminary data in mice suggest
that TB infection leads to dramatic changes in the landscape of B cell subpopulations. We identified a novel B
cell subset with marginal zone (MZ) phenotype that was activated, had a memory phenotype and expressed
receptors recognizing the human cytokines A Proliferation-Inducing Ligand, APRIL, and B cell Activating Factor,
BAFF, critical for B cell development and survival. Functional studies indicated that murine MZ B cells contributed
to Mtb containment in mice. Surprisingly, these B cells expressed a panel of Th1 cytokines, well studied in T
cells, suggesting a possible role in the first line of defense against TB infection. We found that MZ B cells were
depleted in blood of TB patients and TB/HIV coinfected people. Our hypothesis is that MZ B cells can be restored
by antitubercular therapy and harnessed for TB vaccine development. To test this, we genetically engineered
BCG to express the human cytokines APRIL and BAFF that stimulate development and longevity of BAFF
receptor- and APRIL receptor-expressing B cells, including MZ B cells. We will determine the safety,
immunogenicity and prophylactic efficacy in mice. The therapeutic efficacy will be evaluated in two novel
innovative mouse models that allow us to determine the capacity of cytokine expression in BCG strains to prevent
relapse after drug treatment and to reduce the reactivation frequency of paucibacillary TB mimicking aspect of
LTBI in humans. We will determine the frequency of MZ B cells in peripheral blood mononuclear cells (PBMC)
from people having LTBI and TB, across HIV status, including antitubercular and antiretroviral therapy. We will
stimulate PBMC of the same cohorts with cytokine-expressing BCG strains to study the immunological
consequences and to demonstrate, in principle, the feasibility of these vaccines during therapy of TB, HIV and
TB/HIV coinfection. We will monitor the global landscapes of T cells and B cells by high parameter flow cytometry
to define immunological correlates of TB infection and vaccine protection. Our proposal will determine whether
B cells can be harnessed by cytokine-secreting B cell-targeting BCG vaccines for TB vaccine development.
