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Harnessing B cells for TB vaccine development to improve therapy of TB and TB-HIV coinfection

Award Number: R01AI161013
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $1,273,323 )
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	6/7/2024	NON-COMPETING CONTINUATION	$1,273,323
														Subtotal = $1,273,323

Issue Date FY: 2023 ( Subtotal = $1,276,503 )
2023	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	6/22/2023	NON-COMPETING CONTINUATION	$1,276,503
														Subtotal = $1,276,503

Issue Date FY: 2022 ( Subtotal = $1,294,431 )
2022	2022	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	7/7/2022	NON-COMPETING CONTINUATION	$1,294,431
														Subtotal = $1,294,431

Issue Date FY: 2021 ( Subtotal = $1,297,094 )
2021	2021	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	6/30/2021	NEW	$1,297,094
														Subtotal = $1,297,094

Grand Total All Awards = $5,141,351

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Harnessing B cells for TB vaccine development to improve therapy of TB and TB-HIV coinfection

Award Number: R01AI161013

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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