Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanisms of a therapeutic DNA vaccine targeting Mycobacterium tuberculosis persisters

Award Number: K08AI174959
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/11/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

Group Awards By:

View Award Description

Mechanisms of a therapeutic DNA vaccine targeting Mycobacterium tuberculosis persisters - PROJECT SUMMARY Host status plays a major role in tuberculosis (TB) disease outcomes, with many efforts to develop host-directed therapies to boost immune response. It is unknown how these strategies will perform in people living with HIV/AIDS (PLWHA) who are at increased risk of adverse TB treatment outcomes. Persistent Mycobacterium tuberculosis (Mtb), which obligates prolonged TB treatment, highly expresses the stringent response protein RelMtb. One attractive host-directed therapeutic strategy is boosting RelMtb-specific cellular responses. We developed a novel therapeutic DNA TB vaccine that promotes immune responses to RelMtb, which are further enhanced by fusion with a chemokine gene, Macrophage Inflammatory Protein-3 alpha (MIP-3α), that targets relMtb to immature dendritic cells (DCs). Our data show that an intranasal (IN) or intramuscular (IM) DNA vaccine expressing MIP-3α/relMtb (“fusion” vaccine) demonstrated greater adjunctive therapeutic efficacy when combined with the first-line TB treatment in Mtb-infected mice as compared to IM vaccination with relMtb alone (“non-fusion” vaccine). This proposal will dissect the mechanisms of this novel therapeutic strategy, specifically with IN administration which had the highest efficacy. We will also test whether this strategy is likely to perform in PLWHA, analyzing whether RelMtb-specific immune responses in PLWHA can predict therapeutic TB outcomes. Aim 1 will investigate the molecular mechanism by which the IN administration potentiates anti-TB drugs, while Aim 2 will focus on the role of DCs in the adjunctive therapeutic efficacy of the fusion vaccination strategy. Aim 3 will test the translational potential of the RelMtb-specific T-cell immunity in PLWHA. In Aim 1, we test if IN vaccine administration enhances the host response to Mtb infection through increased IL-17A secretion. We will perform single-cell transcriptomics on cells from murine lungs to confirm the upregulation of IL-17A response pathways in the IN arm, followed by Mtb-infected IL-17A knockout murine experiments. In Aim 2, we hypothesize that the IN fusion vaccine leads to more efficient systemic and local T-cell maturation, activation, and differentiation through enhanced DC activation compared to the IN non-fusion vaccine. Aim 2a will assess differences in DC activation by flow cytometry, DC and T-cell co-localization in murine tissues, and differences in T-cell activation/differentiation using co-culture experiments with DCs derived from each vaccination group. In Aim 2b, we will adoptively transfer DCs from mice immunized with either vaccine into Mtb-infected mice concurrently with TB treatment to compare the adjunctive therapeutic efficacy. In Aim 3, we hypothesize that RelMtb-specific Th1/Th17 cell responses in peripheral blood mononuclear cells derived from HIV-infected and uninfected patients receiving treatment for pulmonary TB, correlate inversely with sputum culture conversion and TB recurrence rates, independently of HIV status. The proposed studies will uncover critical details of the mechanism of a novel therapeutic vaccination approach against TB with important implications in PLWHA and help the PI to gain significant expertise in TB/HIV immunology.


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: 2026 ( Subtotal = $200,880 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	11/26/2025	NON-COMPETING CONTINUATION	$200,880
														Subtotal = $200,880

Issue Date FY: 2025 ( Subtotal = $200,880 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	11/12/2024	NON-COMPETING CONTINUATION	$200,880
														Subtotal = $200,880

Issue Date FY: 2024 ( Subtotal = $200,880 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	1	7/24/2024	NEW	$0
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	12/11/2023	NEW	$200,880
														Subtotal = $200,880

Grand Total All Awards = $602,640

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of a therapeutic DNA vaccine targeting Mycobacterium tuberculosis persisters

Award Number: K08AI174959

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/11/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer