# Therapeutic vaccination to augment stringent response-specific T-cell immunity to MTB persisters

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $732,434

## Abstract

Mycobacterium tuberculosis (Mtb) is the leading infectious disease-related cause of death among people
living with HIV worldwide. Shorter tuberculosis (TB) treatment regimens are needed to achieve global TB
elimination. The protracted nature of the current 6-month TB treatment course reflects the unique ability of a
subpopulation of “persister” bacteria to remain in a growth-limited, antibiotic-tolerant state through various
adaptive strategies, including induction of the stringent response. The key stringent response enzyme RelMtb
is essential for long-term Mtb survival under physiologically relevant stresses in vitro and in animal lungs.
Recently, we have generated a therapeutic relMtb DNA vaccine, which induces RelMtb-specific cellular immunity,
and significantly augments the activity of the first-line drug isoniazid against active TB in mice. We also have
developed a novel vaccination strategy involving fusion of the antigen of interest with the immature dendritic
cell (iDC)-targeting chemokine MIP3α, which significantly enhances antigen-specific T-cell responses. In the
current proposal, we will determine if this iDC-targeting strategy, as well as a promising new adjuvant
approach involving the use of cyclic dinucleotides to activate the stimulator of interferon genes (STING)
pathway, enhance the immunogenicity of our relMtb DNA vaccine. The ideal vaccine platform will be used to
test the novel hypothesis that enhanced cellular immunity against RelMtb potentiates the activity of the first-
line anti-TB regimen and accelerates cure in the standard murine model of TB. Since HIV infection is
associated with disturbed T-cell homeostasis, including depletion of CD4+ T cells and persistent expansion of
CD8+ T cells, we will characterize the contribution of each of these cell types to the therapeutic efficacy of the
relMtb DNA vaccine in mice. In order to transition our findings to the clinical setting, we will next test the
immunogenicity of this vaccination strategy in rhesus macaques, which develop immune response patterns
most analogous to those of humans. Finally, leveraging archived clinical samples available through the
RePORT South Africa longitudinal cohort of HIV-infected and uninfected patients with pulmonary TB receiving
first-line anti-tubercular treatment, we will measure RelMtb-specific T-cell responses during TB therapy. This
proposal represents a unique collaboration between Investigators with significant expertise in microbiology,
molecular biology, immunology, DNA vaccines, and animal models. Our findings are expected to have far-
reaching implications for the development of novel adjunctive therapies for shortening the duration of
treatment for drug-susceptible and drug-resistant TB, as well as novel diagnostic tools for confirming the
adequacy of TB treatment in HIV-infected and uninfected individuals.

## Key facts

- **NIH application ID:** 9949007
- **Project number:** 1R01AI148710-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Petros C Karakousis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $732,434
- **Award type:** 1
- **Project period:** 2020-03-17 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949007

## Citation

> US National Institutes of Health, RePORTER application 9949007, Therapeutic vaccination to augment stringent response-specific T-cell immunity to MTB persisters (1R01AI148710-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949007. Licensed CC0.

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