# Enhancing cytotoxic lymphocytes in a TB vaccine strategy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $772,170

## Abstract

ABSTRACT: Currently BCG is the most widely administered vaccine worldwide against
tuberculosis (TB). Yet, TB remains one of the most common causes of death from an infectious
disease globally underscoring its limited efficacy. We have shown that BCG’s vaccine efficacy
can be improved if administered by a different route or dose. In fact, intravenous BCG
vaccination resulted in 90% protection in a non-human primate model of TB but this method is
impractical to conduct on a population scale. Features associated with protection include the
presence of CD8 and CD4 T cells in the airways and lung resident T cells. In this proposal we
plan to mimic this immune response and improve upon the existing BCG vaccine in a strategy
that we call “enhanced prime and pull”. We propose to use N-803, an IL-15 agonist, to enhance
the frequency of innate CD8 cells and boost the effects of high dose, intradermal BCG. This is
followed by a dose of aerosolized BCG to pull vaccine-induced immune cells into the areas and
propagate resident T cells in the lungs. Using an animal model that recapitulates human TB, we
will utilized state-of-the-art modern tools such as PET CT, large scale immunologic profiling both
at a transcriptional and flow cytometric level and machine learning techniques. Immunogenicity
in blood and airway immune cells will examined among vaccine and control groups prior to
infection with Mycobacterium tuberculosis (Aim 1). After infection, we will then compare the
ability of the vaccine regimen to prevent infection and/or lower bacterial burden compared to
controls (Aim 2). We will examine the immune responses (including the presence of tissue
resident T cells) in the granuloma, lungs and mediastinal lymph nodes in the context of
bacterial burden among vaccinated and control groups. Lastly, machine learning techniques will
be used to identify immune parameters that correlate with protection in the context of
vaccines. The proposed studies are likely to reveal important information about the role of
innate cytotoxic CD8 cell and their role in vaccine induced protection and mechanisms of
recruiting mucosal immune responses. We may also gain important insights into key surrogate
markers of protection sorely needed in the TB field.

## Key facts

- **NIH application ID:** 10462928
- **Project number:** 1R01AI169707-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JoAnne L. Flynn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $772,170
- **Award type:** 1
- **Project period:** 2022-02-25 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462928

## Citation

> US National Institutes of Health, RePORTER application 10462928, Enhancing cytotoxic lymphocytes in a TB vaccine strategy (1R01AI169707-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10462928. Licensed CC0.

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