# Development of a Self Inactivating, Highly Effective TB Vaccine

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $787,367

## Abstract

Abstract
Tuberculosis remains a major cause of morbidity and mortality worldwide, and is the leading
cause of death due to a single infectious agent, Mycobacterium tuberculosis. Most countries still
vaccinate newborns with the only licensed vaccine against tuberculosis, Bacille Calmette Guerin
(BCG) an attenuated version of Mycobacterium bovis. The vaccine was developed over a
century ago and, although widely used, has limited efficacy. BCG delivered intradermally (ID)
does provide protection against the worst manifestations of tuberculosis in infants but has
variable (0-80%) protection against pulmonary TB. Our recent data in non-human primates
(rhesus macaques) demonstrate that BCG delivered by the intravenous (IV) route provides
sterilizing or near sterilizing protection in 90% of macaques (>10,000 fold reduction in bacterial
burden overall), while ID BCG provides little protection in this model. However, delivery of even
an attenuated live vaccine poses potential safety issues, particularly in immune compromised
subjects. In this proposal, we aim to construct BCG strains that are self-inactivating, using
several innovative molecular approaches. Such strains would persist only for a short time in
vivo, and would likely die by different mechanisms. We will construct and characterize the BCG
self-inactivating strains in vitro (Aim 1), assess persistence and immunogenicity in a murine
model, and then determine persistence, immunogenicity and protection of a subset of BCG
strains in a susceptible non-human primate model (rhesus macaques). Published data indicate
that the robust protection seen by IV BCG in macaques is not recapitulated in mice, which
necessitates testing in macaques. We will use sophisticated technology for construction of
strains, assessment of immune responses and bacterial burden, and PET CT imaging for
tracking protection. This proposal builds on the experience of the Multi-PI team in mycobacterial
genetics, immunology, and animal models, with the goal of developing a safer TB vaccine for IV
delivery.

## Key facts

- **NIH application ID:** 10333368
- **Project number:** 5R01AI143788-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** SABINE EHRT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $787,367
- **Award type:** 5
- **Project period:** 2019-02-06 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333368

## Citation

> US National Institutes of Health, RePORTER application 10333368, Development of a Self Inactivating, Highly Effective TB Vaccine (5R01AI143788-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10333368. Licensed CC0.

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