# Optimization and Advanced Proof-of-Concept Studies of a Listeria-vectored Multi-Antigenic Vaccine against Tuberculosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $1,158,564

## Abstract

PROJECT SUMMARY
Tuberculosis (TB) is one of the world's most important diseases, and a safe and effective vaccine against the
causative agent Mycobacterium tuberculosis (Mtb) that is more potent than the currently available only partially
effective M. bovis strain Bacille Calmette-Guérin (BCG) vaccine is sorely needed. It is generally acknowledged
that both an improved replacement vaccine for BCG and a potent heterologous booster vaccine are needed in
the fight against TB. The purpose of this project is to optimize and conduct advanced proof-of-concept studies
in small animals and non-human primates (NHP) of a second-generation heterologous multiantigenic
recombinant attenuated Listeria monocytogenes-vectored vaccine against TB.
 Live attenuated recombinant Listeria monocytogenes (rLm) vaccines offer major advantages over other
approaches to booster vaccines, including protein in adjuvant and virus-vectored vaccines, in terms of cost,
ease of manufacture, immunogenicity and efficacy. In preliminary studies, we have identified an improved
multi-deletional Listeria vector (Lm ΔactA ΔinlB prfA*) and demonstrated that rLm vaccines expressing four key
immunoprotective Mtb proteins (rLmMtb4Ag) substantially augment protective immunity when used as a
heterologous booster vaccine in a prime-boost vaccination strategy against Mtb aerosol challenge in mice and
guinea pigs. Moreover, delivering the immunoprotective Mtb protein via a first generation rLm vector was more
efficacious than delivering it via a recombinant viral vector or administering it with a potent adjuvant.
 The goal of this application is to optimize expression of an Lm-vectored vaccine expressing 4 Mtb
antigens; expand its antigen repertoire to six antigens to increase its potency; and to evaluate the optimized
final lead rLm vaccine candidate for safety, immunogenicity and efficacy as a standalone vaccine and as a
heterologous booster vaccine to BCG-primed animals in mouse, guinea pig, and non-human primate (NHP)
models of pulmonary TB. We shall accomplish this goal by: a) Optimizing the protein expression cassette of
rLmMtb4Ag vaccine; systematically evaluating additional novel Mtb antigens for immunogenicity and efficacy in
mice, selecting the top two antigens, and subsequently constructing a rLmMtb6Ag lead vaccine candidate; b)
Conducting comprehensive proof-of-concept studies of the optimized rLmMtb6Ag lead vaccine candidate for
safety, immunogenicity, and efficacy as standalone and heterologous booster vaccine in the mouse model of
pulmonary TB; c) Conducting selected proof-of-concept studies of the lead rLmMtb6Ag vaccine as a standa-
lone and heterologous booster vaccine for safety, immunogenicity and efficacy in a guinea pig model of
pulmonary TB; and d) as Aeras requires proof-of-concept in NHP for a vaccine to enter preclinical develop-
ment, evaluating the lead rLmMtb6Ag candidate as a standalone vaccine for safety, immunogenicity and
efficacy in a NHP model of pulmonary TB in c...

## Key facts

- **NIH application ID:** 9824546
- **Project number:** 5R01AI135631-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** MARCUS AARON HORWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,158,564
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824546

## Citation

> US National Institutes of Health, RePORTER application 9824546, Optimization and Advanced Proof-of-Concept Studies of a Listeria-vectored Multi-Antigenic Vaccine against Tuberculosis (5R01AI135631-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9824546. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*