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-Gurin (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 ?actA ?inlB 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 collaboration with Aeras, Bioqual, and Tulane National Primate Research Centre.

Public Health Relevance

Tuberculosis is one of the world's most important diseases, sickening ~10.4 million people and killing ~1.8 million people annually, and it disproportionately affects AIDS patients. The currently administered vaccine against tuberculosis, M. bovis strain Bacille Calmette-Gurin (BCG), is only partially effective. This proposal seeks to optimize and evaluate in advanced proof-of-concept of a highly promising Listeria-vectored multi- antigenic candidate vaccine against tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Eichelberg, Katrin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code