R01AI148122

Development of a Novel TB Vaccine Safer and More Effective than BCG Based on a Precisely Controlled Replication-Limited Mycobacterium Tuberculosis Engineered for Optimal In Vivo Growth and Clearance - Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is one of the world's leading causes of death. BCG, the only licensed vaccine against TB, is an attenuated bacterium highly homologous to MTB, yet safe in immunocompetent individuals because it has lost several genes that confer virulence. BCG has good efficacy against TB in children, but poor efficacy against TB in adolescents and adults. Hence, a vaccine much more potent than BCG is clearly needed.

However, any replacement vaccine will almost certainly need to be based on modified (e.g. recombinant) BCG or attenuated MTB to preserve the substantial benefits of BCG. The goal of this project is to develop an attenuated MTB mutant that is safer and more potent than BCG. Our novel strategy involves manipulating two key characteristics of live vaccines: (1) their initial period of growth in the host and (2) their rate of elimination.

The inadequate protective efficacy induced by BCG and non-replicating MTB mutants can be attributed, at least in part, to their lack of replication in the host. Prolonged persistence in the host is also a negative factor, resulting in the generation of primarily effector and effector memory T cells rather than central memory T cells, important for long-term immunity. We hypothesize that limited replication of an MTB mutant for a brief period after immunization, mimicking the early stage of a natural MTB infection, followed by rapid clearance will induce a potent immune response and yet avoid the negative inflammatory responses induced by prolonged MTB infection.

To achieve our goal, we first shall engineer an attenuated MTB mutant defective in both of its iron acquisition pathways - siderophore-mediated iron acquisition (SMIA) and heme-iron acquisition (HIA). Such a mutant will be unable to obtain iron from the host but can be pre-loaded in vitro with the precise amount of iron to allow optimal replication in the host. Thus, an MTB SMIA HIA mutant will allow us to address the first important factor - controlling the extent of replication in the host.

While growth of MTB SMIA HIA in the host will cease once it exhausts its supply of iron, the organism may persist for a prolonged period. Thus, to address the second important factor, the rate of clearance from the host, we shall further modify MTB SMIA HIA, via two approaches – 1) knocking out persistence genes and 2) conditional silencing of essential genes. While both should result in improved clearance, conditional silencing likely will result in faster clearance.

We shall vaccinate mice with persistence and conditional silencing mutants and perform clearance and protective efficacy studies to determine the optimal replication and clearance. We expect a replication- and persistence-limited MTB mutant with rapid clearance will be much more efficacious than BCG and, in contrast to BCG, safe even in an immunocompromised host.

Once we have optimized the vaccine for protective immunity in mice, we shall examine its immunogenicity in mice to assess preliminary correlates of protection, assess its safety in immunocompromised SCID mice, and examine its safety and efficacy in a second animal model of TB - guinea pigs.

Los Angeles University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Los Angeles, California 900958348 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 397% from $779,991 to $3,876,556.