R01AI161822

Optimizing Vaccine Science to Improve the Outcome of Tuberculosis Treatment - Project Summary

Tuberculosis (TB), caused by pathogenic bacteria Mycobacterium tuberculosis (MTB), is causing significant morbidity and mortality to humans across the world. Live, attenuated M. bovis Bacillus Calmette-Guérin (BCG) is the only TB vaccine currently licensed by the World Health Organization for use in humans. Although BCG prevents severe disease in children with variable efficacy, it fails to protect against pulmonary TB in adults, who are the primary source of transmission of MTB in the community. Moreover, BCG may cause disease in immune-compromised individuals, such as those co-infected with HIV.

To control the development of active disease and to break the chain of MTB transmission, a new, safer, and more effective vaccination approach is urgently required. The development of "paradigm-shifting" protective measures against TB will significantly be aided by the optimization of safe and effective combinatorial platforms, such as integrating novel vaccines with adjunct host-directed therapy (HDT) and/or antimycobacterial drugs. This strategy is aimed at inducing appropriate innate immunity along with potent and durable T cell responses, both of which are necessary for effective control of TB.

Such an integrated approach is urgently needed to control the pathology of active, cavitary TB cases and transmission of MTB, as well as to prevent reactivation of latently infected individuals, estimated to be about a quarter of the world population, who are MTB-infected and mostly asymptomatic but can reactivate the disease upon immune suppression. Selection and usage of a relevant animal model that recapitulates the pathophysiology of cavitary TB, as seen in humans, is vital to screen novel and better intervention strategies to combat the disease, including potent vaccine and drug candidates.

We have established a rabbit model of aerosol MTB infection that mimics the range of human manifestations of pulmonary TB, from cavitary (transmissible) disease to latent infection. Dr. Subbian has established a rabbit model of cavitary TB, and the sub-award PI, Dr. Kupz, has developed a tractable and reproducible mouse model to study the reactivation dynamics of latent MTB infection following the loss of CD4+ T cells as it occurs in HIV co-infected individuals.

Using these two models, we propose to determine the ability of a novel recombinant BCG strain (BCG::ESAT-6-PE25SS developed in Dr. Kupz's lab), in combination with mTOR inhibitor (everolimus) and/or two first-line antibiotics, isoniazid and rifampicin, to protect against progression to cavitary TB (rabbit) and/or induce sterilizing immunity in latency (mice). To compare our approach, we will test individual components in these model animals. We will also define mucosal (lung) and systemic (blood) immune parameters that predict protection against MTB challenge in our model system.

The results of these studies can contribute towards the development of new generation vaccine platforms for targeting other intracellular pathogens, in addition to MTB.

Rutgers The State University Of New Jersey

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]

Newark, New Jersey 071073001 United States

Single Zip Code

Advancing Vaccine Science to Improve Tuberculosis Treatment Outcomes for People Living With or Without HIV (R01 Clinical Trial Not Allowed) (RFA-AI-20-010)

Amendment Since initial award the total obligations have increased 428% from $598,840 to $3,160,810.