Infection with M. tuberculosis (Mtb) can cause TB, which is now the leading global cause of mortality due to a single infectious disease agent. The failure to control TB stems from the lack of an effective vaccine. BCG, the vaccine currently in use, is unable to generate long-lived memory responses and protect against pulmonary TB in adults. New vaccines against TB are therefore, urgently needed. Our work has shown that the ?sigH mutant of Mtb is attenuated for replication and disease in macaques). Aerosol vaccination with this mutant induces strong lung immune signatures that protect against lethal TB. Nonpathogenic ?sigH infection in macaques is not reactivated by SIV co-infection. Additional unrelated mutation(s) are however needed in ?sigH to ensure its complete attenuation. This project aims to develop a ?sigH -based human TB vaccine candidate that could eventually advance to clinical development. ?sigH deletion will be added to 10 recombinant Mtb strains. Some of these mutants generate immune enhancement- or auxotrophy-based attenuation phenotypes, while others render Mtb avirulent in macaque lungs. We will assess the safety of these ten strains in SCID mice and progressively smaller numbers in immunocompetent and SIV co-infected macaques by multiplexing. Two strains that consistently provide the best results in terms of safety/immunogenicity will be evaluated in detail for immunogenicity and efficacy via aerosol (AER) vaccination relative to BCG- and ?sigH - vaccination, in a physiologically relevant macaque model.

Public Health Relevance

This project aims to develop a ?sigH-based human TB vaccine candidate that will advance to clinical development. We will attempt to develop a new effective vaccine against TB using aerosol-delivered mutant Mtb as an approach. ?sigH deletion will be added to 10 other mutant Mtb strains and their safety/efficacy phenotype progressively evaluate in different models for down-selection. Finally, the efficacy of two strains will be evaluated in a relevant macaque model and one strain chosen for clinical development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI138587-03
Application #
9948562
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Eichelberg, Katrin
Project Start
2018-05-17
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78227