title: Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity.
abstract: Tuberculosis (TB) vaccine development is hindered by the lack of clear surrogate markers of protective human immunity to Mycobacterium tuberculosis. This study evaluated the hypothesis that immune-mediated inhibition of mycobacterial growth would more directly correlate with protective TB immunity than other immunologic responses. Bacille Calmette-Guérin (BCG) vaccination, known to induce partial protection against TB, was used as a model system to investigate mechanistic relationships among different parameters of antigen-specific immunity. Effects of primary and booster intradermal BCG vaccinations were assessed in 3 distinct assays of mycobacterial inhibition. Correlations between vaccine-induced growth inhibition and other immune responses were analyzed. BCG significantly enhanced all antigen-specific responses. Peak responses occurred at 2 months after boosting. Statistical analyses suggested that each assay measured unique aspects of mycobacterial immunity. Despite previous evidence that type 1 immune responses are essential for TB immunity, interferon-gamma production did not correlate with mycobacterial inhibition. These results have important implications for TB vaccine development.
authors.affiliation: Division of Infectious Diseases and Immunology and Vaccine and Treatment Evaluation Unit, Saint Louis University Health Sciences Center, St. Louis, Missouri 63110, USA. hoftdf@slu.edu
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.forename: Shewangizaw
authors.initials: S
authors.lastname: Worku
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Whalen
authors.forename: Jerrold J
authors.initials: JJ
authors.lastname: Ellner
authors.forename: Christina S
authors.initials: CS
authors.lastname: Hirsch
authors.forename: Robin B
authors.initials: RB
authors.lastname: Brown
authors.forename: Rhonda
authors.initials: R
authors.lastname: Larkin
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Hyun
authors.initials: H
authors.lastname: Yun
authors.forename: Richard F
authors.initials: RF
authors.lastname: Silver
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007109:Immunity; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D014376:Tuberculosis / Q000517:prevention & control; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D007371:Interferon-gamma