Project 3: Mechanisms of Immune Protection from HIV-associated Tuberculosis

Director

Timothy Lahey, MD MMSc

COBRE Mentors

William Green, Paul Guyre, William Rigby

Mission

Tuberculosis (TB) is the leading cause of death in people with HIV. Unfortunately, the current TB vaccine, bacille Calmette-Guerin (BCG), fails to prevent innumerable cases of TB in people with HIV. Therefore, the identification of a novel TB vaccine is a leading public health priority.

The DarDar Trial has now shown that whole inactivated M. vaccae (MV), a novel TB booster vaccine, protects HIV-infected and BCG-immunized adults with CD4 counts >= 200 cells/ul from TB. This is a major public health advance.

However, the immunological mechanisms through which MV prevents TB disease in HIV-infected individuals are not known. In fact, the nature of the protective immune response against TB is itself incompletely understood. Accordingly, we will address the following specific aims:

  • To delineate the immune response to MV in HIV-infected adults.
  • To characterize the protective immune response to TB in adults with HIV. Through these studies we will test the hypothesis that HIV-infected adults who mount polyfunctional T cell immune response with Th1 cytokines are more protected from TB. These studies take advantage of an unprecedented opportunity to answer critical questions in TB vaccine science.

Results

COBRE funding for these important studies has lead to the publication and submission of multiple manuscripts, and has provided the principal investigator with support for the creation of preliminary data used in the submission of an R01 grant application.

Publications

  1. Lahey et al. Baseline mycobacterial immune responses in HIV-infected adults primed with bacille Calmette-Guerin during childhood and entering a tuberculosis booster vaccine trial. J Infect Dis 2007;195(1):118-23.

  2. Lahey et al. Lymphocyte proliferation to mycobacterial antigens is detectable across a spectrum of HIV-associated tuberculosis. BMC Infectious Diseases 2009; 9:21.

  3. Von Reyn et al. Deaths from disseminated tuberculosis among HIV-infected persons in Tanzania: a prospective clinical and immunologic study. Manuscript submitted.

  4. Lahey et al Baseline interferon gamma responses associated with protection from HIV-associated TB. In press.

  5. Arbeit, Lahey et al (co-1st authors) Immunogenicity of a novel protective TB vaccine in HIV-infected adults. Manuscript submitted.

Relevant Grant Submissions

Application for submitted in response to NIAID RFA RFA-AI-10-014 Ancillary Studies in Immunomodulation Clinical Trials (R01) R01 funding, review underway.