Project Description

Disseminated infection (mycobacteremia) with Mycobacterium tuberculosis (dMTB) has been documented by our group in 10-25% of patients with HIV infection in Africa using lysis-centrifugation blood culture techniques. Unlike pulmonary tuberculosis (pMTB), most cases of dMTB are not recognized or treated and death ensues rapidly. Thus, in developing countries dMTB may be a more important cause of HIV-associated mortality than pMTB. Risk factors for dMTB have not been identified and it is not known if most cases are due to reactivation or to newly acquired infection. We hypothesize that most cases of dMTB are due to newly acquired MTB infection in patients without prior infection with MTB, non-tuberculous mycobacteria (NTM), or Mycobacterium bovis, Bacille Calmette-Guerin (BCG). Mycobacterial immunization in early HIV infection is a potential strategy to prevent dMTB in adults with AIDS. Heat-inactivated Mycobacterium vaccae (MV) is an investigational vaccine prepared by heat inactivation of an NTM, and has been shown protective against MTB in several animal models. Studies conducted by our group in the United States and in Zambia indicate that a 5 dose series of MV is safe in patients with HIV infection and induces a human cellular immune response to mycobacterial antigens. Our hypothesis is that MV immunization will reduce the risk of HIV-associated dMTB by 50%. Our specific aims are: (1) To define risk factors for HIV-associated disseminated tuberculosis and to assess the relative contributions of reactivation versus new infection in the pathogenesis of disseminated tuberculosis, and (2) To assess the safety and efficacy of a 5-dose schedule of inactivated MV vaccine for the prevention of HIV-associated pulmonary and disseminated tuberculosis.

2274 HIV-positive patients and 100 HIV-negative controls will be entered in a 5-year study in Tanzania. Baseline evaluation will include history, examination for BCG scar, chest x-ray, dual skin tests with purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS), and assay for lymphocyte proliferation response and interferon-gamma production in response to MV sonicate, ESAT-6 (a protein antigen unique to MTB) and MTB antigen 85. Subjects with PPD reactions ≥5 mm will receive 6 months of prophylaxis with isoniazid. All subjects will be randomized 1:1 to receive a 5 dose series of MV or placebo over 12 months with repeat skin test and in vitro studies after 5 doses of vaccine (14 months). A subset of 100 HIV positive subjects will have additional follow up visits to assess vaccine side effects and to assess immunogenicity after 3 doses (6 months). All subjects will be followed every 3 months for 3-5 years to assess new pMTB (microbiologic or clinical diagnosis) or dMTB (microbiologic diagnosis). All isolates will have susceptibility tests and IS6110 DNA fingerprinting performed. Potential risk factors for dMTB, including baseline skin test and in vitro immunologic responses, will be assessed in placebo and vaccine groups. Vaccine efficacy against dMTB and pMTB in HIV-positive subjects will be determined, and post immunization skin test and in vitro immunologic responses used to identify a surrogate marker of efficacy. The proposed study has important implications for the reduction in mortality from HIV-associated tuberculosis and for design of future trials of new vaccines against tuberculosis.