Innate Immune Responses to Pro-Apoptotic BCG

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Abstract The current vaccine against tuberculosis, Bacillus Calmette Guerin (BCG), provides inadequate protection against the pulmonary, contagious form of TB. Several groups of investigators are trying to make a more effective TB vaccine ¿ in the past couple of years the most promising technologies have been acquired by the Aeras Global TB Vaccine Foundation (www.aeras.org), a not-for-profit foundation supported by the Bill and Melinda Gates Foundation. Aeras plans to develop, test, manufacture and distribute at least one new TB vaccine within 10 years and favors a prime-boost strategy in which a genetically-modified BCG exhibiting enhanced immunogenicity is given at birth followed by a heterologous subunit boost at 14 weeks. BCG originated from a virulent strain of M. bovis and retains many of the immune-evasive characteristics of virulent mycobacteria. We have modified BCG to reduce its production and secretion of enzymes that mediate immune evasion. The modified vaccine, called ¿pro-apoptotic BCG¿ (paBCG), is more protective than BCG as a vaccine in mice and induces stronger CD4+ and CD8+ T-cell responses. Aeras has licensed this technology and is currently constructing a GMP version of the vaccine, possibly in combination with other technologies. Aeras has a vaccine production facility with capacity to make 150 million doses annually. In the current application, the investigators who built paBCG (DK and MB) have joined colleagues from their institutions with expertise in antigen-presenting cells and lymphocytes (JT and SK). We propose to explore the innate immune responses that lead to enhanced T-cell responses and protection. The specific aims are: 1. To compare the immune response of human monocytes to infection with BCG and paBCG. 2. To compare NK cell responses, cytokine polarization, and in vivo gene expression in mice after vaccination with BCG and paBCG. 3. To determine BLS-specific T cell responses induced by vaccination with 4dBCG expressing recombinant Brucella lumazine synthase (BLS) from Brucella abortus (Vanderbilt). In summary, the paBCG vaccine technology was developed in SERCEB-member institutions and is poised to be part of a ¿deliverable¿ that replaces the current BCG vaccine. This project will explore cell signaling mechanisms associated with antigen presentation to better understand the immune responses unmasked during vaccination with paBCG compared to BCG. This will help in designing vaccines against other intracellular bacterial pathogens and in designing adjuvant strategies to target the early host response.