Vaccine-Elicited T cells are Important for Intravenous BCG Mediated Protection in a Rhesus macaque Model of Tuberculosis

Abstract Our laboratories have shown that intravenous (IV) vaccination with Bacille Calmette-Guerin (BCG; 5×107 CFU) provides robust protection against low-dose Mycobacterium tuberculosis (Mtb) infection in rhesus macaques (9/10 protected [<50 thoracic Mtb CFU]; 100,000-fold reduction compared to intradermal [ID] BCG). IV BCG also resulted in a 100-fold increase in mycobacterium--specific T cells in the airways of animals compared to ID or aerosol administration. To investigate the role of T cells in this protective model, we employed two methodologies: 1. Vaccination with decreasing doses of BCG to stimulate lower-magnitude T cell responses and; 2. Antibody-mediated CD4 and CD8a T cell depletion post-vaccination but pre-infection. Animals were vaccinated for 6 months followed by a 2–3 month low-dose Mtb challenge. Surprisingly, even at low doses of BCG (0.4–2 × 105), a subset of animals was protected, with a range of outcomes across the doses. In the second study, depletion was successful in blood, airways and tissue. Interestingly, depletion of either T cell subset resulted in an intermediate total thoracic CFU phenotype. In both studies, correlates of immunity will be assessed comparing protection (CFU) to BAL and tissue resident immune responses. Our data supports that sterilizing protection is observed across the BCG IV dose spectrum and that T cells are important, but are likely not the only factors involved in this protection. Our findings are critical for identifying correlates of protection and generating a safe and effective vaccine against TB.