Intravenous Bacille Calmette-Guerin provides protection across a dose spectrum in a Rhesus macaque model of tuberculosis

Abstract Our laboratory has demonstrated that intravenous (IV) vaccination with Bacille Calmette-Guerin (BCG; 5x107CFU) provides remarkably robust protection against low-dose Mycobacterium tuberculosis (Mtb) infection in Rhesus macaques (9/10 animals 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 bronchoalveolar lavage (BAL) of animals compared to other routes of administration (ID or aerosol). These results led us to hypothesize that significant protection could be observed at lower IV BCG doses. We therefore vaccinated macaques with decreasing doses of BCG (5x107, 1.6x107, 5x106, 1.6x106, 5x105and 1.6 x105CFU) followed by six months of immune monitoring and a three-month low-dose Mtb challenge. As expected, a mycobacterium-specific T cell dose-dependent response was observed in both the BAL (FACS) and PBMCs (IFNgELIspot) prior to infection, as well as in the lung at time of necropsy (FACS). Remarkably, 17/25 animals had no thoracic Mtb CFU across all groups, and at least one animal from each group was protected (30–100% protection). Mycobacterium-specific CD4 T cell numbers in the BAL appear to be a correlate of protection. These results demonstrate that even at low doses IV BCG can be efficacious in preventing tuberculosis with a potential role for T cell-dependent immunity.