MTBVAC-Based TB-HIV Vaccine Is Safe, Elicits HIV-T Cell Responses, and Protects against Mycobacterium tuberculosis in Mice

摘要

The tuberculosis (TB) vaccine MTBVAC is the only live-attenuated Mycobacterium tuberculosis ( Mtb )-based vaccine in clinical development, and it confers superior protection in different animal models compared to the current vaccine, BCG ( Mycobacterium bovis bacillus Calmette-Guérin). With the aim of using MTBVAC as a vector for a dual TB-HIV vaccine, we constructed the recombinant MTBVAC.HIVAsup2auxo/sup strain. First, we generated a lysine auxotroph of MTBVAC (MTBVACΔ lys ) by deleting the lysA gene. Then the auxotrophic MTBVACΔ lys was transformed with the E.?coli -mycobacterial vector p2auxo.HIVA, harboring the? lysA -complementing gene and the HIV-1 clade A immunogen HIVA. This TB-HIV vaccine conferred similar efficacy to the parental strain MTBVAC against Mtb challenge in mice. MTBVAC.HIVAsup2auxo/sup was safer than BCG and MTBVAC in severe combined immunodeficiency (SCID) mice, and it was shown to be maintained up to 42 bacterial generations in?vitro and up to 100?days after inoculation in?vivo . The MTBVAC.HIVAsup2auxo/sup vaccine, boosted with modified vaccinia virus Ankara (MVA).HIVA, induced HIV-1 and Mtb -specific interferon-γ-producing T?cell responses and polyfunctional HIV-1-specific CD8+ T?cells producing interferon-γ (IFN-γ), tumor necrosis factor alpha (TNF-α), and CD107a in BALB/c mice. Here we describe new tools to develop combined vaccines against TB and HIV with the potential of expansion for other infectious diseases.