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

Abstract

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.HIVA 2auxo 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.HIVA 2auxo 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.HIVA 2auxo 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.

Priming With Recombinant BCG Expressing Novel HIV-1 Conserved Mosaic Immunogens and Boosting With Recombinant ChAdOx1 Is Safe, Stable, and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice

“…The PCR fingerprints of BCG Pasteur and BCG Connaught substrains (Figure 2A) were consistent with previously published results on genetic information of BCG substrains (29). In addition, the PCR pattern of MTBVAC.HIVA (34), a live attenuated M. tuberculosis strain expressing the HIVA immunogen (22), was consistent with the expected M. tuberculosis pattern.…”

Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice

“…Prior studies of whole cell vaccines have included different versions of recombinant BCG, such as AERAS-22 [21,35], in addition to whole cell mycobacterial vaccines based on attenuated clinical Mtb strains such as Mt103 [7,[36][37][38][39][40]. Increasingly, whole cell vaccines have outperformed subunit and viral vectored vaccines in pre-clinical models [39][40][41][42].…”

Vaccine strategies for the Mtb/HIV copandemic

“…Among the promising candidates that have been successfully tested in the mouse model and are now in the human trials is MTBVAC 41 . After demonstrating improved efficacy and immunity relative to BCG in newborn mice 42 , it has recently been used as a vector for the construction of recombinant MTBVAC.HIVA 2 auxo 20 . The vaccine was safer than BCG in severe combined immunodeficiency (SCID) mice and successfully induced immune responses to both HIV-1 and Mtb .…”

“…On the other hand, recent advances in TB vaccines have presented promising candidates such as MTBVAC, revaccination with BCG, H4:IC31 and H56:IC31 16 – 19 that have the potential to be modified for use against TB/HIV coinfection. One such candidate, MTBVAC.HIVA 2 auxo , a live-attenuated vaccine for HIV-1 and TB elicited polyfunctional HIV-1-specific CD8+ T cells and interferon-γ-producing Mtb -specific T cells 20 (Table 1 ).…”