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.HIVA2auxo strain. First, we generated a lysine auxotroph of MTBVAC (MTBVACΔlys) by deleting the lysA gene. Then the auxotrophic MTBVACΔlys 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.HIVA2auxo 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.HIVA2auxo 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.
Highlights
Today, tuberculosis (TB) has reached alarming proportions
This auxotrophic MTBVACDlys strain was used in the subsequent experiments to generate recombinant vaccines expressing the HIVA immunogen
No differences were found between the different MTBVAC strains tested, which validates the protective behavior of MTBVAC.HIVA2auxo vaccine against Mycobacterium tuberculosis (Mtb) despite the genetic manipulations introduced
Summary
Tuberculosis (TB) has reached alarming proportions. An estimated 10 million people have developed TB in 2017 and 9% were people living with HIV (72% in Africa). Molecular Therapy: Methods & Clinical Development Vol 13 June 2019 a 2019 The Author(s). Molecular Therapy: Methods & Clinical Development disease may arise;[9] (2) BCG provides strong protection against disseminated forms of the disease in infants and young children;[10,11] (3) BCG revaccination of adolescents may provide additional benefits for the prevention of TB;[12] and (4) BCG vaccination reduces all-cause mortality through beneficial non-specific (heterologous) effects on the immune system.[13,14] These four effects strengthen the motivation for the inclusion of BCG in the global vaccination program.[15]
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