Advances and challenges in recombinant<i>Mycobacterium bovis</i>BCG-based HIV vaccine development: lessons learned

Kilpeläinen, Athina; Maya-Hoyos, Milena; Saubí, Narcís; Soto, Carlos Y.; Munné, Joan

doi:10.1080/14760584.2018.1534588

Cited by 12 publications

(11 citation statements)

References 142 publications

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“…Considering that the current TB vaccine, BCG, can induce potent innate immune responses and confer pathogen-unspecific trained immunity, they hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in A Mtb -SIV-vaccinated infants. Ideally, an appropriately targeted specific response directed toward beneficial epitopes of HIV would overcome the dangers of trained immunity while maintaining its positive aspects, which have been linked to decreased mortality in children receiving BCG, as well as lead to the control or prevention of HIV infection 58 …”

Section: Discussionmentioning

confidence: 99%

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

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Saubí

Guitart

et al. 2019

Molecular Therapy - Methods & Clinical Development

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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.

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Section: Discussionmentioning

confidence: 99%

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

Broset

Saubí

Guitart

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…First, BCG administration is safe for neonates, infants, and adults. Second, BCG doses are relatively easy and non-expensive to produce, allowing for mass-production, and furthermore, it is temperature stable (45). Finally, BCG acts as auto-adjuvant and induces innate and adaptive immune responses (44).…”

Section: Recombinant Bcg Vaccinesmentioning

confidence: 99%

“…Another remarkable characteristic of BCG is that it can be used as an expression vector for recombinant antigens to develop novel vaccines for pathogenic bacteria and viruses (25–34), as well as for cancer diseases (35–43). BCG has been considered as a good vector given its safety shown in vaccinated neonates, children and adults for almost a 100 years and that BCG antigens may act as adjuvants, inducing innate and adaptive immune responses (11, 22–24, 44, 45).…”

Section: Introductionmentioning

confidence: 99%

BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design

et al. 2019

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The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as “trained immunity.” Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a “trained” state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

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“…Recombinant BCG (rBCG) has been utilized as a vector to express HIV-1/Simian Immunodeficiency Virus (SIV) antigens and assessed regarding the induction of specific T-cell responses in several animal models [18]. The need for adjuvants is overcome as its cell-wall peptidoglycans and lipoproteins act as an adjuvant on their own [19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Recombinant BCG Expressing HTI Prime and Recombinant ChAdOx1 Boost Is Safe and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice

et al. 2019

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Despite the availability of anti-retroviral therapy, HIV-1 infection remains a massive burden on healthcare systems. Bacillus Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis, confers protection against meningitis and miliary tuberculosis in infants. Recombinant BCG has been used as a vaccine vehicle to express both HIV-1 and Simian Immunodeficiemcy Virus (SIV) immunogens. In this study, we constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HTI.int, expressing the HIVACAT T-cell immunogen (HTI). The plasmid was transformed into a lysine auxotrophic Mycobacterium bovis BCG strain (BCGΔLys) to generate the vaccine BCG.HTI2auxo.int. The DNA sequence coding for the HTI immunogen and HTI protein expression were confirmed, and working vaccine stocks were genetically and phenotypically characterized. We demonstrated that the vaccine was stable in vitro for 35 bacterial generations, and that when delivered in combination with chimpanzee adenovirus (ChAd)Ox1.HTI in adult BALB/c mice, it was well tolerated and induced HIV-1-specific T-cell responses. Specifically, priming with BCG.HTI2auxo.int doubled the magnitude of the T-cell response in comparison with ChAdOx1.HTI alone while maintaining its breadth. The use of integrative expression vectors and novel HIV-1 immunogens can aid in improving mycobacterial vaccine stability as well as specific immunogenicity. This vaccine candidate may be a useful tool in the development of an effective vaccine platform for priming protective responses against HIV-1/TB and other prevalent pediatric pathogens.

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Advances and challenges in recombinantMycobacterium bovisBCG-based HIV vaccine development: lessons learned

Cited by 12 publications

References 142 publications

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

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

BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design

Recombinant BCG Expressing HTI Prime and Recombinant ChAdOx1 Boost Is Safe and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice

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