Recombinant BCG ΔureC hly+ Induces Superior Protection Over Parental BCG by Stimulating a Balanced Combination of Type 1 and Type 17 Cytokine Responses

Desel, Christiane; Dorhoi, Anca; Bandermann, Silke; Grode, Leander; Eisele, B.; Kaufmann, Stefan H. E.

doi:10.1093/infdis/jir592

Cited by 140 publications

(120 citation statements)

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“…At least eight distinct cytokine-producing populations of M72-specific CD4 T-cell responses were induced and persisted to at least 7 months after the first vaccination, including a discrete population of Th17 cells. Studies in mice have suggested Th17 cells play an active role in production of chemokines that recruit IFN-g-producing CD4 T cells to the lungs to restrict mycobacterial growth after challenge (16), and may be an important component of long-term control of Mtb infection (17). Moreover, polyfunctional CD4 T cells simultaneously producing IFN-g, TNF-a, and IL-2 in the lung have been correlated with better protection against Mtb challenge in mice (18).…”

Section: Discussionmentioning

confidence: 99%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

106

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Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines. Objectives: We investigated a novel TB vaccine candidate, M72/ AS01, in a phase IIa trial of bacille Calmette-Gué rin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa. Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry. Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67 1 T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants. Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals. Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).Keywords: tuberculosis; vaccine; T cell; cytokine; proliferation Tuberculosis (TB) remains a major cause of morbidity and mortality, with approximately 9 million new cases and 1.5 million deaths worldwide each year (1). Bacille Calmette-Guérin (BCG) provides protection against miliary TB and TB meningitis in children (2); however, BCG provides variable efficacy against pulmonary TB in adults (3), the most common clinical manifestation of the disease. Mycobacterium tuberculosis (Mtb) is transmitted primarily by adults; therefore novel, effective TB vaccines are urgently needed to target this population, and thereby reduce the burden of TB disease worldwide.Phase I and II clinical trials of several novel candidate TB vaccines have either been completed or are currently ongoing (4). These vaccines include the candidate recombinant fusion protein vaccine M72, formulated with GlaxoSmithKline Vaccines Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and despite the widespread use of the bacille Calmette-Guérin vaccine, tuberculosis (TB) remains a major cause of morbidity and mortality. There is an urgent need to develop novel TB vaccines that are safe,...

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Section: Discussionmentioning

confidence: 99%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

106

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“…33,34 The exogenous listeriolysin facilitates the perforation of the phagosome membrane, allowing the release of recombinant BCG antigens into the cytosol of host cells. 35 Hence, the vaccine is able to stimulate the CD8 T cells via major histocompatibility complex (MHC) I presentation, and further activate both T helper (Th)1 and Th17 cytokine responses. 35,36 In addition, an endogenous gene ureC, encoding urease C, has been deleted in VPM1002.…”

Section: Vpm1002mentioning

confidence: 99%

“…35 Hence, the vaccine is able to stimulate the CD8 T cells via major histocompatibility complex (MHC) I presentation, and further activate both T helper (Th)1 and Th17 cytokine responses. 35,36 In addition, an endogenous gene ureC, encoding urease C, has been deleted in VPM1002. 35 Urease C is crucial for the hydrolysis of urea, resulting in the ammonia production and a basic environment in the milieu.…”

Section: Vpm1002mentioning

confidence: 99%

“…35,36 In addition, an endogenous gene ureC, encoding urease C, has been deleted in VPM1002. 35 Urease C is crucial for the hydrolysis of urea, resulting in the ammonia production and a basic environment in the milieu. 32 Because hly has a stringent optimum pH of 5.5, inactivating urease C is necessary to producing the acidic pH environment for hly activity.…”

Section: Vpm1002mentioning

confidence: 99%

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Current status of new tuberculosis vaccine in children

Pang

Zhao

Cohen³

et al. 2016

Human Vaccines & Immunotherapeutics

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Pediatric tuberculosis contributes significantly to the burden of TB disease worldwide. In order to achieve the goal of eliminating TB by 2050, an effective TB vaccine is urgently needed to prevent TB transmission in children. BCG vaccination can protect children from the severe types of TB such as TB meningitis and miliary TB, while its efficacy against pediatric pulmonary TB ranged from no protection to very high protection. In recent decades, multiple new vaccine candidates have been developed, and shown encouraging safety and immunogenicity in the preclinical experiments. However, the limited data on protective efficacy in infants evaluated by clinical trials has been disappointing, an example being MVA85A. To date, no vaccine has been shown to be clinically safer and more effective than the presently licensed BCG vaccine. Hence, before a new vaccine is developed with more promising efficacy, we must reconsider how to better use the current BCG vaccine to maximize its effectiveness in children.

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“…Analyses of the characteristics of ␦2 CDR3 from ␥␦ T cells of TB patients may identify the predominant CDR3 and the sequence that specifically reacts with TB. Furthermore, ␣␤ T cells identify peptide or protein antigens that are related to M. tuberculosis (11)(12)(13)(14)(15), but little is known about the antigens recognized by ␥␦ T cells, except for various phosphoantigens. These phosphoantigens may not inhibit intracellular mycobacterial growth (16).…”

mentioning

confidence: 99%

Characteristics of the Vδ2 CDR3 Sequence of Peripheral γδ T Cells in Patients with Pulmonary Tuberculosis and Identification of a New Tuberculosis-Related Antigen Peptide

Ding

Wang

et al. 2015

Clin. Vaccine Immunol.

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c Antigen-specific ␥␦ T cells may play an important role in the immune response to Mycobacterium tuberculosis. However, little is known about the characteristics of the length distribution of the ␦2-chain complementarity determining region 3 (␦2 CDR3) of the ␥␦ T-cell receptor (TCR) in patients with active pulmonary tuberculosis (TB) on a large scale. In addition, M. tuberculosisactivated ␥␦ T cells potentially inhibit intracellular mycobacterial growth, but phosphoantigen-activated ␥␦ T cells do not. Only a few M. tuberculosis-related antigen peptides or proteins that are recognized by ␥␦ TCR have been identified. Twenty-four healthy donors (HDs) and 27 TB patients were included in the present study. The gene-scanning technique found that the ␦2 CDR3 length distribution patterns of ␥␦ TCR in TB patients were perturbed, and each pattern included different predominant CDR3 sequences. The predominant ␦2 CDR3 sequences of ␥␦ TCRs, which originated from TB patients and HD ␥␦ T cells that were stimulated by M. tuberculosis heat resistance antigen (Mtb-HAg), were used as probes to screen peptides recognized by ␥␦ TCR using a phage display library. We identified four peptides that bound to the predominant ␦2 CDR3 fragments and showed homology to M. tuberculosis genes in a BLAST search. Notably, one peptide was related to M. tuberculosis H37Rv (QHIPKPP), and this fragment was confirmed as a ligand for the ␥␦ TCR. Two fragments, Ag1 and Ag2, activated ␥␦ T cells from HD or TB patients. In summary, the ␦2 CDR3 lineage of TB patients apparently drifts, and the predominant ␦2 CDR3 sequence that recognizes M. tuberculosis may exhibit specificity. The identified M. tuberculosis-related antigen peptides may be used as vaccines or adjuvants for protective immunity against M. tuberculosis. Mycobacterium tuberculosis causes tuberculosis (TB), which is one of the most common serious chronic infectious diseases. TB is a threat to human health, especially with the increasing human immunodeficiency virus (HIV) pandemic and multidrugresistant strains of M. tuberculosis (1). An estimated 8.6 million people developed TB in 2012, and 1.3 million people died from the disease, including 320,000 deaths in people infected with HIV (2). Different pathways and cell types interact to mediate the innate and adaptive immunities against M. tuberculosis (3). The ␥␦ T-cell subset V␥9V␦2 cells was shown to play an important role in host immunity against M. tuberculosis in many studies (4-6). ␥␦ T cells generally recognize antigens in a non-major histocompatibility complex (MHC)-restricted manner, which is similar to how B cells directly recognize a ligand or antigen. The human ␦ chain is composed of eight V␦ gene fragments, two D␦ gene fragments, three J␦ gene fragments, and one C␦ gene fragment, and these fragments are located on the long arm of the 14th chromosome (7). Varying numbers of nucleotides (3 to 24) randomly insert into the connection area of the rearranged T-cell receptor (TCR) V␦ and form a VNDNJ sequence with a highly variable compleme...

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Recombinant BCG ΔureC hly+ Induces Superior Protection Over Parental BCG by Stimulating a Balanced Combination of Type 1 and Type 17 Cytokine Responses

Cited by 140 publications

References 40 publications

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Current status of new tuberculosis vaccine in children

Characteristics of the Vδ2 CDR3 Sequence of Peripheral γδ T Cells in Patients with Pulmonary Tuberculosis and Identification of a New Tuberculosis-Related Antigen Peptide

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