Dataset Information

The tuberculosis vaccine candidate Bacillus Calmette-Guerin ?ureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice.

ABSTRACT: Bacillus Calmette-Guérin (BCG), the only approved tuberculosis vaccine, provides only limited protection. Previously, we generated a recombinant derivative (BCG ?ureC::hly), which secretes the pore-forming toxin listeriolysin O (LLO) of Listeria monocytogenes. This vaccine shows superior protection against tuberculosis in preclinical models and is safe in humans. Here we describe two new vaccine strains which express human interleukin-7 (hIL)-7 or hIL-18 in the genetic background of BCG ?ureC::hly to modulate specific T cell immunity. Both strains exhibited an uncompromised in vitro growth pattern, while inducing a proinflammatory cytokine profile in human dendritic cells (DCs). Human DCs harbouring either strain efficiently promoted secretion of IL-2 by autologous T cells in a coculture system, suggesting superior immunogenicity. BALB/c mice vaccinated with BCG ?ureC::hly, BCG ?ureC::hly_hIL7 or BCG ?ureC::hly_hIL18 developed a more robust Th1 response than after vaccination with parental BCG. Both strains provided significantly better protection than BCG in a murine Mycobacterium tuberculosis challenge model but efficacy remained comparable to that afforded by BCG ?ureC::hly. We conclude that expression of hIL-7 or hIL-18 enhanced specific T cell responses but failed to improve protection over BCG ?ureC::hly in mice.

SUBMITTER: Rao M

PROVIDER: S-EPMC3827306 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The tuberculosis vaccine candidate Bacillus Calmette-Guérin ΔureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice.

Rao Martin M Vogelzang Alexis A Kaiser Peggy P Schuerer Stefanie S Kaufmann Stefan H E SH Gengenbacher Martin M

PloS one 20131113 11

Bacillus Calmette-Guérin (BCG), the only approved tuberculosis vaccine, provides only limited protection. Previously, we generated a recombinant derivative (BCG ΔureC::hly), which secretes the pore-forming toxin listeriolysin O (LLO) of Listeria monocytogenes. This vaccine shows superior protection against tuberculosis in preclinical models and is safe in humans. Here we describe two new vaccine strains which express human interleukin-7 (hIL)-7 or hIL-18 in the genetic background of BCG ΔureC::h ...[more]

PMID: 24236077

Similar Datasets

Project description:UNLABELLED:The only tuberculosis (TB) vaccine in use today, bacillus Calmette-Guérin (BCG), provides insufficient protection and can cause adverse events in immunocompromised individuals, such as BCGosis in HIV(+) newborns. We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG ?ureC::hly, which secretes the pore-forming listeriolysin O of Listeria monocytogenes. Here, we evaluate a second-generation construct, BCG ?ureC::hly ?pdx1, which is deficient in pyridoxine synthase, an enzyme that is required for biosynthesis of the essential cofactor vitamin B6. This candidate was auxotrophic for vitamin B6 in a concentration-dependent manner, as was its survival in vivo. BCG ?ureC::hly ?pdx1 showed markedly restricted dissemination in subcutaneously vaccinated mice, which was ameliorated by dietary supplementation with vitamin B6. The construct was safer in severe combined immunodeficiency mice than the parental BCG ?ureC::hly. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1?, remained independent of vitamin B6 administration, while acquired immunity, notably stimulation of antigen-specific CD4 T cells, B cells, and memory T cells, was contingent on vitamin B6 administration. The early protection provided by BCG ?ureC::hly ?pdx1 in a murine Mycobacterium tuberculosis aerosol challenge model consistently depended on vitamin B6 supplementation. Prime-boost vaccination increased protection against the canonical M. tuberculosis H37Rv laboratory strain and a clinical isolate of the Beijing/W lineage. We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule. This principle fosters the development of safer vaccines required for immunocompromised individuals, notably HIV(+) infants. IMPORTANCE:Mycobacterium tuberculosis can synthesize the essential cofactor vitamin B6, while humans depend on dietary supplementation. Unlike the lipophilic vitamins A, D, and E, water-soluble vitamin B6 is well tolerated at high doses. We generated a vitamin B6 auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Guérin ?ureC::hly. The next-generation candidate was profoundly attenuated compared to the parental strain. Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B6 above the daily required dose. Control of vaccine efficacy via food supplements such as vitamin B6 could provide a fast track toward improved safety. Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines.

Project description:INTRODUCTION:Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M.TB) and other species of the Mycobacterium tuberculosis complex. Globally, TB is ranked as the ninth leading cause of death and the leading cause of death from a single infectious agent. The bacille Calmette-Guerin (BCG) vaccine has been used globally since 1921 for the prevention of TB in humans, and was derived from an attenuated strain of Mycobacterium bovis. Evidence from previous randomised trials show that the efficacy of primary BCG vaccination against pulmonary TB ranged from no protection to very high protection. In addition, some studies suggest a benefit of BCG revaccination. For example, a recent trial conducted in South Africa showed that BCG revaccination of adolescents could reduce the risk of TB infection by half. However, we are not aware of any recent systematic reviews of the effects of BCG revaccination. Thus, the need for this systematic review of the effects of BCG revaccination on protection against TB infection and disease. METHOD AND ANALYSIS:We will search PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, WHO International Clinical Trials Registry Platform and reference lists of relevant publications for potentially eligible studies. We will screen search outputs, select eligible studies, extract data and assess risk of bias in duplicate. Discrepancies will be resolved by discussion and consensus or arbitration. We will use the Grading of Recommendations Assessment, Development and Evaluation method to assess the certainty of the evidence. The planned systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in August 2018. ETHICS AND DISSEMINATION:Publicly available data will be used, hence no formal ethical approval will be required for this review. The findings of the review will be disseminated through conference presentations and publication in an open-access peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42018105916.

Project description:BackgroundThe Bacillus Calmette-Guerin (BCG) vaccine has been in use for 99 years, and is regarded as one of the oldest human vaccines known today. It is recommended primarily due to its effect in preventing the most severe forms of tuberculosis, including disseminated tuberculosis and meningeal tuberculosis in children; however, its efficacy in preventing pulmonary tuberculosis and TB reactivation in adults has been questioned. Several studies however have found that asides from its role in tuberculosis prevention, the BCG vaccine also has protective effects against a host of other viral infections in humans, an effect which has been termed: heterologous, non-specific or off-target.ObjectivesAs we approach 100 years since the discovery of the BCG vaccine, we review the evidence of the non-specific protection offered by the vaccine against viral infections, discuss the possible mechanisms of action of these effects, highlight the implications these effects could have on vaccinology and summarize the recent epidemiological correlation between the vaccine and the on-going COVID-19 pandemic.ResultsSeveral epidemiological studies have established that BCG does reduce all-cause mortality in infants, and also the time of vaccination influences this effect significantly. This effect has been attributed to the protective effect of the vaccine in preventing unrelated viral infections during the neonatal period. Some of such viral infections that have been investigated include: herpes simplex virus (HSV), human Papilloma virus (HPV), yellow fever virus (YFV), respiratory syncytial virus (RSV) and influenza virus type A (H1N1). These effects are thought to be mediated via induction of innate immune memory as well as heterologous lymphocytic activation. While epidemiological studies have suggested a correlation, the potential protection of the BCG vaccine against COVID-19 transmission and mortality rates is currently unclear. Ongoing clinical trials and further research may shed more light on the subject in the future.ConclusionBCG is a multifaceted vaccine, with many numerous potential applications to vaccination strategies being employed for current and future viral infections. There however is a need for further studies into the immunologic mechanisms behind these non-specific effects, for these potentials to become reality, as we usher in the beginning of the second century since the vaccine's discovery.

Dataset Information

The tuberculosis vaccine candidate Bacillus Calmette-Guerin ?ureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice.

Publications

The tuberculosis vaccine candidate Bacillus Calmette-Guérin ΔureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets