Boosting BCG vaccination with MVA85A down-regulates the immunoregulatory cytokine TGF-beta1.
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SUBMITTER: Fletcher HA
PROVIDER: S-EPMC2631167 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
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Boosting BCG vaccination with MVA85A down-regulates the immunoregulatory cytokine TGF-beta1.
Fletcher Helen A HA Pathan Ansar A AA Berthoud Tamara K TK Dunachie Susanna J SJ Whelan Kathryn T KT Alder Nicola C NC Sander Clare R CR Hill Adrian V S AV McShane Helen H
Vaccine 20080803 41
In clinical trials recombinant-modified vaccinia virus Ankara expressing the Mycobacterium tuberculosis antigen 85A (MVA85A) induces approximately 10 times more effector T cells than any other recombinant MVA vaccine. We have found that in BCG primed subjects MVA85A vaccination reduces transforming growth factor beta 1 (TGF-beta1) mRNA in peripheral blood lymphocytes and reduces TGF-beta1 protein in the serum, but increases IFN-gamma ELISPOT responses to the recall antigen SK/SD. TGF-beta1 is es ...[more]
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Project description:OBJECTIVES:To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A. DESIGN:Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-gamma) ELISpot assay and flow cytometry. RESULTS AND CONCLUSIONS:BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNgamma (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated. In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells. TRIAL REGISTRATION:ClinicalTrials.gov NCT00654316 NCT00427830.
| S-EPMC2694271 | biostudies-literature
Project description:AIMS:To evaluate the expression of transforming growth factor beta1 (TGF-beta1) and fibroblast growth factor 2 (FGF-2) mRNA in stromal cells in response to injury in the presence of either TGF-beta1 or FGF-2. It has been shown previously that heparan sulfate proteoglycans and FGF-2 are present transiently during wound repair in vivo and that an increase in TGF-beta1 mRNA is detected rapidly after injury. METHODS:Primary corneal fibroblasts were cultured to confluency, serum starved, and linear wound(s) were made in medium containing TGF-beta1 or FGF-2. TGF-beta1 and FGF-2 mRNA expression were evaluated using both northern blot analysis and in situ hybridisation. Both dose dependent and time course experiments were performed. Whole eye organ culture experiments were also carried out and growth factor expression was assessed. RESULTS:Injury and exogenous TGF-beta1 increased TGF-beta1 mRNA values. The increase in expression of FGF-2 mRNA was not detected until wound closure. In contrast, FGF-2 inhibited the expression of TGF-beta1. TGF-beta1 increased TGF-beta1 mRNA stability but did not alter that of FGF-2. Migration assay data demonstrated that unstimulated stromal cells could be activated to migrate to specific growth factors. CONCLUSIONS:TGF-beta1 specifically enhances cellular responsiveness, as shown by increased stability after injury and the acquisition of a migratory phenotype. These data suggest that there is an integral relation during wound repair between TGF-beta1 and FGF-2.
| S-EPMC1187169 | biostudies-literature
Project description:BackgroundBCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants.MethodsDiluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses.ResultsWe found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants.ConclusionsMalawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.
| S-EPMC3164434 | biostudies-literature
Project description:Interleukin (IL)-10 and transforming growth factor (TGF)-beta1 are suppressor cytokines that frequently occur together during a regulatory T cell response. Here we used a one gene doxycycline (Dox)-inducible plasmid encoding TGF-beta1 to analyze this association and test its utility. In initial studies, we showed that intranasal administration of this plasmid (along with Dox) led to the appearance of TGF-beta1-producing cells (in spleen and lamina propria) and the almost concomitant appearance of IL-10-producing cells. Moreover, we showed that these cells exert Dox-regulated suppression of the T helper cell (Th)1-mediated inflammation in trinitrobenzene sulfonic acid colitis. In subsequent in vitro studies using retroviral TGF-beta1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-beta1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-beta1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-beta1 plasmid administration ameliorates bleomycin-induced fibrosis in wild-type but not IL-10-deficient mice, strongly suggesting that the amelioration is IL-10 dependent and that IL-10 protects mice from TGF-beta1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-beta1 is not fortuitous, but instead fulfills important requirements of TGF-beta1 function after its secretion by regulatory T cells.
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Project description:Abstract This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and summarize the effects of the MVA85A vaccine boosting BCG in humans.
| S-EPMC6491086 | biostudies-literature
Project description:BackgroundTuberculosis causes more deaths than any other infectious disease globally. Bacillus Calmette-Guérin (BCG) is the only available vaccine, but protection is incomplete and variable. The modified Vaccinia Ankara virus expressing antigen 85A (MVA85A) is a viral vector vaccine produced to prevent tuberculosis.ObjectivesTo assess and summarize the effects of the MVA85A vaccine boosting BCG in humans.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); and four other databases. We searched the WHO ICTRP and ClinicalTrials.gov. All searches were run up to 10 May 2018.Selection criteriaWe evaluated randomized controlled trials of MVA85A vaccine given with BCG in people regardless of age or HIV status.Data collection and analysisTwo review authors independently assessed the eligibility and risk of bias of trials, and extracted and analyzed data. The primary outcome was active tuberculosis disease. We summarized dichotomous outcomes using risk ratios (RR) and risk differences (RD), with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses. Where meta-analysis was inappropriate, we summarized results narratively.Main resultsThe search identified six studies relating to four Phase 2 randomized controlled trials enrolling 3838 participants. Funding was by government bodies, charities, and philanthropic donors. Five studies included infants, one of them infants born to HIV-positive mothers. One study included adults living with HIV. All trials included authors from Oxford University who led the laboratory development of the vaccine. Participants received intradermal MVA85A after BCG in some studies, and before selective deferred BCG in HIV-exposed infants.The largest trial in 2797 African children was well conducted with low risk of bias for most parameters. Risk of bias was uncertain for selective reporting because there were no precise case definition endpoints for active tuberculosis published prior to the trial analysis.MVA85A added to BCG compared to BCG alone probably has no effect on the risk of developing microbiologically confirmed tuberculosis (RR 0.97, 95% CI 0.58 to 1.62; 3439 participants, 2 trials; moderate-certainty evidence), or the risk of starting on tuberculosis treatment (RR 1.10, 95% CI 0.92 to 1.33; 3687 participants, 3 trials; moderate-certainty evidence). MVA85A probably has no effect on the risk of developing latent tuberculosis (RR 1.01, 95% CI 0.85 to 1.21; 3831 participants, 4 trials; moderate-certainty evidence). Vaccinating people with MVA85A in addition to BCG did not cause life-threatening serious adverse effects (RD 0.00, 95% CI -0.00 to 0.00; 3692 participants, 3 trials; high-certainty evidence). Vaccination with MVA85A is probably associated with an increased risk of local skin adverse effects (3187 participants, 3 trials; moderate-certainty evidence), but not systemic adverse effect related to vaccination (144 participants, 1 trial; low-certainty evidence). This safety profile is consistent with Phase 1 studies which outlined a transient, superficial reaction local to the injection site and mild short-lived symptoms such as malaise and fever.Authors' conclusionsMVA85A delivered by intradermal injection in addition to BCG is safe but not effective in reducing the risk of developing tuberculosis.
| S-EPMC6488980 | biostudies-literature
Project description:Bacille Calmette-Guérin (BCG) vaccination supposedly imparts and augments “trained immunity” that cross-protects against multiple unrelated pathogens and enhances general immune surveillance. Gradual reductions in tuberculosis burden over the last 3–5 decades have resulted in the withdrawal of BCG vaccination mandates from developed industrialized countries while reducing to a single neonatal shot in the rest. Concurrently, a steady increase in early childhood Brain and CNS (BCNS) tumors has occurred. Though immunological causes of pediatric BCNS cancer are suspected, the identification of a causal protective variable with intervention potential has remained elusive. An examination of the countries with contrasting vaccination policies indicates significantly lower BCNS cancer incidence in 0–4-year-olds (per hundredthousand) of countries following neonatal BCG inoculations (n=146) vs. non-BCG countries (n=33) [Mean: 1.26 vs. 2.64; Median: 0.985 vs. 2.8; IQR: 0.31–2.0 vs. 2.4–3.2; P=<0.0001 (two-tailed)]. Remarkably, natural Mycobacterium spp. reexposure likelihood is negatively correlated with BCNS cancer incidence in 0-4-year-olds of all affected countries [r(154): −0.6085, P=<0.0001]. Seemingly, neonatal BCG vaccination and natural “boosting” are associated with a 15–20-fold lower BCNS cancer incidence. In this opinion article, we attempt to synthesize existing evidence implying the immunological basis of early childhood BCNS cancer incidence and briefly indicate possible causes that could have precluded objective analysis of the existing data in the past. We draw the attention of the stakeholders to consider the comprehensive evaluation of immune training as a potential protective variable through well-designed controlled clinical trials or registry-based studies as feasible for its potential applications in reducing childhood BCNS cancer incidence.
| S-EPMC10295148 | biostudies-literature
Project description:Background: Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population. Methods: We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis. Results: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A. Conclusion: The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies. Trial registration: ClinicalTrials.gov number NCT00953927
2014-06-11 | GSE56559 | GEO
Project description:Background: Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population. Methods: We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis. Results: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A. Conclusion: The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies. Trial registration: ClinicalTrials.gov number NCT00953927 Whole blood collected 1 day post-vaccination with MVA85A or Candin placebo (82 samples)
2014-06-11 | E-GEOD-56559 | biostudies-arrayexpress
Project description:Transforming growth factor (TGF)-beta(1) is an essential regulatory cytokine that has been implicated in the pathogenesis of diverse facets of the injury and repair responses in the lung. The types of responses that it elicits can be appreciated in studies from our laboratory that demonstrated that the transgenic (Tg) overexpression of TGF-beta(1) in the murine lung causes epithelial apoptosis followed by fibrosis, inflammation, and parenchymal destruction. Because a cyclin-dependent kinase inhibitor, p21, is a key regulator of apoptosis, we hypothesized that p21 plays an important role in the pathogenesis of TGF-beta(1)-induced tissue responses. To test this hypothesis we evaluated the effect of TGF-beta(1) on the expression of p21 in the murine lung. We also characterized the effects of transgenic TGF-beta(1) in mice with wild-type and null mutant p21 loci. These studies demonstrate that TGF-beta(1) is a potent stimulator of p21 expression in the epithelial cells and macrophages in the murine lung. They also demonstrate that TGF-beta(1)-induced lung inflammation, fibrosis, myofibroblast accumulation, and alveolar destruction are augmented in the absence of p21, and that these alterations are associated with exaggerated levels of apoptosis and caspase-3 activation. Finally, our studies further demonstrated that TGF-beta(1) induces p21 via a TNF-alpha-signaling pathway and that p21 is a negative modulator of TGF-beta(1)-induced TNF-alpha expression. Collectively, our studies demonstrate that p21 regulates TGF-beta(1)-induced apoptosis, inflammation, fibrosis, and alveolar remodeling by interacting with TNF-alpha-signaling pathways.
| S-EPMC2258454 | biostudies-literature