The Effect of Smallpox and Bacillus Calmette-Guérin Vaccination on the Risk of Human Immunodeficiency Virus-1 Infection in Guinea-Bissau and Denmark

PubMed Central

Villumsen, Marie; Jensen, Mette Lundsby; Ravn, Henrik; da Silva, Zacarias J; Sørup, Signe; Baker, Jennifer Lyn; Rodrigues, Amabélia; Benn, Christine Stabell; Roth, Adam E; Aaby, Peter

2017-01-01

Abstract Background The live smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea-Bissau and Denmark. Methods We conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression. Results Bacillus Calmette-Guérin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36–1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43–1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46–0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10–0.75) as follows: women, aOR = 0.18 (95% CI, 0.05–0.64); men, aOR = 0.52 (95% CI, 0.12–2.33); sex-differential effect, P = .29. Conclusions The studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine. PMID:28852677

Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer

PubMed Central

Shang, Zhiqun; Li, Yanjun; Hsu, Iawen; Zhang, Minghao; Tian, Jing; Wen, Simeng; Han, Ruifa; Messing, Edward M.; Chang, Chawnshang; Niu, Yuanjie; Yeh, Shuyuan

2016-01-01

Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence. PMID:27092883

Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer.

PubMed

Shang, Zhiqun; Li, Yanjun; Hsu, Iawen; Zhang, Minghao; Tian, Jing; Wen, Simeng; Han, Ruifa; Messing, Edward M; Chang, Chawnshang; Niu, Yuanjie; Yeh, Shuyuan

2016-05-10

Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette-Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.

Comparison of fluoxetine and 1-methyl-L-tryptophan in treatment of depression-like illness in Bacillus Calmette-Guerin-induced inflammatory model of depression in mice.

PubMed

Rana, Proteesh; Sharma, Amit K; Jain, Smita; Deshmukh, Pravin; Bhattacharya, S K; Banerjee, B D; Mediratta, Pramod K

2016-11-01

The inflammatory response system has been implicated in the pathophysiology of major depression. The pro-inflammatory cytokines like interferon-γ induce the enzyme indoleamine-2,3-dioxygenase (IDO) of the kynurenine pathway of tryptophan metabolism. The induction of IDO reduces the availability of tryptophan for serotonin synthesis. Furthermore, the metabolites of kynurenine pathway have neurotoxic property, which along with decreased serotonin may account for depression-like illness. The aim of this study was to compare the effects of treatment with fluoxetine and 1-methyl-L-tryptophan (1-MT) on Bacillus Calmette-Guerin (BCG)-induced inflammatory model of depression in mice. Behavioral tests included locomotor activity, forced swim test (FST) and tail suspension test (TST). Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in homogenized whole brain samples. Comet assays were performed to assess neurotoxicity. The results of this study demonstrate that BCG treatment resulted in an increase in duration of immobility in FST and TST as compared to the saline group. Further, it produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. The hippocampal tissue from BCG group had significantly more comet cells than the saline group. 1-MT and fluoxetine were able to reverse the BCG-induced depression-like behavior and the derangement in oxidative stress parameters. Fluoxetine and 1-MT also reversed the BCG-induced neurotoxicity in such mice. 1-Methyl-L-tryptophan exhibits antidepressant-like effect comparable to that of fluoxetine in treating BCG-induced depression-like behavior in mice.

Anti-angiogenic effects of the superantigen staphylococcal enterotoxin B and bacillus Calmette-Guérin immunotherapy for nonmuscle invasive bladder cancer.

PubMed

Reis, Leonardo O; Ferreira, Ubirajara; Billis, Athanase; Cagnon, Valéria H A; Fávaro, Wagner J

2012-02-01

We compared and characterized the effects of intravesical bacillus Calmette-Guérin and/or staphylococcal enterotoxin B for nonmuscle invasive bladder cancer. A total of 75 female Fisher 344 rats were anesthetized. Of the rats 15 received 0.3 ml saline (control) and 60 received 1.5 mg/kg MNU (N-methyl-n-nitrosourea) intravesically every other week for 6 weeks. The rats were divided into 5 groups. The MNU and control groups received 0.3 ml saline. The bacillus Calmette-Guérin group received 10(6) cfu bacillus Calmette-Guérin. The staphylococcal enterotoxin B group received 10 μg/ml staphylococcal enterotoxin B. The bacillus Calmette-Guérin plus staphylococcal enterotoxin B group received the 2 treatments simultaneously. Each group was treated intravesically for 6 weeks. At 15 weeks all bladders were collected for histopathological and immunological evaluation, and Western blot. Papillary carcinoma (pTa) and high grade intraepithelial neoplasia (carcinoma in situ) were more common in the MNU group. Papillary hyperplasia was more common in the bacillus Calmette-Guérin and enterotoxin groups. Flat hyperplasia was more common in the bacillus Calmette-Guérin plus enterotoxin group. No significant toxicity was observed. The apoptosis and cellular proliferation indexes decreased in the bacillus Calmette-Guérin, enterotoxin and bacillus Calmette-Guérin plus enterotoxin groups compared to the MNU group. Intensified vascular endothelial growth factor, matrix metalloproteinase-9, Ki-67 and insulin-like growth factor receptor-1 immunoreactivity was verified in the MNU group, moderate in the bacillus Calmette-Guérin and enterotoxin groups, and weak in the bacillus Calmette-Guérin plus enterotoxin and control groups. In contrast, intense endostatin immunoreactivity was verified in the control and bacillus Calmette-Guérin plus enterotoxin groups. Bacillus Calmette-Guérin and staphylococcal enterotoxin B showed similar anti-angiogenic effects. Bacillus Calmette

Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC::hly Δpdx1 in mice.

PubMed

Gengenbacher, Martin; Vogelzang, Alexis; Schuerer, Stefanie; Lazar, Doris; Kaiser, Peggy; Kaufmann, Stefan H E

2014-06-03

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 ΔureC::hly, which secretes the pore-forming listeriolysin O of Listeria monocytogenes. Here, we evaluate a second-generation construct, BCG ΔureC::hly Δpdx1, 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 ΔureC::hly Δpdx1 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 ΔureC::hly. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1α, 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 ΔureC::hly Δpdx1 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

Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956-1974.

PubMed

Rousseau, Marie-Claude; Conus, Florence; Kâ, Khady; El-Zein, Mariam; Parent, Marie-Élise; Menzies, Dick

2017-08-24

In the province of Québec, Canada, the Bacillus Calmette-Guérin (BCG) vaccine was offered to newborns and school-age children from the 1950s to mid-1970s in an organized tuberculosis prevention program. We aimed to describe the annual rates of skin test administration, proportion of skin tests that were positive, and rates of BCG vaccination from 1956 to 1974 according to age, sex, and administrative region. For rates, numerators were extracted from the Québec BCG Vaccination Registry whereas population denominators were obtained from the Canadian Census and governmental publications. Time trends were assessed with linear regression. A total of 2,755,336 skin tests and 2,531,366 BCG vaccinations were administered. Yearly rates of skin tests, routinely administered before vaccination among all except newborns, were highest among children aged 5-9 (9.3 per 100) and 10-14years (7.9 per 100). The proportion of positive skin tests varied greatly by age, ranging from 10.2% among children <1year to 67.2% among adults ≥20years. The vast majority of individuals who had a negative skin test were subsequently vaccinated, whereas those with a positive result were not, as per recommended guidelines. The average annual vaccination rate was highest among children aged <1year (43.8 per 100) and 5-9year-olds (6.9 per 100). There were salient differences in immunization rates, including positive skin tests and vaccinations, across administrative regions but no difference by sex. This is the first comprehensive description of the tuberculosis prevention program in Québec which offered free, non-mandatory BCG vaccination. Our results confirm that the targeted groups, newborns and school-age children, were preferentially reached. Socioeconomic, demographic, and organizational factors may explain regional differences in immunization rates. Beyond presenting a historical context for this vaccination campaign, our findings are relevant to contemporary uses of the Québec BCG

Bacillus Calmette-Guérin vaccination at birth: Effects on early childhood infections, growth, and development.

PubMed

Kjærgaard, Jesper

2016-11-01

The Bacillus Calmette-Guérin vaccine (BCG), which is used to protect against tuberculosis, has been associated with a variety of other effects since it was developed almost 100 years ago. Most notably, observational studies and randomized clinical trials from low-income countries indicate that it protects against unrelated infections, i.e. a so-called non-specific effect. The Danish Calmette Study was conducted to study these effects in a high-income population. The immune response to BCG is not fully understood but involves a pro-inflammatory profiling of the immune system, also when exposed to unrelated pathogens. Immune changes have been implicated in changes in both child growth and child development and for that reason we also studied these outcomes. We randomized 4262 children at birth to receive BCG vaccination at birth or to a no-intervention control group. We had pre-specified subgroup analyses of child sex, prematurity, and maternal BCG vaccination. The statistical analysis plan was finalized prior to unblinding of the data. Follow-up for the outcomes reported in this thesis consisted of telephone interviews and clinical examination at age 3 and 13 months, as well as online developmental questionnaires distributed to the parents at 12 months and additionally to the parents of premature children at age 6 and 22 months. The outcomes of this thesis were number of parent reported infections, child growth and body composition, and child psychomotor development. Overall, there was no effect of BCG on either incidence of infections, growth, body composition or psychomotor development. A subgroup analysis of children of mothers who were BCG vaccinated showed a reduced incidence of infections from 0 to 3 months among BCG vaccinated children (incidence rate ratio = 0.62, CI: 0.39 to 0.98), but there was no effect from 3 to 13 months. Previous research has shown that maternal exposure to BCG or mycobacteria can alter the effect of BCG in the offspring, and thus the

Vaccine approaches for bovine tuberculosis: Correlates of protection and relevance to human tuberculosis

USDA-ARS?s Scientific Manuscript database

Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is a classic model of the One Health Concept. M. bovis Bacillus Calmette Guerin (BCG) was first proven effective in cattle prior to use in humans. Recent experimental trials with cattle have d...

Subcutaneous administration of a 10-fold-lower dose of a commercial human tuberculosis vaccine, Mycobacterium bovis bacillus Calmette-Guerin Danish, induced levels of protection against bovine tuberculosis and responses in the tuberculin intradermal test similar to those induced by a standard cattle dose.

PubMed

Buddle, Bryce M; Hewinson, R Glyn; Vordermeier, H Martin; Wedlock, D Neil

2013-10-01

Vaccination of cattle with a commercial human tuberculosis (TB) vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG) Danish, at a dose equivalent to 5 human doses of BCG has protected these animals against TB in field and experimental trials. There is interest in determining whether a 10-fold-lower dose could still protect cattle but not induce a tuberculin intradermal test response. Two groups of calves (n = 9/group) were vaccinated subcutaneously with a lyophilized BCG Danish vaccine containing either 0.5 (1 × 10(5) to 4 × 10(5) CFU) or 5 (1 × 10(6) to 4 × 10(6) CFU) human doses of BCG Danish, with an additional group of 10 calves serving as nonvaccinated controls. Fifteen weeks after vaccination, these animals were challenged intratracheally with 5 × 10(3) CFU of virulent M. bovis and another 15 weeks later were slaughtered and examined for the presence of tuberculous lesions. Vaccination of the calves with either 0.5 or 5 equivalent human doses of BCG Danish induced similar levels of protection against challenge with M. bovis, with both groups showing significant reductions in the pathological and microbiological parameters compared to those for the the control group (P < 0.05). Vaccination with either of the two BCG doses induced similar numbers of animals responding to the tuberculin intradermal test at 11 weeks postvaccination. Vaccination with a 0.5 equivalent human dose of a commercial lyophilized BCG vaccine can protect cattle against challenge with M. bovis.

Molecular networks discriminating mouse bladder responses to intravesical bacillus Calmette-Guerin (BCG), LPS, and TNF-α

PubMed Central

Saban, Marcia R; O'Donnell, Michael A; Hurst, Robert E; Wu, Xue-Ru; Simpson, Cindy; Dozmorov, Igor; Davis, Carole; Saban, Ricardo

2008-01-01

Background Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG) remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression in the bladder target organ beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following chronic intravesical BCG therapy and to compare the results to non-specific pro inflammatory stimuli (LPS and TNF-α). For this purpose, C57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-α. Seven days after the last instillation, the urothelium along with the submucosa was removed from detrusor muscle and the RNA was extracted from both layers for cDNA array experiments. Microarray results were normalized by a robust regression analysis and only genes with an expression above a conditional threshold of 0.001 (3SD above background) were selected for analysis. Next, genes presenting a 3-fold ratio in regard to the control group were entered in Ingenuity Pathway Analysis (IPA) for a comparative analysis in order to determine genes specifically regulated by BCG, TNF-α, and LPS. In addition, the transcriptome was precipitated with an antibody against RNA polymerase II and real-time polymerase chain reaction assay (Q-PCR) was used to confirm some of the BCG-specific transcripts. Results Molecular networks of treatment-specific genes generated several hypotheses regarding the mode of action of BCG. BCG-specific genes involved small GTPases and BCG-specific networks overlapped with the following canonical signaling pathways: axonal guidance, B cell receptor, aryl hydrocarbon receptor, IL-6, PPAR, Wnt/β-catenin, and cAMP. In addition, a specific detrusor network expressed a high degree of overlap with the development of the

Modified multiplex PCR for identification of Bacillus Calmette-Guérin substrain Tokyo among clinical isolates.

PubMed

Seki, Masaaki; Sato, Akimasa; Honda, Ikuro; Yamazaki, Toshio; Yano, Ikuya; Koyama, Akira; Toida, Ichiro

2005-05-02

When an adverse reaction occurs and a mycobacterial species is isolated from a person vaccinated with Bacillus Calmette-Guérin (BCG) or a patient receiving BCG immunotherapy, it is essential to identify whether the isolate is BCG or another mycobacterial species. However, differentiation of BCG from other members of Mycobacterium tuberculosis complex has been very difficult. Using several specific primer-pairs, Bedwell et al. [Bedwell J, Kairo SK, Behr MA, Bygraves JA. Identification of substrains of BCG vaccine using multiplex PCR. Vaccine 2001; 19: 2146-51] recently reported that they could distinguish BCG substrains. We modified their method to improve differentiation of Tokyo 172 from other members of the M. tuberculosis complex, and examined whether this modified method could be applied to clinical isolates. Our method clearly identified BCG substrain (BCG Tokyo 172) among clinical isolates and easily distinguished between M. tuberculosis and wild-type Mycobacterium bovis.

Central Memory CD4+ T Cells Are Responsible for the Recombinant Bacillus Calmette-Guérin ΔureC::hly Vaccine's Superior Protection Against Tuberculosis

PubMed Central

Vogelzang, Alexis; Perdomo, Carolina; Zedler, Ulrike; Kuhlmann, Stefanie; Hurwitz, Robert; Gengenbacher, Martin; Kaufmann, Stefan H. E.

2014-01-01

Bacillus Calmette-Guérin (BCG) has been used for vaccination against tuberculosis for nearly a century. Here, we analyze immunity induced by a live tuberculosis vaccine candidate, recombinant BCG ΔureC::hly vaccine (rBCG), with proven preclinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4+ T-cell population, comparing the more efficacious rBCG with canonical BCG to determine which T-cell memory responses are prerequisites for superior protection against tuberculosis. rBCG induced higher numbers and proportions of antigen-specific memory CD4+ T cells than BCG, with a CXCR5+CCR7+ phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We found that the superior protection of rBCG, compared with BCG, correlated with higher proportions and numbers of these central memory T cells and of T follicular helper cells associated with specific antibody responses. Adoptive transfer of mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary tuberculosis. PMID:24943726

Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection Against Bovine Tuberculosis

USDA-ARS?s Scientific Manuscript database

Previous work in small animal laboratory models of tuberculosis have shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacille Calmette-Guerin (BCG) to prime and Modified Vaccinia Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad8...

Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer.

PubMed

Nepple, Kenneth G; Lightfoot, Andrew J; Rosevear, Henry M; O'Donnell, Michael A; Lamm, Donald L

2010-11-01

In a multicenter, prospectively randomized study we evaluated bacillus Calmette-Guérin alone vs bacillus Calmette-Guérin plus interferon α-2b and megadose vitamins vs recommended daily allowance vitamins during induction and maintenance intravesical therapy in the treatment of nonmuscle invasive bladder cancer. Patients who were bacillus Calmette-Guérin naïve with carcinoma in situ, Ta or T1 urothelial cancer were randomized to receive intravesical bacillus Calmette-Guérin or bacillus Calmette-Guérin plus interferon α-2b. Patients were further randomized to receive a recommended daily allowance or megadose vitamin preparation. Induction bacillus Calmette-Guérin treatment was given weekly for 6 weeks, and patients who were recurrence-free received maintenance treatment at 4, 7, 13, 19, 25 and 37 months. Patients were followed with quarterly cystoscopy for 2 years, then semiannually through year 4 and then annually. The primary end point was biopsy confirmed tumor recurrence or positive cytology. A total of 670 patients were accrued and randomized. At 24-month median followup recurrence-free survival was similar in all groups with 63% in the bacillus Calmette-Guérin with recommended daily allowance vitamins group, 59% in bacillus Calmette-Guérin with megadose vitamins, 55% in bacillus Calmette-Guérin/interferon α-2b with recommended daily allowance vitamins and 61% in bacillus Calmette-Guérin/interferon α-2b with megadose vitamins (p >0.05). The addition of interferon α-2b was associated with a more frequent incidence of fever (11% vs 5%) and constitutional symptoms (18% vs 11%) vs bacillus Calmette-Guérin alone (p <0.05). Interferon α-2b added to bacillus Calmette-Guérin induction and maintenance intravesical therapy did not decrease tumor recurrence in bacillus Calmette-Guérin naïve cases, but was associated with increased fever and constitutional symptoms. No difference in time to recurrence was present in patients receiving recommended daily

Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice.

PubMed

Xu, Ying; Yang, Enzhuo; Wang, Jianguang; Li, Rui; Li, Guanghua; Liu, Guoyuan; Song, Na; Huang, Qi; Kong, Cong; Wang, Honghai

2014-10-01

To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette-Guérin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG-primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA-, protein- and lentiviral vector-based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime-boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8(+) cytotoxic T lymphocyte responses, compared with DNA- and protein-based vaccines. However, lentivirus-vectored and DNA-based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB. © 2014 John Wiley & Sons Ltd.

Vaccination and allergy.

PubMed

Rottem, Menachem; Shoenfeld, Yehuda

2004-06-01

Vaccines have had a major effect on controlling the spread of infectious diseases, but use of certain vaccines was linked to potential allergic and autoimmune side effects in healthy and often in certain high-risk populations. In this review the authors summarize the current knowledge of such risks. Immediate systemic allergic reactions after vaccination with commonly used vaccines are extremely rare. Use of certain vaccines was linked to potential allergic side effects in healthy and often in certain high-risk populations. The authors review the data on the risk associated with important vaccines including influenza, smallpox, pneumococcus, Japanese encephalitis, Bacille Calmette-Guerin, pertussis, and measles, mumps, and rubella. Two main components were identified as a source for allergic reactions in vaccines: gelatin and egg protein. There is growing interest in the potential interactions between infant vaccination and risk for development of atopic disease. In addition, there is concern that genetic risk for atopy influences capacity to respond to vaccination during infancy. There is no evidence that vaccines such as Bacille Calmette-Guerin; pertussis; influenza; measles, mumps, and rubella; or smallpox have an effect on the risk of the development of atopy later in life. Immunotherapy provides an efficacious and safe method for the treatment of allergic conditions by immunomodulation of the immune system. The possibility of vaccination triggering or unmasking autoimmunity in genetically susceptible individuals cannot be ruled out, but for the general population the risk-to-benefit ratio is overwhelmingly in favor of vaccinations. Childhood vaccination remains an essential part of child health programs and should not be withheld, even from children predisposed to allergy. Vaccinations are safe, but special attention should be taken in high-risk individuals with anaphylactic reactions to foods, and in patients with autoimmune diseases.

Priming-boosting vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin and a nonreplicating vaccinia virus recombinant leads to long-lasting and effective immunity.

PubMed

Ami, Yasushi; Izumi, Yasuyuki; Matsuo, Kazuhiro; Someya, Kenji; Kanekiyo, Masaru; Horibata, Shigeo; Yoshino, Naoto; Sakai, Koji; Shinohara, Katsuaki; Matsumoto, Sohkichi; Yamada, Takeshi; Yamazaki, Shudo; Yamamoto, Naoki; Honda, Mitsuo

2005-10-01

Virus-specific T-cell responses can limit immunodeficiency virus type 1 (HIV-1) transmission and prevent disease progression and so could serve as the basis for an affordable, safe, and effective vaccine in humans. To assess their potential for a vaccine, we used Mycobacterium bovis bacillus Calmette-Guérin (BCG)-Tokyo and a replication-deficient vaccinia virus strain (DIs) as vectors to express full-length gag from simian immunodeficiency viruses (SIVs) (rBCG-SIVgag and rDIsSIVgag). Cynomolgus macaques were vaccinated with either rBCG-SIVgag dermally as a single modality or in combination with rDIsSIVgag intravenously. When cynomologus macaques were primed with rBCG-SIVgag and then boosted with rDIsSIVgag, high levels of gamma interferon (IFN-gamma) spot-forming cells specific for SIV Gag were induced. This combination regimen elicited effective protective immunity against mucosal challenge with pathogenic simian-human immunodeficiency virus for the 1 year the macaques were under observation. Antigen-specific intracellular IFN-gamma activity was similarly induced in each of the macaques with the priming-boosting regimen. Other groups receiving the opposite combination or the single-modality vaccines were not effectively protected. These results suggest that a recombinant M. bovis BCG-based vector may have potential as an HIV/AIDS vaccine when administered in combination with a replication-deficient vaccinia virus DIs vector in a priming-boosting strategy.

[Intrarenal Bacillus Calmette-Guerin perfusion therapy was effective for carcinoma in situ of the upper urinary tract after ileal conduit replacement : a case report].

PubMed

Hayashi, Takuji; Yamanaka, Yohei; Kinjo, Takanori; Katayama, Kinzo; Kamoto, Akihito; Mori, Naoki; Yoshioka, Toshiaki

2014-04-01

A 63-year-old man who had undergone radical cystectomy and ileal conduit formation for invasive bladder cancer 3 years before presented with continuous positive urinary cytology in the ileal conduit. His diagnosis was carcinoma in situ (CIS) of the left upper urinary tract. He was treated with Bacillus Calmette-Guérin (BCG) perfusion therapy using a single-J ureteric stent. BCG (80 mg) in 100 ml saline was instilled in a one-hour period weekly for 6 weeks. Usage of another catheter was effective for continuing the therapy. Urinary cytology in the left upper urinary tract and the ileal conduit became negative after the therapy. There was no evidence of recurrence or metastasis of urothelial carcinoma 6 months after the therapy.

Dietary Pyridoxine Controls Efficacy of Vitamin B6-Auxotrophic Tuberculosis Vaccine Bacillus Calmette-Guérin ΔureC::hly Δpdx1 in Mice

PubMed Central

Vogelzang, Alexis; Schuerer, Stefanie; Lazar, Doris; Kaiser, Peggy

2014-01-01

ABSTRACT 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 ΔureC::hly, which secretes the pore-forming listeriolysin O of Listeria monocytogenes. Here, we evaluate a second-generation construct, BCG ΔureC::hly Δpdx1, 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 ΔureC::hly Δpdx1 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 ΔureC::hly. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1α, 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 ΔureC::hly Δpdx1 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. PMID

BCG (Bacille Calmette-Guerin) Vaccine

MedlinePlus

... Aggregate Reports Slide Sets Epidemiology of Tuberculosis Among Non-U.S.​–Born Persons in the United States, 1993– ... immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 ...

Treatment of non-muscle invasive bladder cancer with Bacillus Calmette–Guerin (BCG): Biological markers and simulation studies

PubMed Central

Kiselyov, Alex; Bunimovich-Mendrazitsky, Svetlana; Startsev, Vladimir

2015-01-01

Intravesical Bacillus Calmette–Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunological response triggered by the BCG instillation and respective mathematical models of the treatment. Specific examples of markers include diverse immune cells, genetic polymorphisms, miRNAs, epigenetics, immunohistochemistry and molecular biology ‘beacons’ as exemplified by cell surface proteins, cytokines, signaling proteins and enzymes. We identified tumor associated macrophages (TAMs), human leukocyte antigen (HLA) class I, a combination of Ki-67/CK20, IL-2, IL-8 and IL-6/IL-10 ratio as the most promising markers for both pre-BCG and post-BCG treatment suitable for the simulation studies. The intricate and patient-specific nature of these data warrants the use of powerful multi-parametral mathematical methods in combination with molecular/cellular biology insight and clinical input. PMID:26673853

BCG-induced pneumonitis with lymphocytic pleurisy in the absence of elevated KL-6

PubMed Central

2014-01-01

Background Pneumonitis is a rare complication of bacillus Calmette-Guerin (BCG) immunotherapy seen in patients with urothelial cancer following the repeated administration of BCG. However, no case of BCG-induced pleurisy has been reported. Case presentation We here report the first case of pneumonitis with lymphocytic pleurisy following bacillus Calmette-Guerin (BCG) immunotherapy. Although marked T helper cell alveolitis was found by bronchoalveolar lavage and transbronchial biopsies, no acid-fast bacillus could be identified in recovered BALF or pleural effusion. The lymphocyte stimulation test of BCG was strongly positive. However, levels of serum and bronchoalveolar lavage fluid KL-6, a useful marker for hypersensitivity pneumonitis (HP), were within normal ranges. Conclusion We speculate that the pathogenesis of our case may be a hypersensitive reaction to the proteic component of BCG entering the lung and pleural space, which is different from the etiology of the common type of HP. PMID:24593234

Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial.

PubMed

Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby; Jeppesen, Dorthe Lisbeth; Stensballe, Lone Graff; Netea, Mihai G; van der Klis, Fiona; Benn, Christine Stabell; Pryds, Ole

2017-04-11

BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

The interplay between bacillus Calmette-Guérin and Treg cells and its role to prevent or cure inflammatory diseases.

PubMed

Lagranderie, Micheline; Guyonvarc'h, Pierre-Marie

2014-06-01

Clinical evidence indicates that Bacillus Calmette-Guérin (BCG) vaccination exerts anti-inflammatory effects in diseases such as asthma, multiple sclerosis or Type 1 diabetes. Although the exact mechanisms for this activity remain debated, the capacity of mycobacteria to induce regulatory T cells (Tregs) in vivo has been widely reported. However, adverse events associated with live BCG prevent its repeated use, especially in immunocompromised individuals. This article reviews the preclinical data showing a potent, systemic and long-term anti-inflammatory effect in animal models of allergic asthma, inflammatory bowel disease and atherosclerosis with a preparation of BCG inactivated by Extended Freeze-Drying (EFD BCG). It also presents the characteristics of EFD BCG-induced Tregs which play a crucial role in the immunomodulation of various inflammatory diseases. Finally, it compares EFD BCG with other approaches based on the therapeutic use of Tregs in humans.

Effects of dietary glutamine supplementation on the body composition and protein status of early-weaned mice inoculated with Mycobacterium bovis Bacillus Calmette-Guerin.

PubMed

Rogero, Marcelo Macedo; Borges, Maria Carolina; de Castro, Inar Alves; Pires, Ivanir S O; Borelli, Primavera; Tirapegui, Julio

2011-09-01

Glutamine, one of the most abundant amino acids found in maternal milk, favors protein anabolism. Early-weaned babies are deprived of this source of glutamine, in a period during which endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress, mainly during infections. The objective of this study was to verify the effects of dietary glutamine supplementation on the body composition and visceral protein status of early-weaned mice inoculated with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Mice were weaned early on their 14th day of life and seperated into two groups, one of which was fed a glutamine-free diet (n = 16) and the other a glutamine-supplemented diet (40 g/kg diet) (n = 16). At 21 days of age, some mice were intraperitoneally injected with BCG. Euthanasia was performed at the 28th day of age. BCG inoculation significantly reduced body weight (P < 0.001), lean mass (P = 0.002), water (P = 0.006), protein (P = 0.007) and lipid content (P = 0.001) in the carcass. Dietary glutamine supplementation resulted in a significant increase in serum IGF-1 (P = 0.019) and albumin (P = 0.025) concentration, muscle protein concentration (P = 0.035) and lipid content (P = 0.002) in the carcass. In conclusion, dietary glutamine supplementation had a positive influence on visceral protein status but did not affect body composition in early-weaned mice inoculated with BCG.

Effects of Dietary Glutamine Supplementation on the Body Composition and Protein Status of Early-Weaned Mice Inoculated with Mycobacterium bovis Bacillus Calmette-Guerin

PubMed Central

Rogero, Marcelo Macedo; Borges, Maria Carolina; de Castro, Inar Alves; Pires, Ivanir S. O.; Borelli, Primavera; Tirapegui, Julio

2011-01-01

Glutamine, one of the most abundant amino acids found in maternal milk, favors protein anabolism. Early-weaned babies are deprived of this source of glutamine, in a period during which endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress, mainly during infections. The objective of this study was to verify the effects of dietary glutamine supplementation on the body composition and visceral protein status of early-weaned mice inoculated with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Mice were weaned early on their 14th day of life and seperated into two groups, one of which was fed a glutamine-free diet (n = 16) and the other a glutamine-supplemented diet (40 g/kg diet) (n = 16). At 21 days of age, some mice were intraperitoneally injected with BCG. Euthanasia was performed at the 28th day of age. BCG inoculation significantly reduced body weight (P < 0.001), lean mass (P = 0.002), water (P = 0.006), protein (P = 0.007) and lipid content (P = 0.001) in the carcass. Dietary glutamine supplementation resulted in a significant increase in serum IGF-1 (P = 0.019) and albumin (P = 0.025) concentration, muscle protein concentration (P = 0.035) and lipid content (P = 0.002) in the carcass. In conclusion, dietary glutamine supplementation had a positive influence on visceral protein status but did not affect body composition in early-weaned mice inoculated with BCG. PMID:22254124

Lipid Phenotype of Two Distinct Subpopulations of Mycobacterium bovis Bacillus Calmette-Guérin Tokyo 172 Substrain*

PubMed Central

Naka, Takashi; Maeda, Shinji; Niki, Mamiko; Ohara, Naoya; Yamamoto, Saburo; Yano, Ikuya; Maeyama, Jun-ichi; Ogura, Hisashi; Kobayashi, Kazuo; Fujiwara, Nagatoshi

2011-01-01

Bacillus Calmette-Guérin (BCG) Tokyo 172 is a predominant World Health Organization Reference Reagent for the BCG vaccine. Recently, the BCG Tokyo 172 substrain was reported to consist of two subpopulations with different colony morphologies, smooth and rough. Smooth colonies had a characteristic 22-bp deletion in Rv3405c of the region of difference (RD) 16 (type I), and rough colonies were complete in this region (type II). We hypothesized that the morphological difference is related to lipid phenotype and affects their antigenicity. We determined the lipid compositions and biosynthesis of types I and II. Scanning electron microscopy showed that type I was 1.5 times longer than type II. Phenolic glycolipid (PGL) and phthiocerol dimycocerosate (PDIM) were found only in type I. Although it has been reported that the RD16 is involved in the expression of PGL, type II did not possess PGL/PDIM. We examined the ppsA-E gene responsible for PGL/PDIM biosynthesis and found that the existence of PGL/PDIM in types I and II is caused by a ppsA gene mutation not regulated by the RD16. PGL suppressed the host recognition of total lipids via Toll-like receptor 2, and this suggests that PGL is antigenic and involved in host responses, acting as a cell wall component. This is the first report to show the difference between lipid phenotypes of types I and II. It is important to clarify the heterogeneity of BCG vaccine substrains to discuss and evaluate the quality, safety, and efficacy of the BCG vaccine. PMID:22030395

Recombinant BCG vaccine candidates.

PubMed

Hernàndez-Pando, Rogelio; Castañòn, Mauricio; Espitia, Clara; Lopez-Vidal, Yolanda

2007-06-01

Given the variable protective efficacy provided by Mycobacterium bovis BCG (Bacillus Calmette-Guérin), there is a concerted effort worldwide to develop better vaccines that could be used to reduce the burden of tuberculosis. Recombinant BCG (rBCG) are vaccine candidates that offer some potential in this area. In this paper, we will discuss the molecular methods used to generate rBCG, and the results obtained with some of these new vaccines as compared with the conventional BCG vaccine in diverse animal models. Tuberculosis vaccine candidates based on rBCG are promising candidates, and some of them are now being tested in clinical trials.

Early Events of the Reaction Elicited by CSF-470 Melanoma Vaccine Plus Adjuvants: An In Vitro Analysis of Immune Recruitment and Cytokine Release.

PubMed

Pampena, María B; Barrio, María M; Juliá, Estefanía P; Blanco, Paula A; von Euw, Erika M; Mordoh, José; Levy, Estrella Mariel

2017-01-01

In a previous work, we showed that CSF-470 vaccine plus bacillus Calmette-Guerin (BCG) and granulocyte macrophage colony-stimulating factor (GM-CSF) as adjuvants resulted in a significant benefit in the distant metastasis-free survival when comparing vaccinated vs . IFN-α2b-treated high-risk cutaneous melanoma patients in a Phase II study. Immune monitoring demonstrated an increase in anti-tumor innate and adaptive immunities of vaccinated patients, with a striking increase in IFN-γ secreting lymphocytes specific for melanoma antigens (Ags). In an effort to dissect the first steps of the immune response elicited by CSF-470 vaccine plus adjuvants, we evaluated, in an in vitro model, leukocyte migration, cytokine production, and monocyte phagocytosis of vaccine cells. Our results demonstrate that leukocytes recruitment, mostly from the innate immune system, is an early event after CSF-470 vaccine plus BCG plus GM-CSF interaction with immune cells, possibly explained by the high expression of CCL2/MCP-1 and other chemokines by vaccine cells. Early release of TNF-α and IL-1β pro-inflammatory cytokines and efficient tumor Ags phagocytosis by monocytes take place and would probably create a favorable context for Ag processing and presentation. Although the presence of the vaccine cells hampered cytokines production stimulated by BCG in a mechanism partially mediated by TGF-β and IL-10, still significant levels of TNF-α and IL-1β could be detected. Thus, BCG was required to induce local inflammation in the presence of CSF-470 vaccine cells.

Drug Treatment Combined with BCG Vaccination Reduces Disease Reactivation in Guinea Pigs Infected with Mycobacterium tuberculosis

PubMed Central

Shang, Shaobin; Shanley, Crystal A.; Caraway, Megan L.; Orme, Eileen A.; Henao-Tamayo, Marcela; Hascall-Dove, Laurel; Ackart, David; Orme, Ian M.; Ordway, Diane J.; Basaraba, Randall J.

2012-01-01

Bacillus-Calmette-Guerin (BCG), the only human tuberculosis vaccine, primes a partially protective immune response against M. tuberculosis infection in humans and animals. In guinea pigs, BCG vaccination slows the progression of disease and reduces the severity of necrotic granulomas, which harbor a population of drug-tolerant bacilli. The objective of this study was to determine if reducing disease severity by BCG vaccination of guinea pigs prior to M. tuberculosis challenge enhanced the efficacy of combination drug therapy. At 20 days of infection, treatment of vaccinated and non-vaccinated animals with rifampin, isoniazid, and pyrizinamide (RHZ) was initiated for 4 or 8 weeks. On days 50, 80 and 190 of infection (10 weeks after drug were withdrawn), treatment efficacy was evaluated by quantifying clinical condition, bacterial loads, lesion severity, and dynamic changes in peripheral blood and lung leukocyte numbers by flow cytometry. In a separate, long-term survival study, treatment efficacy was evaluated by determining disease reactivation frequency post-mortem. BCG vaccination alone delayed pulmonary and extra-pulmonary disease progression, but failed to prevent dissemination of bacilli and the formation of necrotic granulomas. Drug therapy either alone or in combination with BCG, was more effective at lessening clinical disease and lesion severity compared to control animals or those receiving BCG alone. Fewer residual lesions in BCG vaccinated and drug treated animals, equated to a reduced frequency of reactivation disease and improvement in survival even out to 500 days of infection. The combining of BCG vaccination and drug therapy was more effective at resolving granulomas such that fewer animals had evidence of residual infection and thus less reactivation disease. PMID:22244979

Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis

PubMed Central

Taus, Francesco; Santucci, Marilina B.; Greco, Emanuela; Morandi, Matteo; Palucci, Ivana; Mariotti, Sabrina; Poerio, Noemi; Nisini, Roberto; Delogu, Giovanni; Fraziano, Maurizio

2015-01-01

A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination. PMID:26023779

The role of vitamin D in malaria.

PubMed

Lương, Khanh Vinh Quốc; Nguyễn, Lan Thi Hoàng

2015-01-15

An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed.

Effect of media use on mothers' vaccination of their children in sub-Saharan Africa.

PubMed

Jung, Minsoo; Lin, Leesa; Viswanath, Kasisomayajula

2015-05-21

While several studies have examined the crucial role that parents' vaccination behaviors play in reducing disease spread and severity among children, few have evaluated the connection between parents' media use and their decision on whether or not to vaccinate their child, specifically in relation to the BCG (Bacillus Calmetter Guerin), DPT (Diptheria, Pertussis, Tetanus) polio, and measles vaccines. Media channels are a critical source of health information for parents, which is especially true in Sub-Saharan Africa, as there is often a dearth of local healthcare providers. The aim of this paper is to investigate the role that media use plays in a mothers' choice to vaccinate their infant children in sub-Saharan Africa, specifically focusing on whether media use is associated with socioeconomic status (SES) and a mothers' vaccination of their children. Cross-sectional data from the Demographic Health Surveys of 13 sub-Saharan countries (2004-2010) were pooled. A multivariate Poisson regression of 151,209 women was used to calculate adjusted relative ratios and 95% confidence intervals for the associations among SES, media use, and immunization. Education and wealth were found to be strongly and positively associated with vaccine-uptake behaviors. The effects of media use (radio and television) were found to be associated with the relationships between SES and vaccine uptake. However, it did not reduce the impact of SES on vaccination. These findings indicate that mass media may be an important tool for future efforts to reduce the health discrepancies between children from high- and low-socioeconomic backgrounds. Going forward, immunization strategies should include communication plans that will address and mitigate potential immunization disparities among parents of different SES backgrounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Crude childhood vaccination coverage in West Africa: Trends and predictors of completeness.

PubMed

Kazungu, Jacob S; Adetifa, Ifedayo M O

2017-02-15

Background : Africa has the lowest childhood vaccination coverage worldwide. If the full benefits of childhood vaccination programmes are to be enjoyed in sub-Saharan Africa, all countries need to improve on vaccine delivery to achieve and sustain high coverage. In this paper, we review trends in vaccination coverage, dropouts between vaccine doses and explored the country-specific predictors of complete vaccination in West Africa.  Methods : We utilized datasets from the Demographic and Health Surveys Program, available for Benin, Burkina Faso, The Gambia, Ghana, Guinea, Cote d'Ivoire, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone and Togo, to obtain coverage for Bacillus Calmette-Guerin, polio, measles, and diphtheria, pertussis and tetanus (DPT) vaccines in children aged 12 - 23 months. We also calculated the DPT1-to-DPT3 and DPT1-to-measles dropouts, and proportions of the fully immunised child (FIC). Factors predictive of FIC were explored using Chi-squared tests and multivariable logistic regression.  Results : Overall, there was a trend of increasing vaccination coverage. The proportion of FIC varied significantly by country (range 24.1-81.4%, mean 49%). DPT1-to-DPT3 dropout was high (range 5.1% -33.9%, mean 16.3%). Similarly, DPT1-measles dropout exceeded 10% in all but four countries. Although no single risk factor was consistently associated with FIC across these countries, maternal education, delivery in a health facility, possessing a vaccine card and a recent post delivery visit to a health facility were the key predictors of complete vaccination.  Conclusions : The low numbers of fully immunised children and high dropout between vaccine doses highlights weaknesses and the need to strengthen the healthcare and routine immunization delivery systems in this region. Country-specific correlates of complete vaccination should be explored further to identify interventions required to increase vaccination coverage. Despite the promise of an

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

PubMed

Abubakar, I; Pimpin, L; Ariti, C; Beynon, R; Mangtani, P; Sterne, J A C; Fine, P E M; Smith, P G; Lipman, M; Elliman, D; Watson, J M; Drumright, L N; Whiting, P F; Vynnycky, E; Rodrigues, L C

2013-09-01

Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10

An Analysis of Deaths Due to Tuberculosis at the Lagos University Teaching Hospital

PubMed Central

Bandele, E.O.; Olude, I.O.

1985-01-01

An analysis was made of deaths from tuberculosis in the Lagos University Teaching Hospital from 1976 to 1980. Of the 320 patients assessed, 240 were determined to have died from tuberculosis. Tuberculous meningitis was the main cause of death. Forty-two percent of the deaths occurred in the age group of 0 to 10 years old, and 47.5 percent of the patients died within one week of diagnosis. Potentially avoidable factors contributing to death include late reporting by patients to medical personnel, lack of bacillus of Calmette and Guerin (BCG) vaccine, irregular taking of medications by patients, and late referral of patients to specialized hospitals. There is a need for improved education of patients and medical personnel about the management of tuberculosis in Lagos. PMID:4046063

MBCP - Approach - Immunotherapy | Center for Cancer Research

Cancer.gov

Immunotherapy CCR investigators pioneered the use of the tuberculosis vaccine—Bacillus Calmette-Guerin (BCG)—in the treatment of bladder cancer. In cases where the tumor burden is not too high and direct contact can be made with the urothelium surface of the bladder, BCG application appears to elicit an immune response that attacks the tumor as well as the attenuated virus.

Immunology of bovine tuberculosis: Perspectives on one health approaches and defining correlates of protection versus infection

USDA-ARS?s Scientific Manuscript database

Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is an exemplary model of the One Health Concept. The human TB vaccine, M. bovis bacille Calmette-Guerin (BCG), was first proven effective in cattle prior to use in humans. Recent experimental ...

Patterns of in vitro cell-death, metaloproteinase-9 and pro-inflammatory cytokines in human monocytes induced by the BCG vaccine, Moreau strain.

PubMed

Simas, C J A; Silva, D P H; Ponte, C G G; Castello-Branco, L R R; Antas, P R Z

2011-09-02

Mononuclear cells have been implicated in the primary inflammatory response against mycobacteria. Yet, little is known about the interaction of Mycobacterium bovis bacillus Calmette-Guerin (BCG) with human monocytes. Here, we investigated the potential of BCG Moreau strain to induce in vitro specific cell-death utilizing a flow cytometry approach that revealed an increase in apoptosis events in BCG-stimulated monocytes from healthy adults. We also detected a concomitant release of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), but not metalloproteinase (MMP)-9. In addition, annexin V-propidium iodide double staining demonstrated an enhancement of monocytes necrosis, but not apoptosis, following BCG Moreau strain stimulation of umbilical vein cells from naïve, neonate. This pattern was paralleled by different pro-inflammatory cytokine levels, as well as MMP-9 induction when compared to the adults. Our findings support the hypothesis that BCG induces distinct cell-death patterns during the maturation of the immune system and that this pattern might set the stage for a subsequent antimycobacterial immune response that might have profound effects during vaccination. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comparison of the immunogenicity and protection against bovine tuberculosis following immunization by BCG-priming and boosting with adenovirus or protein based vaccines.

PubMed

Dean, G; Whelan, A; Clifford, D; Salguero, F J; Xing, Z; Gilbert, S; McShane, H; Hewinson, R G; Vordermeier, M; Villarreal-Ramos, B

2014-03-05

There is a requirement for vaccines or vaccination strategies that confer better protection against TB than the current live attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine for use in cattle. Boosting with recombinant viral vectors expressing mycobacterial proteins, such as Ag85A, has shown a degree of promise as a strategy for improving on the protection afforded by BCG. Experiments in small animal models have indicated that broadening the immune response to include mycobacterial antigens other than Ag85A, such as Rv0288, induced by boosting with Ad5 constructs has a direct effect on the protection afforded against TB. Here, we compared the immunogenicity and protection against challenge with M. bovis afforded by boosting BCG-vaccinated cattle with a human type 5 (Ad5)-based vaccine expressing the mycobacterial antigens Ag85A (Ad5-85A); or Ag85A, Rv0251, Rv0287 and Rv0288 (Ad5-TBF); or with protein TBF emulsified in adjuvant (Adj-TBF). Boosting with TBF broaden the immune response. The kinetics of Ad5-TBF and Adj-TBF were shown to be different, with effector T cell responses from the latter developing more slowly but being more durable than those induced by Ad5-TBF. No increase in protection compared to BCG alone was afforded by Ad5-TBF or Adj-TBF by gross pathology or bacteriology. Using histopathology, as a novel parameter of protection, we show that boosting BCG vaccinated cattle with Ad5-85A induced significantly better protection than BCG alone. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Tuberculin reactivity in bacille Calmette-Guérin vaccinated populations: a compilation of international data.

PubMed

Joos, T J; Miller, W C; Murdoch, D M

2006-08-01

The effect of previously administered bacille Calmette-Guérin (BCG) vaccine on subsequent tuberculin skin tests (TSTs) complicates screening for latent tuberculosis infection (LTBI) in foreign-born persons. To determine the usefulness of the TST as a screening test for LTBI in foreign-born persons. A literature search was performed of published studies that compared tuberculin reactivity amongst BCG-vaccinated and non-vaccinated groups. The percentages of positive reactors in the two groups were then used to calculate a prevalence ratio. The prevalence ratio varied with the age of the groups tested and the incidence of TB in their countries of origin. The TST performed poorly in vaccinated persons of all ages from countries of low TB incidence, but was a useful screen for LTBI in vaccinated adults from countries of high and intermediate incidence. The test performed poorly as a screening method for vaccinated children under 2 years of age. Its usefulness in vaccinated children aged 2-14 years varied considerably. The usefulness of the TST as a screening method for LTBI depends on the age of the patient and the incidence of TB in their country of origin.

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

PubMed

Shah, Javeed A; Musvosvi, Munyaradzi; Shey, Muki; Horne, David J; Wells, Richard D; Peterson, Glenna J; Cox, Jeffery S; Daya, Michelle; Hoal, Eileen G; Lin, Lin; Gottardo, Raphael; Hanekom, Willem A; Scriba, Thomas J; Hatherill, Mark; Hawn, Thomas R

2017-08-15

The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood. To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis. We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection. We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2 + CD4 + T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection. TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG

Oral vaccination of white-tailed deer (Odocoileus virginianus) with Mycobacterium bovis Bacillus Calmette-Guerin (BCG)

USDA-ARS?s Scientific Manuscript database

Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis from livestock, particularly cattle. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to other deer and cattle. One approach in dealing with this wildlife reservoir is to vaccina...

A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection.

PubMed

Yuan, Xuefeng; Teng, Xindong; Jing, Yukai; Ma, Jilei; Tian, Maopeng; Yu, Qi; Zhou, Lei; Wang, Ruibo; Wang, Weihua; Li, Li; Fan, Xionglin

2015-12-01

Tuberculosis (TB) remains one of the most menacing infectious diseases, although attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine has been widely used to protect children against primary TB. There are increasing evidences that rapid growing and dormant Mycobacterium tuberculosis (M. tuberculosis) coexist in vivo after infection. However, BCG vaccine only elicits cell-mediated immune responses to secretory antigens expressed by rapid growing pathogen. BCG vaccine is thus unable to thwart the reactivation of latent tuberculosis infection (LTBI), and its protection wanes over age after neonatal immunization. In order to extend its ability for a durable protection, a novel recombinant BCG (rBCG) strain, named rBCG::XB, was constructed by overexpressing immunodominant multistage antigens of Ag85B and HspX, which are expressed by both rapid replicating and dormant M. tuberculosis. Long-term protective effect and immunogenicity of rBCG::XB were compared with the parental BCG in vaccinated C57BL/6 mice. Our results demonstrated that rBCG::XB provided the stronger and long-lasting protection against M. tuberculosis H37Rv intranasal infection than BCG. The rBCG::XB not only elicited the more durable multistage antigen-specific CD4(+)Th1-biased immune responses and specific polyfunctional CD4(+)T cells but also augmented the CD8(+) CTL effects against Ag85B in vivo. In particular, higher levels of CD4(+) TEM and CD8(+) TCM cells, dominated by IL2(+) CD4(+) and CD8(+) TCM cells, were obtained in the spleen of rBCG::XB vaccinated mice. Therefore, our findings indicate that rBCG::XB is a promising candidate to improve the efficacy of BCG.

Recent mouse models and vaccine candidates for preventing chronic/latent tuberculosis infection and its reactivation.

PubMed

Pedroza-Roldán, César; Flores-Valdez, Mario Alberto

2017-08-31

Tuberculosis (TB) remains a major challenge in public health worldwide. Until today, the only widely used and approved vaccine is the Mycobacterium bovis bacille Calmette-Guerin (BCG). This vaccine provides a highly variable level of protection against the active, pulmonary form of tuberculosis, and practically none against the latent form of TB infection. This disparity in protection has been extensively studied, and for this reason, several groups have focused their research on the quest for attenuated vaccines based on M. tuberculosis or on the identification of latency-associated antigens that can be incorporated into modified BCG, or that can be used as adjuvanted subunit vaccines. In order to seek new potential antigens relevant for infection, some researchers have performed experiments with highly sensitive techniques such as transcriptomic and proteomic analyses using sputum samples from humans or by using mouse models resembling several aspects of TB. In this review, we focus on reports of new mouse models or mycobacterial antigens recently tested for developing vaccine candidates against chronic/latent tuberculosis and its reactivation.

Timeliness of Childhood Primary Immunization and Risk Factors Related with Delays: Evidence from the 2014 Zhejiang Provincial Vaccination Coverage Survey.

PubMed

Hu, Yu; Li, Qian; Chen, Yaping

2017-09-20

Background: this study aimed to assess both immunization coverage and timeliness, as well as reasons for non-vaccination, and identity the risk factors of delayed immunization, for the vaccines scheduled during the first year of life, in Zhejiang province, east China. Methods: A cluster survey among children aged 24-35 months was conducted. Demographic information and socio-economic characteristics of the selected child, the mother, and the household were collected. Immunization data were transcribed from immunization cards. Timeliness was assessed with Kaplan-Meier analysis for each vaccine given before 12 months of age, based on the time frame stipulated by the expanded program on immunization of China. Cox proportional hazard regression was applied to identify risk factors of delayed immunization. Results: A total of 2772 eligible children were surveyed. The age-appropriate coverage ranged from 25.4% (95% CI: 23.7-27.0%) for Bacillus Calmette-Guerin (BCG) to 91.3% (95% CI: 90.2-92.3%) for the first dose of oral poliomyelitis vaccine (OPV1). The most frequent reason for non-vaccination was parent's fear of adverse events of immunization. Delayed immunizations were associated with mother having a lower education level, mother having a job, delivery at home, increasing number of children per household, and having a lower household income. Conclusions: Although the timeliness of immunization has improved since 2011, necessary steps are still needed to achieve further improvement. Timeliness of immunization should be considered as another important indicator of expanded program on immunization (EPI) performance. Future interventions on vaccination coverage should take into consideration demographic and socio-economic risk factors identified in this study. The importance of adhering to the recommended schedule should be explained to parents.

Safety and Efficacy of Neonatal Vaccination

PubMed Central

Demirjian, Alicia; Levy, Ofer

2009-01-01

Newborns have an immature immune system that renders them at high risk for infection while simultaneously reducing responses to most vaccines, thereby posing challenges in protecting this vulnerable population. Nevertheless, certain vaccines, such as Bacillus Calmette Guérin (BCG) and Hepatitis B vaccine (HBV), do demonstrate safety and some efficacy at birth, providing proof of principal that certain antigen-adjuvant combinations are able to elicit protective neonatal responses. Moreover, birth is a major point of healthcare contact globally meaning that effective neonatal vaccines achieve high population penetration. Given the potentially significant benefit of vaccinating at birth, availability of a broader range of more effective neonatal vaccines is an unmet medical need and a public health priority. This review focuses on safety and efficacy of neonatal vaccination in humans as well as recent research employing novel approaches to enhance the efficacy of neonatal vaccination. PMID:19089811

The use of mutant mycobacteria as new vaccines to prevent tuberculosis.

PubMed

Hernàndez Pando, R; Aguilar, L D; Infante, E; Cataldi, A; Bigi, F; Martin, C; Gicquel, B

2006-01-01

Given the variable protective efficacy generated by Mycobacterium bovis BCG (Bacillus Calmette-Guérin), there is a concerted effort worldwide to develop better vaccines that could be used to reduce the burden of tuberculosis. Rational attenuated mutants of Mycobacterium tuberculosis are vaccine candidates that offer some potential in this area. In this paper, we will discuss the molecular methods used to generate mutant mycobacteria, as well as the results obtained with some of these strains, in terms of attenuation, immunogenicity and level of protection, when compared with the conventional BCG vaccine in diverse animal models. Tuberculosis vaccine candidates based on safe and live mycobacterial mutants could be promising candidates.

Induction of cross-priming of naive CD8+ T lymphocytes by recombinant bacillus Calmette-Guerin that secretes heat shock protein 70-major membrane protein-II fusion protein.

PubMed

Mukai, Tetsu; Maeda, Yumi; Tamura, Toshiki; Matsuoka, Masanori; Tsukamoto, Yumiko; Makino, Masahiko

2009-11-15

Because Mycobacterium bovis bacillus Calmette-Guérin (BCG) unconvincingly activates human naive CD8(+) T cells, a rBCG (BCG-70M) that secretes a fusion protein comprising BCG-derived heat shock protein (HSP)70 and Mycobacterium leprae-derived major membrane protein (MMP)-II, one of the immunodominant Ags of M. leprae, was newly constructed to potentiate the ability of activating naive CD8(+) T cells through dendritic cells (DC). BCG-70M secreted HSP70-MMP-II fusion protein in vitro, which stimulated DC to produce IL-12p70 through TLR2. BCG-70M-infected DC activated not only memory and naive CD8(+) T cells, but also CD4(+) T cells of both types to produce IFN-gamma. The activation of these naive T cells by BCG-70M was dependent on the MHC and CD86 molecules on BCG-70M-infected DC, and was significantly inhibited by pretreatment of DC with chloroquine. Both brefeldin A and lactacystin significantly inhibited the activation of naive CD8(+) T cells by BCG-70M through DC. Thus, the CD8(+) T cell activation may be induced by cross-presentation of Ags through a TAP- and proteosome-dependent cytosolic pathway. When naive CD8(+) T cells were stimulated by BCG-70M-infected DC in the presence of naive CD4(+) T cells, CD62L(low)CD8(+) T cells and perforin-producing CD8(+) T cells were efficiently produced. MMP-II-reactive CD4(+) and CD8(+) memory T cells were efficiently produced in C57BL/6 mice by infection with BCG-70M. These results indicate that BCG-70M activated DC, CD4(+) T cells, and CD8(+) T cells, and the combination of HSP70 and MMP-II may be useful for inducing better T cell activation.

1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer

PubMed Central

Hsu, Jong-Wei; Yin, Peng-Nien; Wood, Ronald; Messing, James; Messing, Edward; Lee, Yi-Fen

2013-01-01

Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy. To test this hypothesis, we examined the impact of 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) on BCG-induced response in BCa cells and macrophage cells. Our data revealed that 1,25-VD promotes BCG-induced interleukin 8 (IL-8) secretion by BCa cells, consequently inducing the migration of macrophage, THP-1. This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody. Furthermore, 1,25-VD increased BCG-induced expression of macrophage markers in THP-1 cell, and enhanced the BCG-induced THP-1 cytotoxicity against low-grade BCa cells. Importantly, a pre-clinical trial using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model revealed that intravesical co-treatment of 1,25-VD with BCG can prolong mice survival. These data demonstrate a novel mechanism by which 1,25-VD promotes BCG-mediated anti-BCa pathways and provides a platform for improving BCG efficacy with combination of 1,25-VD. PMID:24353168

The utility and interpretation of tuberculin skin tests in the Middle East.

PubMed

Al-Jahdali, Hamdan; Memish, Ziad A; Menzies, Dick

2005-04-01

Tuberculin skin test (TST) interpretation can be confounded by Bacillus Calmette-Guerin (BCG) vaccination and infection with nontuberculosis mycobacteria (NTM). However, a wealth of epidemiologic information has allowed the formulation of recommendations for reasonably informed interpretation of the TST in most clinical situations. In the Middle East, the TST remains a useful test. BCG vaccination is given at birth, which should have minimal effect on TST reactions in adolescents or adults. In countries of the Middle East with moderate to high incidence of active smear-positive pulmonary TB (>20 per 100,000 per year), a positive TST will almost always indicate true TB infection. However, in Middle East countries with very low incidence of active TB (<10 per 100,000 per year), a positive TST will more likely be false positive because BCG vaccination is still routinely given; until BCG vaccination is abandoned, the TST will be less useful in these countries. These findings are applicable to countries in other regions of the world, and the utility TST will also be increased where the likelihood of TB infection is higher and lowered where TB infection is unlikely, yet BCG vaccination is still given.

Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy.

PubMed

Rentsch, Cyrill A; Birkhäuser, Frédéric D; Biot, Claire; Gsponer, Joël R; Bisiaux, Aurélie; Wetterauer, Christian; Lagranderie, Micheline; Marchal, Gilles; Orgeur, Mickael; Bouchier, Christiane; Bachmann, Alexander; Ingersoll, Molly A; Brosch, Roland; Albert, Matthew L; Thalmann, George N

2014-10-01

Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown. To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes. Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results. Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses. BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught

Adverse events following immunisation with bacille Calmette-Guérin vaccination: baseline data to inform monitoring in Australia following introduction of new unregistered BCG vaccine.

PubMed

Hendry, Alexandra J; Dey, Aditi; Beard, Frank H; Khandaker, Gulam; Hill, Richard; Macartney, Kristine K

2016-12-24

In recent years there has been a global shortage of bacille Calmette-Guérin (BCG) vaccine and, from September 2012, unregistered vaccines have needed to be used in Australia (a Danish product initially until the end of 2015, and a Polish product used in some jurisdictions from early 2016). We examined rates and types of adverse events following immunisation (AEFI) with BCG vaccine reported to the Therapeutic Goods Administration between 2009 and 2014 in children aged less than 7 years. Reporting rates of AEFI with BCG vaccine increased from 87 per 100,000 doses (registered Sanofi Pasteur product) in 2009 to 201 per 100,000 doses (unregistered Danish Statens Serum Institute product) in 2014, with Victoria having the highest rate each year. Substantial variation between jurisdictions exists, suggesting differential reporting of BCG vaccine doses administered and/or BCG vaccine-related AEFI. The most commonly reported reactions were abscess (31%), injection site reaction (27%) and lymphadenopathy/lymphadenitis (17%). This study provides baseline data on BCG vaccine safety to inform surveillance. Given the current use of unregistered vaccines in the context of vaccine supply issues, improved recording of both administered BCG vaccine doses and the reporting of BCG vaccine-related AEFI are required to facilitate close monitoring of vaccine safety.

Identifying Predictors of Interferon-γ Release Assay Results in Pediatric Latent Tuberculosis: A Protective Role of Bacillus Calmette-Guérin?

PubMed Central

Sotgiu, Giovanni; Altet-Gómez, Neus; Tsolia, Maria; Ruga, Ezia; Velizarova, Svetlana; Kampmann, Beate

2012-01-01

Rationale: Interferon-γ (IFN-γ) release assays are widely used to diagnose latent infection with Mycobacterium tuberculosis in adults, but their performance in children remains incompletely evaluated to date. Objectives: To investigate factors influencing results of IFN-γ release assays in children using a large European data set. Methods: The Pediatric Tuberculosis Network European Trials group pooled and analyzed data from five sites across Europe comprising 1,128 children who were all investigated for latent tuberculosis infection by tuberculin skin test and at least one IFN-γ release assay. Multivariate analyses examined age, bacillus Calmette-Guérin (BCG) vaccination status, and sex as predictor variables of results. Subgroup analyses included children who were household contacts. Measurements and Main Results: A total of 1,093 children had a QuantiFERON-TB Gold In-Tube assay and 382 had a T-SPOT.TB IFN-γ release assay. Age was positively correlated with a positive blood result (QuantiFERON-TB Gold In-Tube: odds ratio [OR], 1.08 per year increasing age [P < 0.0001]; T-SPOT.TB: OR, 1.14 per year increasing age [P < 0.001]). A positive QuantiFERON-TB Gold In-Tube result was shown by 5.5% of children with a tuberculin skin test result less than 5 mm, by 14.8% if less than 10 mm, and by 20.2% if less than 15 mm. Prior BCG vaccination was associated with a negative IFN-γ release assay result (QuantiFERON-TB Gold In-Tube: OR, 0.41 [P < 0.001]; T-SPOT.TB: OR, 0.41 [P < 0.001]). Young age was a predictor of indeterminate IFN-γ release assay results, but indeterminate rates were low (3.6% in children < 5 yr, 1% in children > 5 yr). Conclusions: Our data show that BCG vaccination may be effective in protecting children against Mycobacterium tuberculosis infection. To restrict use of IFN-γ release assays to children with positive skin tests risks underestimating latent infection. PMID:22700862

Identification of novel proteins in culture filtrates of Mycobacterium bovis bacillus Calmette-Guérin in the isoelectric point range 6-11.

PubMed

Florio, Walter; Batoni, Giovanna; Esin, Semih; Bottai, Daria; Maisetta, Giuseppantonio; Pardini, Manuela; Campa, Mario

2003-05-01

Two-dimensional gel electrophoresis and mass spectrometry were used to identify proteins in the isoelectric point range 6-11 in culture filtrates of Mycobacterium bovis bacillus Calmette-Guérin (BCG). Twelve proteins were identified, three of which had not been described previously. The expression of the identified proteins was comparatively analyzed in culture filtrates of BCG in different growth phases and culture conditions. For some of these proteins, the relative protein abundance in the different culture filtrate preparations was significantly different. The differential expression of the identified proteins is discussed in relation to their putative localization and/or biological function.

Needle-free jet injector intradermal delivery of fractional dose inactivated poliovirus vaccine: Association between injection quality and immunogenicity.

PubMed

Resik, Sonia; Tejeda, Alina; Mach, Ondrej; Sein, Carolyn; Molodecky, Natalie; Jarrahian, Courtney; Saganic, Laura; Zehrung, Darin; Fonseca, Magile; Diaz, Manuel; Alemany, Nilda; Garcia, Gloria; Hung, Lai Heng; Martinez, Yenisleydis; Sutter, Roland W

2015-10-26

The World Health Organization recommends that as part of the polio end-game strategy a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries currently using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5 of full dose) IPV (fIPV) by intradermal (ID) injection may reduce costs, but its conventional administration is with Bacillus Calmette-Guerin (BCG) needle and syringe (NS), which is time consuming and technically challenging. We compared injection quality achieved with BCG NS and three needle-free jet injectors and assessed ergonomic features of the injectors. Children between 12 and 20 months of age who had previously received OPV were enrolled in the Camaguey, Cuba study. Subjects received a single fIPV dose administered intradermally with BCG NS or one of three needle-free injector devices: Bioject Biojector 2000® (B2000), Bioject ID Pen® (ID Pen), or PharmaJet Tropis® (Tropis). We measured bleb diameter and vaccine loss as indicators of ID injection quality, with desirable injection quality defined as bleb diameter ≥5mm and vaccine loss <10%. We surveyed vaccinators to evaluate ergonomic features of the injectors. We further assessed the injection quality indicators as predictors of immune response, measured by increase in poliovirus neutralizing antibodies in blood between day 0 (pre-IPV) and 21 (post-vaccination). Delivery by BCG NS and Tropis resulted in the highest proportion of subjects with desirable injection quality; health workers ranked Biojector2000 and Tropis highest for ergonomic features. We observed that vaccine loss and desirable injection quality were associated with an immune response for poliovirus type 2 (P=0.02, P=0.01, respectively). Our study demonstrated the feasibility of fIPV delivery using needle-free injector devices with high acceptability among health workers. We did not observe the indicators of injection quality to be uniformly associated with immune

Vaccination Timeliness in Children Under India's Universal Immunization Program.

PubMed

Shrivastwa, Nijika; Gillespie, Brenda W; Lepkowski, James M; Boulton, Matthew L

2016-09-01

India has the highest number of deaths among children younger than 5 years of age globally; the majority are from vaccine preventable diseases. Untimely vaccination unnecessarily prolongs susceptibility to disease and contributes to the burden of childhood morbidity and mortality, yet there is scarce literature on vaccination delays. The aim of this study is to characterize the timeliness of childhood vaccinations administered under India's routine immunization program using a novel application of an existing statistical methodology. This study utilized the district level household and facility survey data, 2008 from India using vaccination data from children with and without immunization cards. Turnbull estimator of the cumulative distribution function was used to estimate the probability of vaccination at each age. Timeliness of Bacille Calmette-Guerin (BCG), all 3 doses of diphtheria, pertussis and tetanus vaccine (DPT) and measles-containing vaccine (MCV) were considered for this analysis. Vaccination data on 268,553 children who were 0-60 months of age were analyzed; timely administration of BCG, DPT3 and MCV occurred in 31%, 19% and 34% of children, respectively. The estimated vaccination probability plateaued for DPT and BCG around the age of 24 months, whereas MCV uptake increased another 5% after 24 months of age. The 5-year coverage of BCG, DPT3 and MCV in Indian children was 87%, 63% and 76%, respectively. Lack of timely administration of key childhood vaccines, especially DPT3 and MCV, remains a major challenge in India and likely contributes to the significant burden of vaccine preventable disease-related morbidity and mortality in children.

MBCP - Approach - Immunotherapy | Center for Cancer Research

Cancer.gov

Immunotherapy CCR investigators pioneered the use of the tuberculosis vaccine—Bacillus Calmette-Guerin (BCG)—in the treatment of bladder cancer. In cases where the tumor burden is not too high and direct contact can be made with the urothelium surface of the bladder, BCG application appears to elicit an immune response that attacks the tumor as well as the attenuated virus. Ongoing clinical trials focusing on enhancing the patient’s immune system are listed below.

Prolonged remission of advanced bronchoalveolar adenocarcinoma in a dog treated with autologous, tumour-derived chaperone-rich cell lysate (CRCL) vaccine.

PubMed

Epple, Laura M; Bemis, Lynne T; Cavanaugh, Ryan P; Skope, Anne; Mayer-Sonnenfeld, Tehila; Frank, Chad; Olver, Christine S; Lencioni, Alex M; Dusto, Nathaniel L; Tal, Alona; Har-Noy, Michael; Lillehei, Kevin O; Katsanis, Emmanuel; Graner, Michael W

2013-08-01

This paper presents the treatment of a 12-year-old female spayed Great Dane who presented with vestibular signs (ataxia, nystagmus, hind end collapse). Thoracic radiographs revealed a discrete pulmonary nodule in the right cranial lung lobe. Ultrasound-guided fine needle aspirate detected primary bronchoalveolar adenocarcinoma, verified via computed tomography, with a second smaller nodule discovered in the right cranial lung lobe. A lateral thoracotomy with right cranial lung lobectomy was performed. Histopathological analysis of the nodules and an excised lymph node identified grade III bronchoalveolar adenocarcinoma with vascular infiltration and lymph node metastasis - a grim diagnosis with a reported median survival time of 6-27 days. A 10-g sample of the tumour was processed into a chaperone-rich cell lysate (CRCL) vaccine, which was administered weekly to the patient. Imiquimod - a Toll-like receptor 7 (TLR7) agonist - was applied topically for the first 12 treatments to stimulate local Langerhans cells. A single injection of bacillus Calmette-Guerin (BCG) was administered for additional immune stimulation at week 30 of treatment. The dog remained stable and in otherwise good health until diffuse relapse occurred 44 weeks after the initial treatment; following gastrointestinal bleeding, the dog was euthanised 50+ weeks post diagnosis. To the authors' knowledge, this is the first report of significantly prolonged survival following a diagnosis of grade III/stage III bronchoalveolar adenocarcinoma in a canine patient. This case report suggests that CRCL vaccine combined with topical imiquimod is a safe, effective treatment for canine tumours.

Challenges and solutions for a rational vaccine design for TB-endemic regions.

PubMed

Gowthaman, Uthaman; Mushtaq, Khurram; Tan, Amabel C; Rai, Pradeep K; Jackson, David C; Agrewala, Javed N

2015-01-01

Vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. Unfortunately, this success has not been achieved for controlling tuberculosis (TB) worldwide. Bacillus Calmette Guérin (BCG) is the only available vaccine against TB. Paradoxically, BCG has deciphered success in the Western world but has failed in TB-endemic areas. In this article, we highlight and discuss the aspects of immunity responsible for controlling Mycobacterium tuberculosis infection and factors responsible for the failure of BCG in TB-endemic countries. In addition, we also suggest strategies that contribute toward the development of successful vaccine in protecting populations where BCG has failed.

Challenges in vaccinating infants born to mothers taking immunoglobulin biologicals during pregnancy.

PubMed

Ling, Juejing; Koren, Gideon

2016-01-01

While immunoglobulin biologicals are increasingly used during pregnancy, there have been concerns on the immune function and vaccination of infants born to mothers taking immunoglobulin biologicals. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fatal dissemination of Bacillus Calmette-Guérin (BCG) have been reported. With increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants. This review summarizes the available evidence to discuss the issues of immunoglobulin biological exposure in utero, neonatal immune function, long-term immune development, and the challenges and strategies of vaccinating newborns and infants who were born to mothers taking biologicals during pregnancy.

Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination.

PubMed

Clark, Simon O; Kelly, Dominic L F; Badell, Edgar; Castello-Branco, Luiz Roberto; Aldwell, Frank; Winter, Nathalie; Lewis, David J M; Marsh, Philip D

2010-10-08

There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette-Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post-challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained

Progress and challenges in TB vaccine development

PubMed Central

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H.E.; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development. PMID:29568497

Progress and challenges in TB vaccine development.

PubMed

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H E; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

Non-specific effects of diphtheria tetanus pertussis vaccination on child mortality in Cebu, The Philippines.

PubMed

Chan, Grace J; Moulton, Lawrence H; Becker, Stan; Muñoz, Alvaro; Black, Robert E

2007-10-01

To determine the non-specific effects of diphtheria, tetanus and pertussis (DTP) vaccination and sex on mortality before 30 months of age among those who received Bacille Calmette Guerin (BCG) vaccine in a high mortality area. This analysis used a longitudinal study of child survival monitoring the use of primary care services, morbidity and mortality in Metro Cebu, The Philippines. Participants included 14 537 children under 30 months of age who received a BCG vaccination from July 1988 to January 1991. The main outcome measure was all-cause mortality. Mortality before 30 months of age was 57% lower among BCG-vaccinated children who received DTP vaccination than BCG-vaccinated children who did not receive DTP vaccination {hazard ratio (HR) for vaccinated vs unvaccinated 0.43 [95% confidence interval (CI) 0.21-0.88]}. Females had lower mortality rates [HR = 0.19 (0.04-0.86), P = 0.03] than males among DTP-unvaccinated children. The protective effect of DTP vaccination was more pronounced in males [HR 0.32 (0.14-0.73)] than in females [HR 0.86 (0.18-4.23)]. DTP vaccination increased (interaction term P = 0.08) the female-to-male mortality ratio to 0.76 (0.52-1.12). Among BCG-vaccinated children under 30 months of age, DTP vaccination is associated with improved survival. The increased female-male mortality ratio is associated with reduced mortality among males following DTP vaccination rather than increased mortality among female children.

Dismantling the Taboo against Vaccines in Pregnancy

PubMed Central

de Martino, Maurizio

2016-01-01

Vaccinating pregnant women in order to protect them, the fetus, and the child has become universal in no way at all. Prejudice in health professionals add to fears of women and their families. Both these feelings are not supported by even the smallest scientific data. Harmlessness for the mother and the child has been observed for seasonal, pandemic, or quadrivalent influenza, mono, combined polysaccharide or conjugated meningococcal or pneumococcal, tetanus toxoid, acellular pertussis, human papillomavirus, cholera, hepatitis A, Japanese encephalitis, rabies, anthrax, smallpox, yellow fever, mumps, measles and rubella combined, typhoid fever, inactivated or attenuated polio vaccines, and Bacillus Calmétte Guerin vaccines. Instead, the beneficial effects of influenza vaccine for the mother and the child as well as of pertussis vaccine for the child have been demonstrated. Obstetrician-gynecologists, general practitioners, and midwives must incorporate vaccination into their standard clinical care. Strong communication strategies effective at reducing parental vaccine hesitancy and approval of regulatory agencies for use of vaccines during pregnancy are needed. It must be clear that the lack of pre-licensure studies in pregnant women and, consequently, the lack of a statement about the use of the vaccine in pregnant women does not preclude its use in pregnancy. PMID:27338346

Dismantling the Taboo against Vaccines in Pregnancy.

PubMed

de Martino, Maurizio

2016-06-07

Vaccinating pregnant women in order to protect them, the fetus, and the child has become universal in no way at all. Prejudice in health professionals add to fears of women and their families. Both these feelings are not supported by even the smallest scientific data. Harmlessness for the mother and the child has been observed for seasonal, pandemic, or quadrivalent influenza, mono, combined polysaccharide or conjugated meningococcal or pneumococcal, tetanus toxoid, acellular pertussis, human papillomavirus, cholera, hepatitis A, Japanese encephalitis, rabies, anthrax, smallpox, yellow fever, mumps, measles and rubella combined, typhoid fever, inactivated or attenuated polio vaccines, and Bacillus Calmétte Guerin vaccines. Instead, the beneficial effects of influenza vaccine for the mother and the child as well as of pertussis vaccine for the child have been demonstrated. Obstetrician-gynecologists, general practitioners, and midwives must incorporate vaccination into their standard clinical care. Strong communication strategies effective at reducing parental vaccine hesitancy and approval of regulatory agencies for use of vaccines during pregnancy are needed. It must be clear that the lack of pre-licensure studies in pregnant women and, consequently, the lack of a statement about the use of the vaccine in pregnant women does not preclude its use in pregnancy.

Revisiting the structure of the anti-neoplastic glucans of Mycobacterium bovis Bacille Calmette-Guerin. Structural analysis of the extracellular and boiling water extract-derived glucans of the vaccine substrains.

PubMed

Dinadayala, Premkumar; Lemassu, Anne; Granovski, Pierre; Cérantola, Stéphane; Winter, Nathalie; Daffé, Mamadou

2004-03-26

The attenuated strain of Mycobacterium bovis Bacille Calmette-Guérin (BCG), used worldwide to prevent tuberculosis and leprosy, is also clinically used as an immunotherapeutic agent against superficial bladder cancer. An anti-tumor polysaccharide has been isolated from the boiling water extract of the Tice substrain of BCG and tentatively characterized as consisting primarily of repeating units of 6-linked-glucosyl residues. Mycobacterium tuberculosis and other mycobacterial species produce a glycogen-like alpha-glucan composed of repeating units of 4-linked glucosyl residues substituted at some 6 positions by short oligoglucosyl units that also exhibits an anti-tumor activity. Therefore, the impression prevails that mycobacteria synthesize different types of anti-neoplastic glucans or, alternatively, the BCG substrains are singular in producing a unique type of glucan that may confer to them their immunotherapeutic property. The present study addresses this question through the comparative analysis of alpha-glucans purified from the extracellular materials and boiling water extracts of three vaccine substrains. The polysaccharides were purified, and their structural features were established by mono- and two-dimensional NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of the enzymatic and chemical degradation products of the purified compounds. The glucans isolated by the two methods from the three substrains of BCG were shown to exhibit identical structural features shared with the glycogen-like alpha-glucan of M. tuberculosis and other mycobacteria. Incidentally, we observed an occasional release of dextrans from Sephadex columns that may explain the reported occurrence of 6-substituted alpha-glucans in mycobacteria.

A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice.

PubMed

Céspedes, Pablo F; Rey-Jurado, Emma; Espinoza, Janyra A; Rivera, Claudia A; Canedo-Marroquín, Gisela; Bueno, Susan M; Kalergis, Alexis M

2017-02-01

Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×10 7 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8 + and CD4 + T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population. Copyright © 2016 Elsevier Ltd. All rights reserved.

Intravesical Bacillus Calmette-Guérin therapy for murine bladder tumors: initiation of the response by fibronectin-mediated attachment of Bacillus Calmette-Guérin.

PubMed

Ratliff, T L; Palmer, J O; McGarr, J A; Brown, E J

1987-04-01

Intravesical Bacillus Calmette-Guérin (BCG) is considered to be one of the most effective treatments for superficial bladder cancer. Although the mechanisms by which BCG inhibits tumor growth are not known, previous studies have shown that systemic immunization to BCG and the local expression of the immune response in the bladder are associated with a favorable response to BCG therapy. We have investigated the conditions required for the initiation of an immunological response after the intravesical instillation of BCG. Initial histological studies showed that BCG attached to the bladder wall only in areas where the urothelium was damaged by electrocautery and suggested that attachment was associated with the fibrin clot. Quantitative studies verified the histological observations. Minimal BCG attachment (mean less than 10(2) colony forming units) was observed in normal bladders in contrast with a mean of 1.42 X 10(4) colony forming units/bladder in bladders damaged by electrocautery (10 separate experiments). BCG attachment to the bladder wall was durable since organisms were observed in bladders 48 h after instillation. To investigate the proteins to which BCG attached, we tested the binding of BCG to extracellular matrix and inflammatory proteins which comprise a significant portion of the fibrin clot. BCG bound in vitro to coverslips coated in vivo with extracellular matrix proteins but did not bind to control albumin-coated coverslips. BCG also bound to coverslips coated with purified plasma fibronectin but not to coverslips coated with other purified extracellular matrix proteins including laminin, fibrinogen, and type IV collagen. BCG attachment to coverslips coated with either extracellular matrix proteins or purified fibronectin was inhibited by antibodies specific for fibronectin. Moreover, BCG attachment to cauterized bladders in vivo was inhibited by antifibronectin antibodies. These results demonstrate that fibronectin mediates the attachment of BCG

A Promising Listeria-Vectored Vaccine Induces Th1-Type Immune Responses and Confers Protection Against Tuberculosis.

PubMed

Yin, Yuelan; Lian, Kai; Zhao, Dan; Tao, Chengwu; Chen, Xiang; Tan, Weijun; Wang, Xiaobo; Xu, Zhengzhong; Hu, Maozhi; Rao, Yan; Zhou, Xiaohui; Pan, Zhiming; Zhang, Xiaoming; Jiao, Xin'an

2017-01-01

Deaths associated with tuberculosis (TB) is rising and accounted for 1.4 million deaths in 2015 many of which were due to drug-resistant bacteria. Vaccines represent an important medical intervention, but the current Bacilli Calmette-Guerin (BCG) vaccine is not ideal for the protection of teenagers and adults. Therefore, a safe and effective vaccine is urgently needed. In this study, we designed a novel vaccine using an attenuated Listeria monocytogenes strain carrying fusion antigen FbpB-ESAT-6 (rLM) and characterized its safety and protective efficacy against Mycobacterium tuberculosis ( M.tb ) infection in mice. Compared to the wild type strain yzuLM4 and parental strain LMΔ actA/plcB (LM1-2), the virulence of rLM was significantly reduced as judged by its infectious kinetics and LD 50 dose. Further characterization of intravenous immunization showed that prime-boost vaccination significantly increased the levels of Th1 cytokines (IFN-γ, IL-17, and IL-6), and enhanced cytotoxic T lymphocyte (CTL) CTLs activity, suggesting that rLM could elicit potent Th1/Th17 responses. More importantly, rLM significantly conferred the protection against M.tb H37Rv challenge. Collectively, our findings indicated that rLM is a novel and useful tool to prevent M.tb infection, and can be potentially be used to boost BCG-primed immunity.

Non-tuberculous mycobacteria have diverse effects on BCG efficacy against Mycobacterium tuberculosis.

PubMed

Poyntz, Hazel C; Stylianou, Elena; Griffiths, Kristin L; Marsay, Leanne; Checkley, Anna M; McShane, Helen

2014-05-01

The efficacy of Bacillus Calmette-Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation for this variability is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). This study used a murine model to determine the effect that exposure to NTM after BCG vaccination had on the efficacy of BCG against aerosol Mycobacterium tuberculosis challenge. The effects of administering live Mycobacterium avium (MA) by an oral route and killed MA by a systemic route on BCG-induced protection were evaluated. CD4+ and CD8+ T cell responses were profiled to define the immunological mechanisms underlying any effect on BCG efficacy. BCG efficacy was enhanced by exposure to killed MA administered by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. BCG efficacy was reduced by exposure to live MA administered by the oral route; T helper 2 cells were associated with reduced protection. These findings demonstrate that exposure to NTM can induce opposite effects on BCG efficacy depending on route of exposure and viability of NTM. A reproducible model of NTM exposure would be valuable in the evaluation of novel TB vaccine candidates. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

In silico design of Mycobacterium tuberculosis epitope ensemble vaccines.

PubMed

Shah, Preksha; Mistry, Jaymisha; Reche, Pedro A; Gatherer, Derek; Flower, Darren R

2018-05-01

Effective control of Mycobacterium tuberculosis is a global necessity. In 2015, tuberculosis (TB) caused more deaths than HIV. Considering the increasing prevalence of multi-drug resistant forms of M. tuberculosis, the need for effective TB vaccines becomes imperative. Currently, the only licensed TB vaccine is Bacillus Calmette-Guérin (BCG). Yet, BCG has many drawbacks limiting its efficacy and applicability. We applied advanced computational procedures to derive a universal TB vaccine and one targeting East Africa. Our approach selects an optimal set of highly conserved, experimentally validated epitopes, with high projected population coverage (PPC). Through rigorous data analysis, five different potential vaccine combinations were selected each with PPC above 80% for East Africa and above 90% for the World. Two potential vaccines only contained CD8+ epitopes, while the others included both CD4+ and CD8+ epitopes. Our prime vaccine candidate was a putative seven-epitope ensemble comprising: SRGWSLIKSVRLGNA, KPRIITLTMNPALDI, AAHKGLMNIALAISA, FPAGGSTGSL, MLLAVTVSL, QSSFYSDW and KMRCGAPRY, with a 97.4% global PPC and a 92.7% East African PPC. Copyright © 2018 Elsevier Ltd. All rights reserved.

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry*

PubMed Central

Zheng, Jianhua; Ren, Xianwen; Wei, Candong; Yang, Jian; Hu, Yongfeng; Liu, Liguo; Xu, Xingye; Wang, Jin; Jin, Qi

2013-01-01

Tuberculosis (TB) is an infectious bacterial disease that causes morbidity and mortality, especially in developing countries. Although its efficacy against TB has displayed a high degree of variability (0%–80%) in different trials, Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been recognized as an important weapon for preventing TB worldwide for over 80 years. Because secreted proteins often play vital roles in the interaction between bacteria and host cells, the secretome of mycobacteria is considered to be an attractive reservoir of potential candidate antigens for the development of novel vaccines and diagnostic reagents. In this study, we performed a proteomic analysis of BCG culture filtrate proteins using SDS-PAGE and high-resolution Fourier transform mass spectrometry. In total, 239 proteins (1555 unique peptides) were identified, including 185 secreted proteins or lipoproteins. Furthermore, 17 novel protein products not annotated in the BCG database were detected and validated by means of RT-PCR at the transcriptional level. Additionally, the translational start sites of 52 proteins were confirmed, and 22 proteins were validated through extension of the translational start sites based on N-terminus-derived peptides. There are 103 secreted proteins that have not been reported in previous studies on the mycobacterial secretome and are unique to our study. The physicochemical characteristics of the secreted proteins were determined. Major components from the culture supernatant, including low-molecular-weight antigens, lipoproteins, Pro-Glu and Pro-Pro-Glu family proteins, and Mce family proteins, are discussed; some components represent potential predominant antigens in the humoral and cellular immune responses. PMID:23616670

Factors associated with dropout between Bacille Calmette Guerin (BCG) and measles vaccination in a village development committee of a district.

PubMed

Basel, P L; Shrestha, I B

2012-05-01

The Expanded Programme on Immunization is one of the first priorities of the Government of Nepal. The high national dropout rate (11.3%) demonstrates that immunization opportunities are lost as approximately one of every nine children in contact with immunization services are slipping "out of the system" before the age of 12 months. This study is an attempt to explore the situation of the enhancing factors for dropout. The main objective of the study was to identify the reasons of dropout between BCG and Measles vaccination in Kapan Village Development Committee (VDC) of Kathmandu district. This was a descriptive study. of children ranging from 12 to 23 months of age residing in Kapan VDC. (N=81) mothers were interviewed to obtain the information. The study revealed that Magar/Gurung in the area were found to dropout more (78.6%). Female children were more likely to dropout than male children. About 70% of children dropout were from labor class, and/or illiterate families. Majority of the mothers (42.5 %) said that the child was ill so they did not go for routine vaccination. However, 50.7% of dropout children received quality care. These findings were corroborated with the findings of key informant interview. The major reason of dropout of measles vaccine was found to be the perceived contraindication regarding the immunization.

The Tuberculosis Vaccine Candidate Bacillus Calmette-Guérin ΔureC::hly Coexpressing Human Interleukin-7 or -18 Enhances Antigen-Specific T Cell Responses in Mice

PubMed Central

Rao, Martin; Vogelzang, Alexis; Kaiser, Peggy; Schuerer, Stefanie; Kaufmann, Stefan H. E.; Gengenbacher, Martin

2013-01-01

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::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 ΔureC::hly, BCG ΔureC::hly_hIL7 or BCG ΔureC::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 ΔureC::hly. We conclude that expression of hIL-7 or hIL-18 enhanced specific T cell responses but failed to improve protection over BCG ΔureC::hly in mice. PMID:24236077

Nanoparticle-Fusion Protein Complexes Protect against Mycobacterium tuberculosis Infection.

PubMed

Hart, Peter; Copland, Alastair; Diogo, Gil Reynolds; Harris, Shane; Spallek, Ralf; Oehlmann, Wulf; Singh, Mahavir; Basile, Juan; Rottenberg, Martin; Paul, Matthew John; Reljic, Rajko

2018-03-07

Tuberculosis (TB) is the leading cause of death from infectious disease, and the current vaccine, Bacillus Calmette-Guerin (BCG), is inadequate. Nanoparticles (NPs) are an emerging vaccine technology, with recent successes in oncology and infectious diseases. NPs have been exploited as antigen delivery systems and also for their adjuvantic properties. However, the mechanisms underlying their immunological activity remain obscure. Here, we developed a novel mucosal TB vaccine (Nano-FP1) based upon yellow carnauba wax NPs (YC-NPs), coated with a fusion protein consisting of three Mycobacterium tuberculosis (Mtb) antigens: Acr, Ag85B, and HBHA. Mucosal immunization of BCG-primed mice with Nano-FP1 significantly enhanced protection in animals challenged with low-dose, aerosolized Mtb. Bacterial control by Nano-FP1 was associated with dramatically enhanced cellular immunity compared to BCG, including superior CD4 + and CD8 + T cell proliferation, tissue-resident memory T cell (Trm) seeding in the lungs, and cytokine polyfunctionality. Alongside these effects, we also observed potent humoral responses, such as the generation of Ag85B-specific serum IgG and respiratory IgA. Finally, we found that YC-NPs were able to activate antigen-presenting cells via an unconventional IRF-3-associated activation signature, without the production of potentially harmful inflammatory mediators, providing a mechanistic framework for vaccine efficacy and future development. Copyright © 2017. Published by Elsevier Inc.

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

PubMed

Nieuwenhuizen, Natalie E; Kulkarni, Prasad S; Shaligram, Umesh; Cotton, Mark F; Rentsch, Cyrill A; Eisele, Bernd; Grode, Leander; Kaufmann, Stefan H E

2017-01-01

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ ureC :: hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination

PubMed Central

Lewinsohn, Deborah A.; Lewinsohn, David M.; Scriba, Thomas J.

2017-01-01

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG). Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4+ T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2) as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4+ T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4+ T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4+ T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4+ T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4+ T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in the immune

The Effects of Vole Bacillus Vaccination of African Mine Workers in the Northern Rhodesian Copper Mines

PubMed Central

Paul, R.

1961-01-01

African mine workers exposed to siliceous dust in the metalliferous mines of Northern Rhodesia were tuberculin tested; of 17,697 tested, 13,667 were tuberculin positive and 4,030 negative. The negative reactors were divided at random into two approximately equal groups and 1,984 were vaccinated with vole bacillus vaccine and 2,046 were left unvaccinated. These two groups were subsequently followed up and their original radiological categories at the time of tuberculin testing and vaccination were compared with their radiological categories after varying periods of further dust exposure. The object of the investigation was to ascertain whether or not vaccination with vole bacillus vaccine introduced an acclerating factor in the rate of radiological change in pneumoconiosis. The results of the investigation showed that radiological changes in the two groups were minimal and that there was virtually no difference between them. No accelerated changes were recorded in the negative vaccinated group. This is regarded as evidence that anti-tuberculosis vaccine does not introduce an accelerating factor in pneumoconiosis. No case of pulmonary tuberculosis occurred in the negative vaccinated group. Three cases were recorded in the negative non-vaccinated group, suggesting that vaccination with vole bacillus vaccine affords some measure of protection against tuberculosis, and in view of the absence of any evidence that it had an accelerating effect in pneumoconiosis it appears desirable that miners should receive this protection. PMID:13733457

Bacillus Calmette-Guérin enhances production and secretion of type IV collagenases in peripheral blood mononuclear cells.

PubMed

Kageyama, Y; Kawakami, S; Fujii, Y; Kihara, K; Oshima, H

1997-03-01

Intravesical administration of bacillus Calmette-Guérin (BCG) is an effective and widely accepted treatment for superficial bladder cancer. Rapid progression of the disease after BCG therapy, however, has been reported in some cases refractory to the treatment. We examined whether BCG treatment and coexistence of peripheral blood mononuclear cells (PBMCs) alter the invasive potential of bladder cancer cells. Production and secretion of two type IV collagenases, matrix metalloproteinase (MMP) 2 and MMP 9, by PBMCs from five healthy donors or bladder cancer cells (T24, JTC 30, and JTC 32) were evaluated by gelatin zymography, western blot analysis, and northern blot analysis. Invasion of bladder cancer cells was also examined using reconstituted basement membrane (Matrigel). BCG (5, 50, and 500 micrograms/ml) had no effect on secretion of MMP 2 and MMP 9 by bladder cancer cells, but increased the production and secretion of MMP 9 by PBMCs in a dose-dependent manner. The coexistence of PBMCs increased invasion of T24 cells and BCG further enhanced the invasion. Thus, BCG promotes invasion of bladder cancer cells under certain conditions. An increase in the secretion of MMP 9 by PBMCs may account in part for the effect.

Prospects in Mycobacterium bovis Bacille Calmette et Guérin (BCG) Vaccine Diversity and Delivery: Why does BCG fail to protect against Tuberculosis?

PubMed Central

Moliva, Juan I.; Turner, Joanne; Torrelles, Jordi B.

2015-01-01

Mycobacterium tuberculosis (M.tb) infection leads to active tuberculosis (TB), a disease that kills one human every 18 seconds. Current therapies available to combat TB include chemotherapy and the preventative vaccine Mycobacterium bovis Bacille Calmette et Guérin (BCG). Increased reporting of drug resistant M.tb strains worldwide indicates that drug development cannot be the primary mechanism for eradication. BCG vaccination has been used globally for protection against childhood and disseminated TB, however, its efficacy at protecting against pulmonary TB in adult and aging populations is highly variable. In this regard, the immune response generated by BCG vaccination is incapable of sterilizing the lung post M.tb infection as indicated by the large proportion of individuals with latent TB infection that have received BCG. Although many new TB vaccine candidates have entered the development pipeline, only a few have moved to human clinical trials; where they showed no efficacy and/or were withdrawn due to safety regulations. These trials highlight our limited understanding of protective immunity against the development of active TB. Here, we discuss current vaccination strategies and their impact on the generation and sustainability of protective immunity against TB. PMID:26319069

Persistence of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) in White-tailed Deer (Odocoileus virginianus) After Oral or Parenteral Vaccination

USDA-ARS?s Scientific Manuscript database

Mycobacterium bovis is the cause of tuberculosis in cattle and a serious zoonotic pathogen, most commonly contracted through consumption of unpasteurized dairy products. To control this zoonosis, many countries have developed bovine tuberculosis eradication programs. Although relatively successful, ...

Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance.

PubMed

Cernuschi, Tania; Malvolti, Stefano; Nickels, Emily; Friede, Martin

2018-01-25

Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management. Copyright © 2017. Published by Elsevier Ltd.

Drying a tuberculosis vaccine without freezing.

PubMed

Wong, Yun-Ling; Sampson, Samantha; Germishuizen, Willem Andreas; Goonesekera, Sunali; Caponetti, Giovanni; Sadoff, Jerry; Bloom, Barry R; Edwards, David

2007-02-20

With the increasing incidence of tuberculosis and drug resistant disease in developing countries due to HIV/AIDS, there is a need for vaccines that are more effective than the present bacillus Calmette-Guérin (BCG) vaccine. We demonstrate that BCG vaccine can be dried without traditional freezing and maintained with remarkable refrigerated and room-temperature stability for months through spray drying. Studies with a model Mycobacterium (Mycobacterium smegmatis) revealed that by removing salts and cryoprotectant (e.g., glycerol) from bacterial suspensions, the significant osmotic pressures that are normally produced on bacterial membranes through droplet drying can be reduced sufficiently to minimize loss of viability on drying by up to 2 orders of magnitude. By placing the bacteria in a matrix of leucine, high-yield, free-flowing, "vial-fillable" powders of bacteria (including M. smegmatis and M. bovis BCG) can be produced. These powders show relatively minor losses of activity after maintenance at 4 degrees C and 25 degrees C up to and beyond 4 months. Comparisons with lyophilized material prepared both with the same formulation and with a commercial formulation reveal that the spray-dried BCG has better overall viability on drying.

Current state of immunotherapy for bladder cancer.

PubMed

Kassouf, Wassim; Kamat, Ashish M

2004-12-01

Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b.

A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity.

PubMed

Etna, Marilena P; Giacomini, Elena; Severa, Martina; Pardini, Manuela; Aguilo, Nacho; Martin, Carlos; Coccia, Eliana M

2014-01-01

Among the tuberculosis (TB) vaccine candidates, SO2 is the prototype of the first live-attenuated vaccine that recently entered into clinical trials. To investigate the capacity of SO2 to stimulate an appropriate immune response in vitro within a human immunological context, a comparative analysis of the effects promoted by SO2, the current Bacille Calmette-Guerin (BCG) vaccine and Mycobacterium tuberculosis (Mtb) was conducted in human primary dendritic cells (DC), which are critical modulators of vaccine-induced immunity. In particular, we found that SO2 promotes the expression of maturation markers similarly to BCG but at a lower extent than Mtb. Moreover, SO2-infected DC released higher levels of interleukin (IL)-23 than BCG-infected cells, which account for the expansion of interferon (IFN)-γ-producing T cells in an IL-12-independent manner. In the autologous mixed leukocyte reaction setting, the expansion of IL-17-producing T cells was also observed in response to SO2 infection. Interestingly, apoptosis and autophagic flux, events required for the antigen presentation within MHC class II complex, were not affected in DC infected with SO2, conversely to what observed upon Mtb stimulation. Collectively, our results indicate that SO2 represents a promising TB vaccine candidate, which displays an attenuated phenotype and promotes in DC a stronger capacity to stimulate the Th response than BCG vaccine. Interestingly, the data obtained by using the human DC-based experimental setting mirrored the results derived from studies in animal models, suggesting that this system could be used for an efficient and rapid down-selection of new TB vaccine candidates, contributing to achieve the "3Rs" objective.

Multi-parametric MRI findings of granulomatous prostatitis developing after intravesical bacillus calmette-guérin therapy.

PubMed

Gottlieb, Josh; Princenthal, Robert; Cohen, Martin I

2017-07-01

To evaluate the multi-parametric MRI (mpMRI) findings in patients with biopsy-proven granulomatous prostatitis and prior Bacillus Calmette-Guérin (BCG) exposure. MRI was performed in six patients with pathologically proven granulomatous prostatitis and a prior history of bladder cancer treated with intravesical BCG therapy. Multi-parametric prostate MRI images were recorded on a GE 750W or Philips Achieva 3.0 Tesla MRI scanner with high-resolution, small-field-of-view imaging consisting of axial T2, axial T1, coronal T2, sagittal T2, axial multiple b-value diffusion (multiple values up to 1200 or 1400), and dynamic contrast-enhanced 3D axial T1 with fat suppression sequence. Two different patterns of MR findings were observed. Five of the six patients had a low mean ADC value <1000 (decreased signal on ADC map images) and isointense signal on high-b-value imaging (b = 1200 or 1400), consistent with nonspecific granulomatous prostatitis. The other pattern seen in one of the six patients was decreased signal on the ADC map images with increased signal on the high-b-value sequence, revealing true restricted diffusion indistinguishable from aggressive prostate cancer. This patient had biopsy-confirmed acute BCG prostatitis. Our study suggests that patients with known BCG exposure and PI-RADS v2 scores ≤3, showing similar mpMRI findings as demonstrated, may not require prostate biopsy.

Role of a bacillus Calmette-Guérin fibronectin attachment protein in BCG-induced antitumor activity.

PubMed

Zhao, W; Schorey, J S; Bong-Mastek, M; Ritchey, J; Brown, E J; Ratliff, T L

2000-04-01

Intravesical Mycobacterium bovis bacillus Calmette-Gu*erin (BCG) is the treatment of choice for superficial bladder cancer. Previous studies showed that attachment of BCG to fibronectin within the bladder was necessary for mediation of the antitumor response. Further studies identified a bacterial receptor, fibronectin attachment protein (FAP), as an important mediator of BCG attachment to fibronectin. In vitro studies showed that a stable BCG/fibronectin interaction was dependent on FAP binding to fibronectin; however, no role for FAP in the attachment of BCG in vivo has been characterized. We now report the cloning of the M. bovis BCG FAP (FAP-B) and demonstrate an important role for FAP in the in vivo attachment of BCG to the bladder wall and in the induction of BCG-mediated antitumor activity. The predicted amino acid sequence for FAP-B shows 61% and 71% homology, respectively, with Mycobacterium avium FAP (FAP-A) and Mycobacterium leprae FAP (FAP-L). Rabbit polyclonal antibodies against Mycobacterium vaccae FAP (FAP-V) reacted with all 3 recombinant FAP proteins on Western blots. Functional studies show FAP-B to bind fibronectin via the highly conserved attachment regions previously identified for FAP-A and FAP-L and also to competitively inhibit attachment of BCG to matrix fibronectin. In vivo studies show FAP to be a necessary protein for the stable attachment of BCG to the bladder wall. Moreover, stable binding of BCG via FAP was shown to be necessary for the expression of BCG-induced antitumor activity. Our results demonstrate a biological role for FAP in the mediation of BCG-induced antitumor activity.

Bacillus Calmette-Guérin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice.

PubMed

de Bree, Charlotte L C J; Marijnissen, Renoud J; Kel, Junda M; Rosendahl Huber, Sietske K; Aaby, Peter; Benn, Christine Stabell; Wijnands, Marcel V W; Diavatopoulos, Dimitri A; van Crevel, Reinout; Joosten, Leo A B; Netea, Mihai G; Dulos, John

2018-01-01

Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

Ag85A-specific CD4+ T cell lines derived after boosting BCG-vaccinated cattle with Ad5-85A possess both mycobacterial growth inhibition and anti-inflammatory properties.

PubMed

Metcalfe, Hannah J; Biffar, Lucia; Steinbach, Sabine; Guzman, Efrain; Connelley, Tim; Morrison, Ivan; Vordermeier, H Martin; Villarreal-Ramos, Bernardo

2018-05-11

There is a need to improve the efficacy of the BCG vaccine against human and bovine tuberculosis. Previous data showed that boosting bacilli Calmette-Guerin (BCG)-vaccinated cattle with a recombinant attenuated human type 5 adenovirally vectored subunit vaccine (Ad5-85A) increased BCG protection and was associated with increased frequency of Ag85A-specific CD4 + T cells post-boosting. Here, the capacity of Ag85A-specific CD4 + T cell lines - derived before and after viral boosting - to interact with BCG-infected macrophages was evaluated. No difference before and after boosting was found in the capacity of these Ag85A-specific CD4 + T cell lines to restrict mycobacterial growth, but the secretion of IL-10 in vitro post-boost increased significantly. Furthermore, cell lines derived post-boost had no statistically significant difference in the secretion of pro-inflammatory cytokines (IL-1β, IL-12, IFNγ or TNFα) compared to pre-boost lines. In conclusion, the protection associated with the increased number of Ag85A-specific CD4 + T cells restricting mycobacterial growth may be associated with anti-inflammatory properties to limit immune-pathology. Copyright © 2018 Department for Environment Food and Rural Affairs. Published by Elsevier Ltd.. All rights reserved.

Health Impacts of Environmental Mycobacteria†

PubMed Central

Primm, Todd P.; Lucero, Christie A.; Falkinham, Joseph O.

2004-01-01

Environmental mycobacteria are emerging pathogens causing opportunistic infections in humans and animals. The health impacts of human-mycobacterial interactions are complex and likely much broader than currently recognized. Environmental mycobacteria preferentially survive chlorination in municipal water, using it as a vector to infect humans. Widespread chlorination of water has likely selected more resistant environmental mycobacteria species and potentially explains the shift from M. scrofulaceum to M. avium as a cause of cervical lymphadenitis in children. Thus, human activities have affected mycobacterial ecology. While the slow growth and hydrophobicity of environmental mycobacteria appear to be disadvantages, the unique cell wall architecture also grants high biocide and antibiotic resistance, while hydrophobicity facilitates nutrient acquisition, biofilm formation, and spread by aerosolization. The remarkable stress tolerance of environmental mycobacteria is the major reason they are human pathogens. Environmental mycobacteria invade protozoans, exhibiting parasitic and symbiotic relationships. The molecular mechanisms of mycobacterial intracellular pathogenesis in animals likely evolved from similar mechanisms facilitating survival in protozoans. In addition to outright infection, environmental mycobacteria may also play a role in chronic bowl diseases, allergies, immunity to other pulmonary infections, and the efficacy of bacillus Calmette-Guerin vaccination. PMID:14726457

Health impacts of environmental mycobacteria.

PubMed

Primm, Todd P; Lucero, Christie A; Falkinham, Joseph O

2004-01-01

Environmental mycobacteria are emerging pathogens causing opportunistic infections in humans and animals. The health impacts of human-mycobacterial interactions are complex and likely much broader than currently recognized. Environmental mycobacteria preferentially survive chlorination in municipal water, using it as a vector to infect humans. Widespread chlorination of water has likely selected more resistant environmental mycobacteria species and potentially explains the shift from M. scrofulaceum to M. avium as a cause of cervical lymphadenitis in children. Thus, human activities have affected mycobacterial ecology. While the slow growth and hydrophobicity of environmental mycobacteria appear to be disadvantages, the unique cell wall architecture also grants high biocide and antibiotic resistance, while hydrophobicity facilitates nutrient acquisition, biofilm formation, and spread by aerosolization. The remarkable stress tolerance of environmental mycobacteria is the major reason they are human pathogens. Environmental mycobacteria invade protozoans, exhibiting parasitic and symbiotic relationships. The molecular mechanisms of mycobacterial intracellular pathogenesis in animals likely evolved from similar mechanisms facilitating survival in protozoans. In addition to outright infection, environmental mycobacteria may also play a role in chronic bowl diseases, allergies, immunity to other pulmonary infections, and the efficacy of bacillus Calmette-Guerin vaccination.

The Potential for Transmission of BCG from Orally Vaccinated White-Tailed Deer (Odocoileus virginianus) to Cattle (Bos taurus) through a Contaminated Environment: Experimental Findings

PubMed Central

Nol, Pauline; Rhyan, Jack C.; Robbe-Austerman, Suelee; McCollum, Matt P.; Rigg, Tara D.; Saklou, Nadia T.; Salman, Mo D.

2013-01-01

White-tailed deer (Odocoileus virginianus) experimentally infected with a virulent strain of Mycobacterium bovis have been shown to transmit the bacterium to other deer and cattle (Bos taurus) by sharing of pen waste and feed. The risk of transmission of M. bovis bacille Calmette-Guerin (BCG) vaccine from orally vaccinated white-tailed deer to other deer and cattle, however, is not well understood. In order to evaluate this risk, we orally vaccinated 14 white-tailed deer with 1×109 colony forming units BCG in lipid-formulated baits and housed them with nine non-vaccinated deer. Each day we exposed the same seven naïve cattle to pen space utilized by the deer to look for transmission between the two species. Before vaccination and every 60 days until the end of the study, we performed tuberculin skin testing on deer and cattle, as well as interferon-gamma testing in cattle, to detect cellular immune response to BCG exposure. At approximately 27 weeks all cattle and deer were euthanized and necropsied. None of the cattle converted on either caudal fold, comparative cervical tests, or interferon-gamma assay. None of the cattle were culture positive for BCG. Although there was immunological evidence that BCG transmission occurred from deer to deer, we were unable to detect immunological or microbiological evidence of transmission to cattle. This study suggests that the risk is likely to be low that BCG-vaccinated white-tailed deer would cause domestic cattle to react to the tuberculin skin test or interferon-gamma test through exposure to a BCG-contaminated environment. PMID:23565211

GD3/proteosome vaccines induce consistent IgM antibodies against the ganglioside GD3.

PubMed

Livingston, P O; Calves, M J; Helling, F; Zollinger, W D; Blake, M S; Lowell, G H

1993-09-01

The gangliosides of melanoma and other tumours of neuroectodermal origin are suitable targets for immune intervention with tumour vaccines. The optimal vaccines in current use contain ganglioside plus bacillus Calmette-Guérin and induce considerable morbidity. We have screened a variety of new adjuvants in the mouse, and describe one antigen-delivery system, proteosomes, which is especially effective. Highly hydrophobic Neisserial outer membrane proteins (OMP) form multimolecular liposome-like vesicular structures termed proteosomes which can readily incorporate amphiphilic molecules such as GD3 ganglioside. The optimal GD3/proteosome vaccine formulation for induction of GD3 antibodies in the mouse is determined. Interestingly, the use of potent immunological adjuvants in addition to proteosomes augments the IgM and IgG antibody titres against OMP in these vaccines but GD3 antibody titres are unaffected. The application of proteosomes to enhance the immune response to GD3 extends the concept of the proteosome immunopotentiating system from lipopeptides to amphipathic carbohydrate epitopes such as cell-surface gangliosides. The demonstrated safety of meningococcal OMP in humans and the data in mice presented here suggest that proteosome vaccines have potential for augmenting the immunogenicity of amphipathic tumour antigens in humans.

Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection.

PubMed

Chancellor, Andrew; White, Andrew; Tocheva, Anna S; Fenn, Joe R; Dennis, Mike; Tezera, Liku; Singhania, Akul; Elliott, Tim; Tebruegge, Marc; Elkington, Paul; Gadola, Stephan; Sharpe, Sally; Mansour, Salah

2017-07-01

Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4 + /CD8 + iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8 + iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modifying effects of 5-azacytidine on metal-containing proteins profile in Guerin carcinoma with different sensitivity to cytostatics.

PubMed

Chekhun, V F; Lozovska, Y V; Naleskina, L A; Borikun, T V; Burlaka, A P; Todor, I N; Demash, D V; Yalovenko, T M; Zadvornyi, T V; Pavlova, A O; Storchay, D M; Lukianova, N Yu

2016-12-01

To assess the influence of the treatment with 5-azacytidine (5-aza) on the profile of metal-containing proteins and factors of their regulation in Guerin carcinoma cells in vivo. The study was conducted on Wistar rats transplanted with wild-type Guerin carcinoma (Guerin/WT) and its strains resistant to cisplatin (Guerin/CP) or doxorubicin (Guerin/Dox). Animals were distributed in 6 groups treated with 5-aza and control animals without treatment. 5-Aza was injected by i.v. route (1 injection in 4 days at a dose of 2 mg/kg starting from the 4 th day after tumor transplantation, 4 injections in total). Ferritin levels in blood serum and tumor tissue were measured by ELISA, transferrin and free iron complexes - by low-temperature EPR, miRNA-200b, -133a and -320a levels and promoter methylation - by real-time quantitative reverse transcription polymerase chain reaction. The study has shown that 5-aza treatment caused demethylation of promoter regions of fth1 and tfr1 genes in all studied Guerin carcinoma strains. 5-Aza treatment resulted in a significant decrease of ferritin levels in tumor tissue (by 32.1% in Guerin/WT strain, by 29.8% in Guerin/Dox and by 69.1% in Guerin/CP). These events were accompanied by 3.5-fold and 2-fold increase of free iron complexes levels in tumor tissue of doxorubicin and cisplatin resistant strains, respectively. Also, 5-aza treatment resulted in significantly elevated levels of miR-200b, -133a, 320a expression in tumor tissue. After 5-aza treatment, ferritin levels in blood serum of animals with Guerin/Dox were increased by 23.9%, while in Guerin/Wt and Guerin/CP they were decreased by 17 and 16%, respectively. Alterations of epigenetic regulation upon in vivo treatment with 5-aza change the levels of metal-containing proteins due to DNA demethylation and altered miRNA expression profiles in Guerin carcinoma cells.

Isolation and characterization of elongation factor EF-2 from Guerin tumour.

PubMed

Jabłonowska, K; Kopacz-Jodczyk, T; Niedźwiecka, J; Gałasiński, W

1983-01-01

A homogeneous preparation of EF-2 from Guerin tumour cells was obtained. Its Mr (68 000), pI (6.5), optimum pH (7.0) and amino acid composition are very close to those of rat liver elongation factor. EF-2 from Guerin tumour cells is active in the heterologous liver - tumour system, although half as effective as in the homologous system.

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

PubMed

Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

2016-07-25

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. Published by Elsevier Ltd.

Tuberculosis Vaccines and Prevention of Infection

PubMed Central

Day, Tracey A.; Scriba, Thomas J.; Hatherill, Mark; Hanekom, Willem A.; Evans, Thomas G.; Churchyard, Gavin J.; Kublin, James G.; Bekker, Linda-Gail; Self, Steven G.

2014-01-01

SUMMARY Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation. PMID:25428938

Community vaccine perceptions and its role on vaccination uptake among children aged 12-23 months in the Ileje District, Tanzania: a cross section study

PubMed Central

Chambongo, Pai Elia; Nguku, Patrick; Wasswa, Peter; Semali, Innocent

2016-01-01

Introduction Underutilization of vaccines still remains a challenge in many regions across the world. Ileje district is one of the districts in Tanzania with consistently low pentavalent vaccine uptake (69%) and with drop out of 15%. We determined the vaccination completion with regard to Oral Polio virus, Measles, Bacillus Calmette-Guérin, and pentavalent vaccines and its association with community perceptions on vaccines. Methods We conducted a cross sectional study in Ileje district from October to December 2013. We sampled 380 mothers using a multistage random sampling technique. We analysed data using EPI INFO. We summarized descriptive variables using mean and standard deviation and categorical variables using proportions. We conducted bivariate and multivariate logistic regression to identify factors influencing vaccination uptake, statistical significance was assessed at 95% confidence interval. Results Mean age of the mothers was 27 years (SD 6.5 years) while that of their children was 16 months (SD 3.6 months). Fully vaccinated children were 71.1% and partially vaccinated were 28.9%, 99.2% were vaccinated with BCG vaccine and 73.4% were vaccinated with all OPV vaccine. Predictors of vaccination completion included negative perception on the vaccine provider-client relationship (AOR 1.86, 95%CI1.03-3.35), Perceived satisfaction with vaccination services (AOR 2.63, 95%CI 1.1 - 6.3). Others include child being born in the health facility (AOR 13.8 95% CI 8.04-25.8) and younger age of a child (AOR 0.51, 95%CI 0.29-0.9). Conclusion Improving quality of vaccination services, promoting health education and sensitizing community on health facility delivery will improve child vaccination completion in the district PMID:27303578

Community vaccine perceptions and its role on vaccination uptake among children aged 12-23 months in the Ileje District, Tanzania: a cross section study.

PubMed

Chambongo, Pai Elia; Nguku, Patrick; Wasswa, Peter; Semali, Innocent

2016-01-01

Underutilization of vaccines still remains a challenge in many regions across the world. Ileje district is one of the districts in Tanzania with consistently low pentavalent vaccine uptake (69%) and with drop out of 15%. We determined the vaccination completion with regard to Oral Polio virus, Measles, Bacillus Calmette-Guérin, and pentavalent vaccines and its association with community perceptions on vaccines. We conducted a cross sectional study in Ileje district from October to December 2013. We sampled 380 mothers using a multistage random sampling technique. We analysed data using EPI INFO. We summarized descriptive variables using mean and standard deviation and categorical variables using proportions. We conducted bivariate and multivariate logistic regression to identify factors influencing vaccination uptake, statistical significance was assessed at 95% confidence interval. Mean age of the mothers was 27 years (SD 6.5 years) while that of their children was 16 months (SD 3.6 months). Fully vaccinated children were 71.1% and partially vaccinated were 28.9%, 99.2% were vaccinated with BCG vaccine and 73.4% were vaccinated with all OPV vaccine. Predictors of vaccination completion included negative perception on the vaccine provider-client relationship (AOR 1.86, 95%CI1.03-3.35), Perceived satisfaction with vaccination services (AOR 2.63, 95%CI 1.1 - 6.3). Others include child being born in the health facility (AOR 13.8 95% CI 8.04-25.8) and younger age of a child (AOR 0.51, 95%CI 0.29-0.9). Improving quality of vaccination services, promoting health education and sensitizing community on health facility delivery will improve child vaccination completion in the district.

CAPR - Theresa Guerin | Center for Cancer Research

Cancer.gov

Theresa Guerin oversees animal colony management and provides support in breeding experimental animal cohort, preparing documentation for CAPR preclinical studies, as well as assistance in designing drug treatment plans. She also maintains multiple database resources. Expertise

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence.

PubMed

Lipner, Ettie M; Gopi, P G; Subramani, R; Kolappan, C; Sadacharam, K; Kumaran, Paul; Prevots, D Rebecca; Narayanan, P R; Nutman, Thomas B; Kumaraswami, V

2006-05-01

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.

Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau.

PubMed

Frankel, H; Byberg, S; Bjerregaard-Andersen, M; Martins, C L; Aaby, P; Benn, C S; Fisker, A B

2016-08-31

Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. During 2011-2013, infants in the Bandim Health Project's urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74-2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mucosal immune response in broilers following vaccination with inactivated influenza and recombinant Bacillus subtilis

USDA-ARS?s Scientific Manuscript database

Mucosal and systemic immunity were observed in broilers vaccinated with mannosylated chitosan adjuvated (MCA) inactivated A/Turkey/Virginia/158512/2002 (H7N2) and administered with and without recombinant Bacillus subtilis to elicit heterologous influenza strain protection. Previously, mucosal immu...

Determinants of vaccination coverage in rural Nigeria

PubMed Central

Odusanya, Olumuyiwa O; Alufohai, Ewan F; Meurice, Francois P; Ahonkhai, Vincent I

2008-01-01

Background Childhood immunization is a cost effective public health strategy. Expanded Programme on Immunisation (EPI) services have been provided in a rural Nigerian community (Sabongidda-Ora, Edo State) at no cost to the community since 1998 through a privately financed vaccination project (private public partnership). The objective of this survey was to assess vaccination coverage and its determinants in this rural community in Nigeria Methods A cross-sectional survey was conducted in September 2006, which included the use of interviewer-administered questionnaire to assess knowledge of mothers of children aged 12–23 months and vaccination coverage. Survey participants were selected following the World Health Organization's (WHO) immunization coverage cluster survey design. Vaccination coverage was assessed by vaccination card and maternal history. A child was said to be fully immunized if he or she had received all of the following vaccines: a dose of Bacille Calmette Guerin (BCG), three doses of oral polio (OPV), three doses of diphtheria, pertussis and tetanus (DPT), three doses of hepatitis B (HB) and one dose of measles by the time he or she was enrolled in the survey, i.e. between the ages of 12–23 months. Knowledge of the mothers was graded as satisfactory if mothers had at least a score of 3 out of a maximum of 5 points. Logistic regression was performed to identify determinants of full immunization status. Results Three hundred and thirty-nine mothers and 339 children (each mother had one eligible child) were included in the survey. Most of the mothers (99.1%) had very positive attitudes to immunization and > 55% were generally knowledgeable about symptoms of vaccine preventable diseases except for difficulty in breathing (as symptom of diphtheria). Two hundred and ninety-five mothers (87.0%) had a satisfactory level of knowledge. Vaccination coverage against all the seven childhood vaccine preventable diseases was 61.9% although it was

Determinants of vaccination coverage in rural Nigeria.

PubMed

Odusanya, Olumuyiwa O; Alufohai, Ewan F; Meurice, Francois P; Ahonkhai, Vincent I

2008-11-05

Childhood immunization is a cost effective public health strategy. Expanded Programme on Immunisation (EPI) services have been provided in a rural Nigerian community (Sabongidda-Ora, Edo State) at no cost to the community since 1998 through a privately financed vaccination project (private public partnership). The objective of this survey was to assess vaccination coverage and its determinants in this rural community in Nigeria A cross-sectional survey was conducted in September 2006, which included the use of interviewer-administered questionnaire to assess knowledge of mothers of children aged 12-23 months and vaccination coverage. Survey participants were selected following the World Health Organization's (WHO) immunization coverage cluster survey design. Vaccination coverage was assessed by vaccination card and maternal history. A child was said to be fully immunized if he or she had received all of the following vaccines: a dose of Bacille Calmette Guerin (BCG), three doses of oral polio (OPV), three doses of diphtheria, pertussis and tetanus (DPT), three doses of hepatitis B (HB) and one dose of measles by the time he or she was enrolled in the survey, i.e. between the ages of 12-23 months. Knowledge of the mothers was graded as satisfactory if mothers had at least a score of 3 out of a maximum of 5 points. Logistic regression was performed to identify determinants of full immunization status. Three hundred and thirty-nine mothers and 339 children (each mother had one eligible child) were included in the survey. Most of the mothers (99.1%) had very positive attitudes to immunization and > 55% were generally knowledgeable about symptoms of vaccine preventable diseases except for difficulty in breathing (as symptom of diphtheria). Two hundred and ninety-five mothers (87.0%) had a satisfactory level of knowledge. Vaccination coverage against all the seven childhood vaccine preventable diseases was 61.9% although it was significantly higher (p = 0.002) amongst

Delayed BCG vaccination results in minimal alterations in T cell immunogenicity of acellular pertussis and tetanus immunizations in HIV-exposed infants.

PubMed

Blakney, Anna K; Tchakoute, Christophe Toukam; Hesseling, Anneke C; Kidzeru, Elvis B; Jones, Christine E; Passmore, Jo-Ann S; Sodora, Donald L; Gray, Clive M; Jaspan, Heather B

2015-09-11

Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, in utero or perinatal HIV infection is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants. Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens. Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035, respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age. Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants. NCT02062580. Copyright © 2015 Elsevier Ltd. All rights reserved.

[The tuberculin skin test in BCG-vaccinated individualse].

PubMed

Miret Cuadras, P; Pina Gutiérrez, J M

1998-10-01

The aim of this study was to evaluate the tuberculin skin test in individuals vaccinated with bacillus Calmette-Guérin (BCG) using 2 IU of RT-23. One hundred ninety-six individuals aged 22-40 years-old who had been vaccinated with BCG between 1965 and 1974 were enrolled along with 375 non-vaccinated individuals of the same age and with similar level of risk of infection. The positive predictive value of the test was assessed for three levels of response as indicated by areas of thickening in three diameters: 5, 10 and 15 mm. Vaccinated individuals with negative results were given a second skin test 7 days later to detect a booster effect. Positive diameters 5 mm were observed in 66% of the vaccinated individuals and 24% of the non-vaccinated subjects. Positive diameters 10 mm were observed in 51% of the vaccinated individuals and 19% of the non vaccinated ones. Positive diameters 15 mm were observed in 29% of the vaccinated subjects and in 13% of the non vaccinated ones. The differences were significant for all diameters. The positive predictive value of the test was 36.4% for a diameter 5 mm, 37.6% for diameter 10 mm and 44.8% for diameter 15 mm. The booster effect was detected in 25.8% of the vaccinated individuals who had tested negative at first. In vaccinated individuals, no guidelines can be established to guarantee that a positive reaction is due to infection by Mycobacterium tuberculosis infection, although the likelihood of infection (increased positive predictive value) increases with diameter. It is also impossible to fix a time limit. A second skin test is needed to detect a booster effect in all vaccinated individuals whose first test is negative.

Urinary fibronectin levels in patients treated with intravesical bacillus Calmette-Guérin for superficial bladder cancer.

PubMed

Danişman, A; Bulut, K; Kukul, E; Ozen, I; Sevük, M

2000-01-01

Intravesical bacillus Calmette-Guérin (BCG) has been shown to be an effective treatment for superficial transitional cell carcinoma (TCC) of the bladder, but the precise mechanism of action of BCG remains poorly understood. Fibronectin (FN), an important component of the extracellular matrix, has been found to play a role in BCG therapy. Some studies have shown that the soluble form of FN can compete efficiently with the matrix form of binding to the specific receptors on the bacteria and could consequently diminish the effect of BCG treatment. To evaluate a possible correlation between the urinary levels of FN and the efficacy of BCG therapy, we determined prospectively the urinary FN levels in 38 patients with TCC of the bladder and in 25 control subjects without malignancy matched for age and sex. All TCC patients were treated with transurethral tumor resection plus 6 weekly intravesical BCG instillations. After an average follow-up of 30 months, 8 patients (21.1%) had recurrent tumors, while 30 (78.9%) were free of tumor after intravesical BCG therapy. Urinary levels of FN in cancer patients have been shown to be significantly higher than controls (p < 0.001). These elevated levels were not decreased significantly after the operation (p > 0. 05). It was also found that the mean urinary FN levels were not statistically significant between patients with recurrence and complete remission. The data suggest that BCG-bladder tumor cell binding is not influenced by soluble fibronectin and urinary FN may not be a ideal marker for selecting patients to BCG therapy. Copyright 2000 S. Karger AG, Basel

Retrospective study of efficacy of intravesical BCG alone in treatment of superficial bladder cancer.

PubMed

Mydlo, J H; Usher, S M; Camacho, F; Freed, S

1986-09-01

This is a review of 100 patients at our institution who were treated for superficial bladder cancer. In those patients with carcinoma in situ of the bladder who were treated with conventional therapy (resection and/or fulguration) and intravesical bacillus Calmette-Guerin (BCG) without intradermal BCG, and those patients who were treated with conventional therapy alone, we found a response rate of 60 per cent versus 40 per cent at the end of three months. In comparing those patients with superficial papillary cancer, we found a response of 39 per cent after conventional therapy and 63 per cent after conventional therapy and intravesical BCG. This suggests that intravesical BCG without intradermal BCG can be an important adjunct to the conventional therapy of bladder tumors.

Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization.

PubMed

Okayasu, Hiromasa; Sein, Carolyn; Chang Blanc, Diana; Gonzalez, Alejandro Ramirez; Zehrung, Darin; Jarrahian, Courtney; Macklin, Grace; Sutter, Roland W

2017-07-01

A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Predictors of vaccination in India for children aged 12-36 months.

PubMed

Shrivastwa, Nijika; Gillespie, Brenda W; Kolenic, Giselle E; Lepkowski, James M; Boulton, Matthew L

2015-11-27

India has one of the lowest immunization rates worldwide despite a longstanding Universal Immunization Program (UIP) that provides free childhood vaccines. This study characterizes the predictors for under- and non-vaccination among Indian children aged 12-36 months. This study utilized District Level Household and Facility Survey Data, 2008 (DLHS3), from India. DLHS3 is a nationally representative sample collected from December 2007 through December 2008; this analysis was conducted during 2014. Children's vaccination status was categorized as fully, under-, and non-vaccinated based on whether children received all, some, or none of the UIP-recommended vaccines (one dose each of bacillus Calmette-Guérin and measles, and three doses of diphtheria-pertussis-tetanus). A multinomial logistic regression model estimated the odds of undervaccination compared with full vaccination, and odds of non-vaccination compared with full vaccination. Analytic predictors included socioeconomic, cultural, household, maternal, and childhood characteristics. The analysis included 108,057 children; the estimated proportions of fully, under-, and non-vaccinated children were 57%, 31%, and 12%, respectively. After adjusting for state of residence, age, gender, household wealth, and maternal education, additional significant predictors of children's vaccination status were religion, caste, place of delivery, number of antenatal care visits, and maternal tetanus vaccination, all of which demonstrated large effect sizes. India's immunization coverage remained low in 2008, with just slightly more than half of all children aged 12-36 months fully vaccinated with UIP-recommended vaccines. A better understanding of the predictors for vaccination can help shape interventions to reduce disparities in full vaccination among children of differing demographic/cultural groups. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Immunogenicity and protective efficacy of heterologous prime-boost regimens with mycobacterial vaccines and recombinant adenovirus- and poxvirus-vectored vaccines against murine tuberculosis.

PubMed

You, Qingrui; Wu, Yongge; Wu, Yang; Wei, Wei; Wang, Changyong; Jiang, Dehua; Yu, Xianghui; Zhang, Xizhen; Wang, Yong; Tang, Zhijiao; Jiang, Chunlai; Kong, Wei

2012-11-01

To evaluate regimens using bacillus Calmette-Guérin (BCG) or recombinant BCG (rBCG) overexpressing Ag85B for priming, followed by boosting with a modified vaccinia virus Ankara strain (MVA) and/or adenovirus vector (AD) expressing an Ag85B-ESAT6 fusion protein. Cellular and humoral immune responses were determined after subcutaneous vaccination, which was employed to trigger systemic immunity against intravenous infection in a mouse model of tuberculosis (TB). Bacterial loads and lung histology were evaluated. The relative IgG2a and IgG1 antibody levels indicated that the viral-vectored vaccines generated a T-helper type 1 (Th1)-biased response after two doses of viral boost vaccinations. Boosting BCG-primed mice with viral vaccines induced a Th1 immune response that included both CD4 and CD8 T-cells generating antigen-specific interferon-gamma (IFN-γ) and CD8 T cytotoxic activity. Only mice vaccinated with two different viral boosters after BCG priming exhibited a significant reduction in bacterial burden in the lung after challenge. Histology examinations confirmed the attenuation of lung damage and more compact granulomas. After mycobacteria priming, boosting with AD85B-E6 followed by MVA85B-E6 afforded better protection than the reverse order of administration of the viral vectors. This study demonstrates the potential of multiple heterologous viral booster vaccines, although the exact correlates of protection and optimal regimens should be further investigated for the rational design of future vaccine strategies. Copyright © 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

"Lay epidemiology": an important factor in Danish parents' decision of whether to allow their child to receive a BCG vaccination. A qualitative exploration of parental perspective.

PubMed

Pihl, Gitte Thybo; Johannessen, Helle; Ammentorp, Jette; Jensen, Jane Schmidt; Kofoed, Poul-Erik

2017-11-21

Vaccination is used worldwide to prevent infectious diseases. However, vaccination programmes in western countries face challenges in sustaining high coverage rates. The aim of this study was to explore how parents in Denmark make a decision about whether to allow their child to receive a Bacille Calmette Guerin vaccine at birth for the purpose of achieving non-specific effects on the immune system. A total of five focus groups were conducted with expectant mothers and fathers. Written information about the vaccine and information about the hypothesis of non-specific effects of the vaccine were delivered in order to discuss considerations and determinants of parents' decisions. Heritable factors and the possibility of stimulating the immune system of the child to achieve less atopic diseases and fewer infections were identified as arguments in favour of receiving the BCG vaccine. Arguments against receiving BCG mainly focused on concerns about its described and non-described side effects. Both arguments for and arguments against the vaccine were seen as parents attempt to make an individual risk evaluation for their child. Attitudes and beliefs in the local network were identified as important for parents' decisions. It is discussed how "lay epidemiology" characterizes parents' risk evaluation as an individual addition to the population-based risk declaration. It is furthermore discussed how health professionals should engage with both the empirical element and the value element of "Lay epidemiology". "Lay epidemiology" forms the basis for the parental decision of whether to allow their child to receive a BCG vaccination. Attitudes and beliefs about the causes and distribution of illnesses in the family or local network influence parents' risk evaluations. It would be ideal for parents if health professionals focused their communication about the BCG vaccine on individual risk evaluations.

Vaccination and All-Cause Child Mortality From 1985 to 2011: Global Evidence From the Demographic and Health Surveys

PubMed Central

McGovern, Mark E.; Canning, David

2015-01-01

Based on models with calibrated parameters for infection, case fatality rates, and vaccine efficacy, basic childhood vaccinations have been estimated to be highly cost effective. We estimated the association of vaccination with mortality directly from survey data. Using 149 cross-sectional Demographic and Health Surveys, we determined the relationship between vaccination coverage and the probability of dying between birth and 5 years of age at the survey cluster level. Our data included approximately 1 million children in 68,490 clusters from 62 countries. We considered the childhood measles, bacillus Calmette-Guérin, diphtheria-pertussis-tetanus, polio, and maternal tetanus vaccinations. Using modified Poisson regression to estimate the relative risk of child mortality in each cluster, we also adjusted for selection bias that resulted from the vaccination status of dead children not being reported. Childhood vaccination, and in particular measles and tetanus vaccination, is associated with substantial reductions in childhood mortality. We estimated that children in clusters with complete vaccination coverage have a relative risk of mortality that is 0.73 (95% confidence interval: 0.68, 0.77) times that of children in a cluster with no vaccinations. Although widely used, basic vaccines still have coverage rates well below 100% in many countries, and our results emphasize the effectiveness of increasing coverage rates in order to reduce child mortality. PMID:26453618

Vaccines Through Centuries: Major Cornerstones of Global Health

PubMed Central

Hajj Hussein, Inaya; Chams, Nour; Chams, Sana; El Sayegh, Skye; Badran, Reina; Raad, Mohamad; Gerges-Geagea, Alice; Leone, Angelo; Jurjus, Abdo

2015-01-01

Multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. The story began with Hippocrates 400 B.C. with his description of mumps and diphtheria. No further discoveries were recorded until 1100 A.D. when the smallpox vaccine was described. During the eighteenth century, vaccines for cholera and yellow fever were reported and Edward Jenner, the father of vaccination and immunology, published his work on smallpox. The nineteenth century was a major landmark, with the “Germ Theory of disease” of Louis Pasteur, the discovery of the germ tubercle bacillus for tuberculosis by Robert Koch, and the isolation of pneumococcus organism by George Miller Sternberg. Another landmark was the discovery of diphtheria toxin by Emile Roux and its serological treatment by Emil Von Behring and Paul Ehrlih. In addition, Pasteur was able to generate the first live-attenuated viral vaccine against rabies. Typhoid vaccines were then developed, followed by the plague vaccine of Yersin. At the beginning of World War I, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. In 1974, The Expanded Program of Immunization was established within the WHO for bacille Calmette–Guerin, Polio, DTP, measles, yellow fever, and hepatitis B. The year 1996 witnessed the launching of the International AIDS Vaccine Initiative. In 1988, the WHO passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. In 2010, “The Decade of vaccines” was launched, and on April 1st 2012, the United Nations launched the “shot@Life” campaign. In brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. This mini review highlights the major historical events and pioneers in the course of development

Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur.

PubMed

Berrêdo-Pinho, Marcia; Kalume, Dario E; Correa, Paloma R; Gomes, Leonardo H F; Pereira, Melissa P; da Silva, Renata F; Castello-Branco, Luiz R R; Degrave, Wim M; Mendonça-Lima, Leila

2011-04-20

Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB) and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO) affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE) and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs) from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3-8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa), Rv1926c (BCG1965c, Mpb63) and Rv1886c (BCG1923c, Ag85B) in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2) and Rv0350 (BCG0389, DnaK), show the opposite pattern. Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB.

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

PubMed Central

Jensen, Kara; dela Pena-Ponce, Myra Grace; Piatak, Michael; Shoemaker, Rebecca; Oswald, Kelli; Jacobs, William R.; Fennelly, Glenn; Lucero, Carissa; Mollan, Katie R.; Hudgens, Michael G.; Amedee, Angela; Kozlowski, Pamela A.; Estes, Jacob D.; Lifson, Jeffrey D.; Van Rompay, Koen K. A.; Larsen, Michelle

2016-01-01

ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. PMID:27655885

A novel vaccine p846 encoding Rv3615c, Mtb10.4, and Rv2660c elicits robust immune response and alleviates lung injury induced by Mycobacterium infection.

PubMed

Kong, Hongmei; Dong, Chunsheng; Xiong, Sidong

2014-01-01

Development of effective anti-tuberculosis (TB) vaccines is one of the important steps to improve control of TB. Cell-mediated immune response significantly affects the control of M. tuberculosis infection. Thus, vaccines able to elicit strong cellular immune response hold special advantages against TB. In this study, three well-defined mycobacterial antigens (Rv3615c, Mtb10.4 [Rv0228], and Rv2660c) were engineered as a novel triple-antigen fusion DNA vaccine p846. The p846 vaccine consists of a high density of CD4(+) and CD8(+) T-cell epitopes. Intramuscular immunization of p846 induced robust T cells mediated immune response comparable to that of bacillus Calmette-Guérin (BCG) vaccination but more effective than that of individual antigen vaccination. After mycobacterial challenge, p846 immunization decreased bacterial burden at least 15-fold compared with individual antigen-based vaccination. Notably, the lungs of mice immunized with p846 exhibited fewer inflammatory cell infiltrates and less damage than those of control group mice. Our data demonstrate that the potential of p846 vaccine to protect against TB and the feasibility of this design strategy for further TB vaccine development.

Comprehensive definition of human immunodominant CD8 antigens in tuberculosis.

PubMed

Lewinsohn, Deborah A; Swarbrick, Gwendolyn M; Park, Byung; Cansler, Meghan E; Null, Megan D; Toren, Katelynne G; Baseke, Joy; Zalwango, Sarah; Mayanja-Kizza, Harriet; Malone, LaShaunda L; Nyendak, Melissa; Wu, Guanming; Guinn, Kristi; McWeeney, Shannon; Mori, Tomi; Chervenak, Keith A; Sherman, David R; Boom, W Henry; Lewinsohn, David M

2017-01-01

Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with Mycobacterium tuberculosis , remains a leading cause of morbidity and mortality worldwide. As CD8 + T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8 + T cell response, an effective tuberculosis vaccine may need to induce CD8 + T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis. Herein, we report the results of the first ever HLA allele independent genome-wide CD8 antigen discovery program. Using CD8 + T cells derived from humans with latent tuberculosis infection or tuberculosis and an interferon-γ ELISPOT assay, we screened a synthetic peptide library representing 10% of the Mycobacterium tuberculosis proteome, selected to be enriched for Mycobacterium tuberculosis antigens. We defined a set of immunodominant CD8 antigens including part or all of 74 Mycobacterium tuberculosis proteins, only 16 of which are previously known CD8 antigens. Immunogenicity was associated with the degree of expression of mRNA and protein. Immunodominant antigens were enriched in cell wall proteins with preferential recognition of Esx protein family members, and within proteins comprising the Mycobacterium tuberculosis secretome. A validation study of immunodominant antigens demonstrated that these antigens were strongly recognized in Mycobacterium tuberculosis -infected individuals from a tuberculosis endemic region in Africa. The tuberculosis vaccine field will likely benefit from this greatly increased known repertoire of CD8 immunodominant antigens and definition of properties of Mycobacterium tuberculosis proteins important for CD8 antigenicity.

Naive helper T cells from BCG-vaccinated volunteers produce IFN-gamma and IL-5 to mycobacterial antigen-pulsed dendritic cells.

PubMed

Kowalewicz-Kulbat, Magdalena; Kaźmierczak, Dominik; Donevski, Stefan; Biet, Franck; Pestel, Joël; Rudnicka, Wiesława

2008-01-01

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a live vaccine that has been used in routine vaccination against tuberculosis for nearly 80 years. However, its efficacy is controversial. The failure of BCG vaccination may be at least partially explained by the induction of poor or inappropriate host responses. Dendritic cells (DCs) are likely to play a key role in the induction of immune response to mycobacteria by polarizing the reactivity of T lymphocytes toward a Th1 profile, contributing to the generation of protective cellular immunity against mycobacteria. In this study we aimed to investigate the production of Th1 and Th2 cytokines by naive CD4+ T cells to mycobacterial antigen-pulsed DCs in the group of young, healthy BCG vaccinated volunteers. The response of naive helper T cells was compared with the response of total blood lymphocytes. Our present results clearly showed that circulating naive CD45RA+CD4+ lymphocytes from BCG-vaccinated subjects can become effector helper cells producing IFN-gamma and IL-5 under the stimulation by autologous dendritic cells presenting mycobacterial protein antigen-PPD or infected with live M. bovis BCG bacilli.

Evaluation of bacille Calmette-Guérin immunisation programs in Australia.

PubMed

Khandaker, Gulam; Beard, Frank H; Dey, Aditi; Coulter, Chris; Hendry, Alexandra J; Macartney, Kristine K

2017-03-31

bacille Calmette-Guérin (BCG) immunisation programs in Australia are funded and operated by the individual states and territories. In recent years BCG vaccine shortages have required use of unregistered products. We aimed to evaluate BCG immunisation programs in Australia, with particular reference to program implementation and national consistency.
 Methods: Between September and November 2015, 12 key stakeholders, representing Australian states and territories, completed surveys. We analysed BCG vaccination coverage data from the Australian Childhood Immunisation Register (ACIR), and data on adverse events following immunisation (AEFI) with BCG vaccine from the Therapeutic Goods Administration's Adverse Drug Reactions System, for 2001 to 2014.
 Results: Access to BCG vaccination varies between jurisdictions, with some states providing this only in major city locations. Analysis of ACIR data suggests significant differences in vaccine delivery between jurisdictions, but varying levels of under-reporting to the ACIR were also acknowledged. The rate of BCG AEFI appeared to increase between 2011 and 2014; however, these data need to be interpreted with caution due to small numbers, likely under-reporting of both numerator (AEFI) and denominator (vaccine doses administered), and the general increase in reporting of AEFI related to other vaccines in children over this period.
 Conclusions: BCG immunisation programs aim to prevent severe forms of tuberculosis in young children who live in or travel to high burden settings. A range of factors, particularly inconsistent vaccine supply are leading to low, variable and inequitable vaccine delivery across Australian jurisdictions. Improved BCG vaccination uptake and AEFI data quality are required for accurate monitoring of program delivery and vaccine safety - this is particularly important given the current need to use unregistered vaccines. Improved and consistent access to BCG vaccine is suggested to optimise

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.

PubMed

Arts, Rob J W; Moorlag, Simone J C F M; Novakovic, Boris; Li, Yang; Wang, Shuang-Yin; Oosting, Marije; Kumar, Vinod; Xavier, Ramnik J; Wijmenga, Cisca; Joosten, Leo A B; Reusken, Chantal B E M; Benn, Christine S; Aaby, Peter; Koopmans, Marion P; Stunnenberg, Hendrik G; van Crevel, Reinout; Netea, Mihai G

2018-01-10

The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of fibronectin in intravesical BCG therapy for superficial bladder cancer.

PubMed

Ratliff, T L; Kavoussi, L R; Catalona, W J

1988-02-01

Intravesical bacillus Calmette-Guerin (BCG) has been demonstrated to be effective both for prophylaxis and treatment of superficial bladder cancer. In order to identify the progression of events that result in BCG-mediated antitumor activity, studies were performed to evaluate the mechanism of binding of BCG within the bladder. Histological and quantitative studies in a mouse model revealed that BCG attached to the bladder wall only in areas of urothelial damage. Preliminary in vitro data showed that BCG attached to surfaces coated with extracellular matrix proteins. Further studies were then performed using purified extracellular matrix proteins to identify the proteins responsible for attachment. BCG were observed to attach to surfaces coated only with purified fibronectin (FN) but not to other purified proteins including laminin, collagen or fibrinogen. The attachment of BCG to purified FN in vitro was dose dependent and was inhibited by anti-FN antibodies. Moreover, BCG attachment in vivo to bladders with damaged urothelial surfaces was inhibited more than 95% by anti-FN antibodies, but binding was not affected by anti-laminin antibodies or preimmune serum. A survey of commercially available BCG vaccines (Pasteur, Tice, Glaxo, Connaught) showed that only Glaxo BCG did not attach to FN-coated surfaces. Glaxo BCG also was shown to express inferior antitumor activity suggesting that the absence of FN binding by Glaxo may have been associated with the absence of antitumor activity of the vaccine.

THE IMMUNOPATHOBIOLOGY OF SYPHILIS: THE MANIFESTATIONS AND COURSE OF SYPHILIS ARE DETERMINED BY THE LEVEL OF DELAYED-TYPE HYPERSENSITIVITY

PubMed Central

Carlson, J. Andrew; Dabiri, Ganary; Cribier, Bernard; Sell, Stewart

2013-01-01

Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. While there has been a significant reduction of tertiary disease, and recognition of facilitative interactions with HIV infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and more importantly, activation of macrophages by sensitized CD4 T-cells. The Bacillus Calmette Guerin (BCG) vaccination can enhance DTH and has been shown to produce a low, but measurable beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response. PMID:21694502

Identification of proteins from Mycobacterium tuberculosis missing in attenuated Mycobacterium bovis BCG strains.

PubMed

Mattow, J; Jungblut, P R; Schaible, U E; Mollenkopf, H J; Lamer, S; Zimny-Arndt, U; Hagens, K; Müller, E C; Kaufmann, S H

2001-08-01

A proteome approach, combining high-resolution two-dimensional electrophoresis (2-DE) with mass spectrometry, was used to compare the cellular protein composition of two virulent strains of Mycobacterium tuberculosis with two attenuated strains of Mycobacterium bovis Bacillus Calmette-Guerin (BCG), in order to identify unique proteins of these strains. Emphasis was given to the identification of M. tuberculosis specific proteins, because we consider these proteins to represent putative virulence factors and interesting candidates for vaccination and diagnosis of tuberculosis. The genome of M. tuberculosis strain H37Rv comprises nearly 4000 predicted open reading frames. In contrast, the separation of proteins from whole mycobacterial cells by 2-DE resulted in silver-stained patterns comprising about 1800 distinct protein spots. Amongst these, 96 spots were exclusively detected either in the virulent (56 spots) or in the attenuated (40 spots) mycobacterial strains. Fifty-three of these spots were analyzed by mass spectrometry, of which 41 were identified, including 32 M. tuberculosis specific spots. Twelve M. tuberculosis specific spots were identified as proteins, encoded by genes previously reported to be deleted in M. bovis BCG. The remaining 20 spots unique for M. tuberculosis were identified as proteins encoded by genes that are not known to be missing in M. bovis BCG.

Co-infection of tuberculosis and parasitic diseases in humans: a systematic review

PubMed Central

2013-01-01

Co-infection of tuberculosis and parasitic diseases in humans is an important public problem in co-endemic areas in developing countries. However, there is a paucity of studies on co-infection and even fewer reviews. This review examines 44 appropriate papers by PRISMA from 289 papers searched in PubMed via the NCBI Entrez system (no grey literature) up to December 2012 in order to analyze the factors that influence epidemic and host’s immunity of co-infection. The limited evidence in this review indicates that most common parasite species are concurrent with Mycobacterium tuberculosis in multiple organs; socio-demographics such as gender and age, special populations with susceptibility such as renal transplant recipients, patients on maintenance haemodialysis, HIV positive patients and migrants, and living in or coming from co-endemic areas are all likely to have an impact on co-infection. Pulmonary tuberculosis and parasitic diseases were shown to be risk factors for each other. Co-infection may significantly inhibit the host’s immune system, increase antibacterial therapy intolerance and be detrimental to the prognosis of the disease; in addition, infection with parasitic diseases can alter the protective immune response to Bacillus Calmette-Guerin vaccination against Mycobacterium tuberculosis. PMID:23522098

[Complete genome sequencing and sequence analysis of BCG Tice].

PubMed

Wang, Zhiming; Pan, Yuanlong; Wu, Jun; Zhu, Baoli

2012-10-04

The objective of this study is to obtain the complete genome sequence of Bacillus Calmette-Guerin Tice (BCG Tice), in order to provide more information about the molecular biology of BCG Tice and design more reasonable vaccines to prevent tuberculosis. We assembled the data from high-throughput sequencing with SOAPdenovo software, with many contigs and scaffolds obtained. There are many sequence gaps and physical gaps remained as a result of regional low coverage and low quality. We designed primers at the end of contigs and performed PCR amplification in order to link these contigs and scaffolds. With various enzymes to perform PCR amplification, adjustment of PCR reaction conditions, and combined with clone construction to sequence, all the gaps were finished. We obtained the complete genome sequence of BCG Tice and submitted it to GenBank of National Center for Biotechnology Information (NCBI). The genome of BCG Tice is 4334064 base pairs in length, with GC content 65.65%. The problems and strategies during the finishing step of BCG Tice sequencing are illuminated here, with the hope of affording some experience to those who are involved in the finishing step of genome sequencing. The microarray data were verified by our results.

Gene Deletions in Mycobacterium bovis BCG Stimulate Increased CD8+ T Cell Responses

PubMed Central

Panas, Michael W.; Sixsmith, Jaimie D.; White, KeriAnn; Korioth-Schmitz, Birgit; Shields, Shana T.; Moy, Brian T.; Lee, Sunhee; Schmitz, Joern E.; Jacobs, William R.; Porcelli, Steven A.; Haynes, Barton F.; Letvin, Norman L.

2014-01-01

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8+ T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8+ T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8+ T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8+ T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. PMID:25287928

Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses.

PubMed

Panas, Michael W; Sixsmith, Jaimie D; White, KeriAnn; Korioth-Schmitz, Birgit; Shields, Shana T; Moy, Brian T; Lee, Sunhee; Schmitz, Joern E; Jacobs, William R; Porcelli, Steven A; Haynes, Barton F; Letvin, Norman L; Gillard, Geoffrey O

2014-12-01

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

[Hemocyanins as immunostimulants].

PubMed

Del Campo, Miguel; Arancibia, Sergio; Nova, Esteban; Salazar, Fabián; González, Andrea; Moltedo, Bruno; De Ioannes, Pablo; Ferreira, Jorge; Manubens, Augusto; Becker, María Inés

2011-02-01

Hemocyanins, the giant oxygen transporter glycoproteins of diverse mollusks, are xenogenic to the mammalian immune system and they display a remarkable immuno-genicity. Therefore they are ideal non-specific immunostimulants to treat some types of cancer. They are used as an alternative therapy for superficial urinary bladder cancer (SBC), that has been traditionally treated with Bacillus Calmette-Guerin (BCG). In contrast to BCG, hemocyanins do not cause side-effects, making them ideal for long-term repetitive treatments. Hemocyanins have also been exploited as carriers to develop antibodies against hapten molecules and peptides, as carrier-adjuvants for cutting-edge vaccines against cancer, drug addiction, and infectious diseases and in the diagnosis of parasitic diseases, such as Schistosomiasis. The hemocyanin from Megathura crenulata, also known as keyhole limpet hemocyanin (KLH), has been used for over thirty years for the purposes described above. More recently, hemoc yanin from the Chilean mollusk Concholepas concholepas (CCH) has proved to be a reliable alternative to KLH, either as carrier protein, and as a likely alternative for the immunotherapy of SBC. Despite KLH and CCH differ significantly in their origin and structure, we have demonstrated that both hemocyanins stimulate the immune system of mammals in a similar way by inducing a potent Thl-polarized cellular and humoral response.

Testing of a palatable bait and compatible vaccine carrier for the oral vaccination of European badgers (Meles meles) against tuberculosis.

PubMed

Gowtage, Sonya; Williams, Gareth A; Henderson, Ray; Aylett, Paul; MacMorran, Duncan; Palmer, Si; Robertson, Andy; Lesellier, Sandrine; Carter, Stephen P; Chambers, Mark A

2017-02-07

The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette-Guérin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log 10 reduction in titre after 117weeks' storage at -20°C. BCG stability in bait was also evaluated at +4°C and under simulated environmental conditions (20°C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Predictors of Vaccination in India for Children Aged 12-36 Months.

PubMed

Shrivastwa, Nijika; Gillespie, Brenda W; Kolenic, Giselle E; Lepkowski, James M; Boulton, Matthew L

2015-12-01

India has one of the lowest immunization rates worldwide despite a longstanding Universal Immunization Program (UIP) that provides free childhood vaccines. This study characterizes the predictors for under- and non-vaccination among Indian children aged 12-36 months. This study utilized District Level Household and Facility Survey Data, 2008 (DLHS3), from India. DLHS3 is a nationally representative sample collected from December 2007 through December 2008; this analysis was conducted during 2014. Children's vaccination status was categorized as fully, under-, and non-vaccinated based on whether children received all, some, or none of the UIP-recommended vaccines (one dose each of bacillus Calmette-Guérin and measles, and three doses of diphtheria-pertussis-tetanus). A multinomial logistic regression model estimated the odds of under-vaccination compared with full vaccination, and odds of non-vaccination compared with full vaccination. Analytic predictors included socioeconomic, cultural, household, maternal, and childhood characteristics. The analysis included 108,057 children; the estimated proportions of fully, under-, and non-vaccinated children were 57%, 31%, and 12%, respectively. After adjusting for state of residence, age, gender, household wealth, and maternal education, additional significant predictors of children's vaccination status were religion, caste, place of delivery, number of antenatal care visits, and maternal tetanus vaccination, all of which demonstrated large effect sizes. India's immunization coverage remained low in 2008, with just slightly more than half of all children aged 12-36 months fully vaccinated with UIP-recommended vaccines. A better understanding of the predictors for vaccination can help shape interventions to reduce disparities in full vaccination among children of differing demographic/cultural groups. Copyright © 2015 by American Journal of Preventive Medicine and Elsevier Ltd. Published by Elsevier Inc. All rights

Modulation of autophagy as a strategy for development of new vaccine candidates against tuberculosis.

PubMed

Flores-Valdez, Mario Alberto; Segura-Cerda, Cristian Alfredo; Gaona-Bernal, Jorge

2018-05-01

Effective prevention of tuberculosis (Tb) would undoubtedly be of paramount relevance in the control of its global burden, which resulted in more than 6 million new cases in 2016. Research aimed to improve the current vaccine, Bacillus Calmette- Guérin (BCG), or directed to develop new candidates, has taken into account the interaction between the host and Mycobacterium tuberculosis (Mtb). Recently, autophagy, an intracellular process of the host, has been shown to act as a mechanism that contributes to bacilli clearance in vitro and in vivo. Stimulation of autophagy, if correctly balanced, is an approach that has the potential to enhance the immune response of the host, and offers new avenues for developing immunogens that may give an improved protection upon immunization, given that in fact, some recent rBCG vaccine candidates have been shown to modulate autophagy. In this Discussion, we analyze the role of autophagy in the context of mycobacterial infection, its modulation via mycobacterial elements, and the management of host response as an alternative to develop new, hopefully improved, Tb-vaccine candidates. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guérin.

PubMed

Kelley, Keith W; O'Connor, Jason C; Lawson, Marcus A; Dantzer, Robert; Rodriguez-Zas, Sandra L; McCusker, Robert H

2013-08-01

Geriatric depression is a costly health issue, but little is known about its physiological underpinnings. Systemic inflammation sensitizes the innate immune system of aged animals and humans, but it is unknown if chronic, low-grade infections affect the duration of depressive-like behaviors. In this report, we infected adult (4-6 months) and aged (20-24 months) Balb/c mice with an attenuated strain of Mycobacterium bovis, Bacillus Calmette-Guérin (BCG), to induce a chronic infection. We then measured depression-like behaviors that have construct, face and predictive validity for human inflammation-associated clinical depression. Exposure to BCG caused acute sickness responses in both adult and aged mice. However, sickness behavior was prolonged in aged mice, as assessed by both locomotor and rearing activity. Two measures of depression-like behavior, which were tests involving sucrose preference and tail suspension, both showed that adult mice displayed depression-like behaviors at one day and seven days after exposure to BCG. However, aged mice continued to express both of these depression-like behaviors at three weeks following infection. Infection with BCG caused an increase in tryptophan catabolism, as evidenced by a significant rise in the plasma kynurenine/tryptophan ratio that peaked at 7 days post-infection. In aged mice, greater tryptophan catabolism persisted longer and remained elevated at 21 days post-infection. This finding is consistent with the prolonged duration of depression-like behaviors in aged mice. These are the first data using a chronic infection model to establish that recovery from inflammation-induced depression-like behavior and tryptophan catabolism are prolonged in aged animals. Copyright © 2013 Elsevier Inc. All rights reserved.

Increased B and T Cell Responses in M. bovis Bacille Calmette-Guérin Vaccinated Pigs Co-Immunized with Plasmid DNA Encoding a Prototype Tuberculosis Antigen

PubMed Central

Bruffaerts, Nicolas; Pedersen, Lasse E.; Vandermeulen, Gaëlle; Préat, Véronique; Stockhofe-Zurwieden, Norbert; Huygen, Kris; Romano, Marta

2015-01-01

The only tuberculosis vaccine currently available, bacille Calmette-Guérin (BCG) is a poor inducer of CD8+ T cells, which are particularly important for the control of latent tuberculosis and protection against reactivation. As the induction of strong CD8+ T cell responses is a hallmark of DNA vaccines, a combination of BCG with plasmid DNA encoding a prototype TB antigen (Ag85A) was tested. As an alternative animal model, pigs were primed with BCG mixed with empty vector or codon-optimized pAg85A by the intradermal route and boosted with plasmid delivered by intramuscular electroporation. Control pigs received unformulated BCG. The BCG-pAg85A combination stimulated robust and sustained Ag85A specific antibody, lymphoproliferative, IL-6, IL-10 and IFN-γ responses. IgG1/IgG2 antibody isotype ratio reflected the Th1 helper type biased response. T lymphocyte responses against purified protein derivative of tuberculin (PPD) were induced in all (BCG) vaccinated animals, but responses were much stronger in BCG-pAg85A vaccinated pigs. Finally, Ag85A-specific IFN-γ producing CD8+ T cells were detected by intracellular cytokine staining and a synthetic peptide, spanning Ag85A131-150 and encompassing two regions with strong predicted SLA-1*0401/SLA-1*0801 binding affinity, was promiscuously recognized by 6/6 animals vaccinated with the BCG-pAg85A combination. Our study provides a proof of concept in a large mammalian species, for a new Th1 and CD8+ targeting tuberculosis vaccine, based on BCG-plasmid DNA co-administration. PMID:26172261

Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine

PubMed Central

Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

2015-01-01

Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8+ epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6′-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4+ Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ+ CD8+ T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8+ T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine. PMID:25905680

Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine.

PubMed

Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

2015-01-01

Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8(+) epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6'-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4(+) Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ(+) CD8(+) T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8(+) T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine.

Prime-boost BCG vaccination with DNA vaccines based in β-defensin-2 and mycobacterial antigens ESAT6 or Ag85B improve protection in a tuberculosis experimental model

PubMed Central

Cervantes-Villagrana, Alberto R.; Hernández-Pando, Rogelio; Biragyn, Arya; Castañeda-Delgado, Julio; Bodogai, Monica; Martínez-Fierro, Margarita; Sada, Eduardo; Trujillo, Valentin; Enciso-Moreno, Antonio; Rivas-Santiago, Bruno

2018-01-01

The World Health Organization (WHO) has estimated that there are about 8 million new cases annually of active Tuberculosis (TB). Despite its irregular effectiveness (0–89%), the Bacillus Calmette-Guérin) BCG is the only vaccine available worldwide for prevention of TB; thus, the design is important of novel and more efficient vaccination strategies. Considering that β-defensin-2 is an antimicrobial peptide that induces dendritic cell maturation through the TLR-4 receptor and that both ESAT-6 and Ag85B are immunodominant mycobacterial antigens and efficient activators of the protective immune response, we constructed two DNA vaccines by the fusion of the gene encoding β-defensin-2 and antigens ESAT6 (pDE) and 85B (pDA). After confirming efficient local antigen expression that induced high and stable Interferon gamma (IFN-γ) production in intramuscular (i.m.) vaccinated Balb/c mice, groups of mice were vaccinated with DNA vaccines in a prime-boost regimen with BCG and with BCG alone, and 2 months later were challenged with the mild virulence reference strain H37Rv and the highly virulent clinical isolate LAM 5186. The level of protection was evaluated by survival, lung bacilli burdens, and extension of tissue damage (pneumonia). Vaccination with both DNA vaccines showed similar protection to that of BCG. After the challenge with the highly virulent Mycobacterium tuberculosis strain, animals that were prime-boosted with BCG and then boosted with both DNA vaccines showed significant higher survival and less tissue damage than mice vaccinated only with BCG. These results suggest that improvement of BCG vaccination, such as the prime-boost DNA vaccine, represents a more efficient vaccination scheme against TB. PMID:23196205

Prime-boost BCG vaccination with DNA vaccines based in β-defensin-2 and mycobacterial antigens ESAT6 or Ag85B improve protection in a tuberculosis experimental model.

PubMed

Cervantes-Villagrana, Alberto R; Hernández-Pando, Rogelio; Biragyn, Arya; Castañeda-Delgado, Julio; Bodogai, Monica; Martínez-Fierro, Margarita; Sada, Eduardo; Trujillo, Valentin; Enciso-Moreno, Antonio; Rivas-Santiago, Bruno

2013-01-11

The World Health Organization (WHO) has estimated that there are about 8 million new cases annually of active Tuberculosis (TB). Despite its irregular effectiveness (0-89%), the Bacillus Calmette-Guérin) BCG is the only vaccine available worldwide for prevention of TB; thus, the design is important of novel and more efficient vaccination strategies. Considering that β-defensin-2 is an antimicrobial peptide that induces dendritic cell maturation through the TLR-4 receptor and that both ESAT-6 and Ag85B are immunodominant mycobacterial antigens and efficient activators of the protective immune response, we constructed two DNA vaccines by the fusion of the gene encoding β-defensin-2 and antigens ESAT6 (pDE) and 85B (pDA). After confirming efficient local antigen expression that induced high and stable Interferon gamma (IFN-γ) production in intramuscular (i.m.) vaccinated Balb/c mice, groups of mice were vaccinated with DNA vaccines in a prime-boost regimen with BCG and with BCG alone, and 2 months later were challenged with the mild virulence reference strain H37Rv and the highly virulent clinical isolate LAM 5186. The level of protection was evaluated by survival, lung bacilli burdens, and extension of tissue damage (pneumonia). Vaccination with both DNA vaccines showed similar protection to that of BCG. After the challenge with the highly virulent Mycobacterium tuberculosis strain, animals that were prime-boosted with BCG and then boosted with both DNA vaccines showed significant higher survival and less tissue damage than mice vaccinated only with BCG. These results suggest that improvement of BCG vaccination, such as the prime-boost DNA vaccine, represents a more efficient vaccination scheme against TB. Copyright © 2012 Elsevier Ltd. All rights reserved.

Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis

PubMed Central

Gengenbacher, Martin; Nieuwenhuizen, Natalie; Vogelzang, Alexis; Liu, Haipeng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim

2016-01-01

ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. PMID:27222470

Modulation of fibronectin-mediated Bacillus Calmette-Guérin attachment to murine bladder mucosa by drugs influencing the coagulation pathways.

PubMed

Hudson, M A; Brown, E J; Ritchey, J K; Ratliff, T L

1991-07-15

Adjuvant intravesical Bacillus Calmette-Guérin (BCG) has proved to be an effective treatment for superficial bladder cancer. Intraluminal attachment of BCG organisms via binding to the extracellular matrix protein, fibronectin (FN), appears to be required for expression of the antitumor efficacy of BCG against a murine bladder tumor. Initial studies demonstrated that radiolabeled FN localized to the acutely injured urothelium but not to intact urothelium. These studies also demonstrated that exogenous administration of FN enhanced BCG attachment to the injured but not to the intact urothelium. Because FN has been shown to be an integral part of clot formation at sites of urothelial injury, drugs known to affect fibrin clot formation were tested for their effects on BCG attachment and antitumor efficacy in a murine bladder tumor model. A stabilizer of fibrin clot formation was shown to enhance both BCG attachment and antitumor efficacy in the same model. An increased number of BCG organisms were also retained in the lymph nodes and spleens of mice receiving fibrin clot stabilizers, suggesting indirectly that immunological mechanisms are involved in the antitumor efficacy of BCG. The data presented herein provide further support for the hypothesis that BCG attachment to the injured bladder is mediated by FN. Furthermore, modulation of BCG-FN attachment is demonstrated to be possible with drugs influencing the coagulation pathway. This attachment is shown to be required for the antitumor efficacy in a murine bladder tumor model, and thus modulation of BCG-FN attachment appears to have significant influence on the antitumor efficacy of BCG in the murine bladder tumor model.

Killed but metabolically active Bacillus anthracis vaccines induce broad and protective immunity against anthrax.

PubMed

Skoble, Justin; Beaber, John W; Gao, Yi; Lovchik, Julie A; Sower, Laurie E; Liu, Weiqun; Luckett, William; Peterson, Johnny W; Calendar, Richard; Portnoy, Daniel A; Lyons, C Rick; Dubensky, Thomas W

2009-04-01

Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which allowed inactive but immunogenic toxins to be produced. Photochemically inactivated vaccine strains maintained a high degree of metabolic activity and secreted protective antigen (PA), lethal factor, and edema factor. KBMA B. anthracis vaccines were avirulent in mice and induced less injection site inflammation than recombinant PA adsorbed to aluminum hydroxide gel. KBMA B. anthracis-vaccinated animals produced antibodies against numerous anthrax antigens, including high levels of anti-PA and toxin-neutralizing antibodies. Vaccination with KBMA B. anthracis fully protected mice against challenge with lethal doses of toxinogenic unencapsulated Sterne 7702 spores and rabbits against challenge with lethal pneumonic doses of fully virulent Ames strain spores. Guinea pigs vaccinated with KBMA B. anthracis were partially protected against lethal Ames spore challenge, which was comparable to vaccination with the licensed vaccine anthrax vaccine adsorbed. These data demonstrate that KBMA anthrax vaccines are well tolerated and elicit potent protective immune responses. The use of KBMA vaccines may be broadly applicable to bacterial pathogens, especially those for which the correlates of protective immunity are unknown.

Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis.

PubMed

Vordermeier, H Martin; Villarreal-Ramos, Bernardo; Cockle, Paul J; McAulay, Martin; Rhodes, Shelley G; Thacker, Tyler; Gilbert, Sarah C; McShane, Helen; Hill, Adrian V S; Xing, Zhou; Hewinson, R Glyn

2009-08-01

Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.

Alum-precipitated autoclaved Leishmania major plus bacille Calmette-Guérrin, a candidate vaccine for visceral leishmaniasis: safety, skin-delayed type hypersensitivity response and dose finding in healthy volunteers.

PubMed

Kamil, A A; Khalil, E A G; Musa, A M; Modabber, F; Mukhtar, M M; Ibrahim, M E; Zijlstra, E E; Sacks, D; Smith, P G; Zicker, F; El-Hassan, A M

2003-01-01

In a previous efficacy study, autoclaved Leishmania major (ALM) + bacille Calmette-Guérrin (BCG) vaccine was shown to be safe, but not superior to BCG alone, in protecting against visceral leishmaniasis. From June 1999 to June 2000, we studied the safety and immunogenicity of different doses of alum-precipitated ALM + BCG vaccine mixture administered intradermally to evaluate whether the addition of alum improved the immunogenicity of ALM. Twenty-four healthy adult volunteers were recruited and sequentially allocated to receive either 10 microg, 100 microg, 200 microg, or 400 microg of leishmanial protein in the alum-precipitated ALM + BCG vaccine mixture. Side effects were minimal for all doses and confined to the site of injection. All volunteers in the 10 microg, 100 microg, and 400 microg groups had a leishmanin skin test (LST) reaction of > or = 5 mm by day 42 and this response was maintained when tested after 90 d. Only 1 volunteer out of 5 in the 200 microg group had a LST reaction of > or = 5 mm by day 42 and the reasons for the different LST responses in this group are unclear. This is the first time that an alum adjuvant with ALM has been in used in humans and the vaccine mixture was safe and induced a strong delayed type hypersensitivity (DTH) reaction in the study volunteers. On the basis of this study we suggest that 100 1 microg of leishmanial protein in the vaccine mixture is a suitable dose for future efficacy studies, as it induced the strongest DTH reaction following vaccination.

Optimization and scale-up of cell culture and purification processes for production of an adenovirus-vectored tuberculosis vaccine candidate.

PubMed

Shen, Chun Fang; Jacob, Danielle; Zhu, Tao; Bernier, Alice; Shao, Zhongqi; Yu, Xuefeng; Patel, Mehul; Lanthier, Stephane; Kamen, Amine

2016-06-17

Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. The only available TB vaccine is the Bacille Calmette-Guerin (BCG). However, parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. AdAg85A, an adenoviral vector expressing the mycobacterial protein Ag85A, is a new tuberculosis vaccine candidate, and has shown promising results in pre-clinical studies and phase I trial. This adenovirus vectored vaccine is produced using HEK 293 cell culture. Here we report on the optimization of cell culture conditions, scale-up of production and purification of the AdAg85A at different scales. Four commercial serum-free media were evaluated under various conditions for supporting the growth of HEK293 cell and production of AdAg85A. A culturing strategy was employed to take advantages of two culture media with respective strengths in supporting the cell growth and virus production, which enabled to maintain virus productivity at higher cell densities and resulted in more than two folds of increases in culture titer. The production of AdAg85A was successfully scaled up and validated at 60L bioreactor under the optimal conditions. The AdAg85A generated from the 3L and 60L bioreactor runs was purified through several purification steps. More than 98% of total cellular proteins was removed, over 60% of viral particles was recovered after the purification process, and purity of AdAg85A was similar to that of the ATCC VR-1516 Ad5 standard. Vaccination of mice with the purified AdAg85A demonstrated a very good level of Ag85A-specific antibody responses. The optimized production and purification conditions were transferred to a GMP facility for manufacturing of AdAg85A for generation of clinical grade material to support clinical trials. Crown Copyright © 2016. Published by Elsevier Ltd. All rights

Chronic Mycobacterium infection of first dorsal web space after accidental Bacilli Calmette-Guérin injection in a health worker: case report.

PubMed

Vigler, Mordechai; Mulett, Hanan; Hausman, Michael R

2008-11-01

We present a case of inoculation of the first dorsal web space by a nurse practitioner who accidentally stuck herself while preparing Bacilli Calmette-Guérin vaccine for treatment of bladder tumor. We report the evolution and management of this resistant chronic Mycobacterium infection that ultimately required use of a vacuum wound management system followed by a microvascular free tissue transfer.

Mycobacterium bovis Bacille Calmette-Guérin Infection in the CNS Suppresses Experimental Autoimmune Encephalomyelitis and Th17 Responses in an IFN-gamma-independent Manner1

PubMed Central

Lee, JangEun; Reinke, Emily K.; Zozulya, Alla L.; Sandor, Matyas; Fabry, Zsuzsanna

2009-01-01

Multiple sclerosis (MS) and an animal model resembling MS, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases of the central nervous system (CNS) that are suppressed by systemic mycobacterial infection in mice and BCG vaccination in humans. Host defense responses against Mycobacterium in mice are influenced by T lymphocytes and their cytokine products, particularly IFN-γ, which plays a protective regulatory role in EAE. To analyze the counter-regulatory role of mycobacterial infection-induced IFN-γ in the CNS on the function of the pathological Th17 cells and the clinical outcome of EAE, we induced EAE in mice that were intracerebrally infected with Mycobacterium bovis bacille Calmette-Guerin (BCG). Here we demonstrate that intracerebral (i.c.) BCG infection prevented inflammatory cell recruitment to the spinal cord and suppressed the development of EAE. Concomitantly, there was a significant decrease in the frequency of MOG-specific IFN-γ-producing CD4+ T cells in the CNS. IL-17+CD4+ T cell responses were significantly suppressed in i.c. BCG-infected mice following EAE induction regardless of T cell specificity. The frequency of Foxp3+CD4+ T cells in these mice was equivalent to that of control mice. The i.c. BCG infection-induced protection of EAE and suppression of MOG-specific IL-17+CD4+ T cell responses were similar in both wild type (WT) and IFN-γ deficient mice. These data show that live BCG infection in the brain suppresses CNS autoimmunity. These findings also reveal that the regulation of Th17-mediated autoimmunity in the CNS can be independent of IFN-γ-mediated mechanisms. PMID:18941210

Detection of circulating Mycobacterium tuberculosis-specific DNA by droplet digital PCR for vaccine evaluation in challenged monkeys and TB diagnosis.

PubMed

Song, Neng; Tan, Yang; Zhang, Lingyun; Luo, Wei; Guan, Qing; Yan, Ming-Zhe; Zuo, Ruiqi; Liu, Weixiang; Luo, Feng-Ling; Zhang, Xiao-Lian

2018-04-24

Mycobacterium tuberculosis (M. tb) is emerging as a more serious pathogen due to the increased multidrug-resistant TB and co-infection of human immunodeficiency virus (HIV). The development of an effective and sensitive detection method is urgently needed for bacterial load evaluation in vaccine development, early TB diagnosis, and TB treatment. Droplet digital polymerase chain reaction (ddPCR) is a newly developed sensitive PCR method for the absolute quantification of nucleic acid concentrations. Here, we used ddPCR to quantify the circulating virulent M. tb-specific CFP10 (10-kDa culture filtrate protein, Rv3874) and Rv1768 DNA copy numbers in the blood samples from Bacille Calmette-Guerin (BCG)-vaccinated and/or virulent M. tb H37Rv-challenged rhesus monkeys. We found that ddPCR was more sensitive compared to real-time fluorescence quantitative PCR (qPCR), as the detection limits of CFP10 were 1.2 copies/μl for ddPCR, but 15.8 copies/μl for qPCR. We demonstrated that ddPCR could detect CFP10 and Rv1768 DNA after 3 weeks of infection and at least two weeks earlier than qPCR in M.tb H37Rv-challenged rhesus monkey models. DdPCR could also successfully quantify CFP10 and Rv1768 DNA copy numbers in clinical TB patients' blood samples (active pulmonary TB, extrapulmonary TB (EPTB), and infant TB). To our knowledge, this study is the first to demonstrate that ddPCR is an effective and sensitive method of measuring the circulating CFP10 and Rv1768 DNA for vaccine development, bacterial load evaluation in vivo, and early TB (including EPTB and infant TB) diagnosis as well.

Interruption of persistent exposure to leprosy combined or not with recent BCG vaccination enhances the response to Mycobacterium leprae specific antigens.

PubMed

de Carvalho, Fernanda Marques; Rodrigues, Luciana Silva; Duppre, Nádia Cristina; Alvim, Iris Maria Peixoto; Ribeiro-Alves, Marcelo; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal; Pereira, Geraldo Moura Batista

2017-05-01

Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-β, IL-6, IL-17, TNF, IFN-γ, MIP1-β, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through "trained immunity", that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens.

Interruption of persistent exposure to leprosy combined or not with recent BCG vaccination enhances the response to Mycobacterium leprae specific antigens

PubMed Central

de Carvalho, Fernanda Marques; Rodrigues, Luciana Silva; Duppre, Nádia Cristina; Alvim, Iris Maria Peixoto; Ribeiro-Alves, Marcelo; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal

2017-01-01

Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-β, IL-6, IL-17, TNF, IFN-γ, MIP1-β, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through “trained immunity”, that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens. PMID:28467415

Vaccination and all-cause child mortality from 1985 to 2011: global evidence from the Demographic and Health Surveys.

PubMed

McGovern, Mark E; Canning, David

2015-11-01

Based on models with calibrated parameters for infection, case fatality rates, and vaccine efficacy, basic childhood vaccinations have been estimated to be highly cost effective. We estimated the association of vaccination with mortality directly from survey data. Using 149 cross-sectional Demographic and Health Surveys, we determined the relationship between vaccination coverage and the probability of dying between birth and 5 years of age at the survey cluster level. Our data included approximately 1 million children in 68,490 clusters from 62 countries. We considered the childhood measles, bacillus Calmette-Guérin, diphtheria-pertussis-tetanus, polio, and maternal tetanus vaccinations. Using modified Poisson regression to estimate the relative risk of child mortality in each cluster, we also adjusted for selection bias that resulted from the vaccination status of dead children not being reported. Childhood vaccination, and in particular measles and tetanus vaccination, is associated with substantial reductions in childhood mortality. We estimated that children in clusters with complete vaccination coverage have a relative risk of mortality that is 0.73 (95% confidence interval: 0.68, 0.77) times that of children in a cluster with no vaccinations. Although widely used, basic vaccines still have coverage rates well below 100% in many countries, and our results emphasize the effectiveness of increasing coverage rates in order to reduce child mortality. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Nitric Oxide and KLF4 Protein Epigenetically Modify Class II Transactivator to Repress Major Histocompatibility Complex II Expression during Mycobacterium bovis Bacillus Calmette-Guérin Infection*

PubMed Central

Ghorpade, Devram Sampat; Holla, Sahana; Sinha, Akhauri Yash; Alagesan, Senthil Kumar; Balaji, Kithiganahalli Narayanaswamy

2013-01-01

Pathogenic mycobacteria employ several immune evasion strategies such as inhibition of class II transactivator (CIITA) and MHC-II expression, to survive and persist in host macrophages. However, precise roles for specific signaling components executing down-regulation of CIITA/MHC-II have not been adequately addressed. Here, we demonstrate that Mycobacterium bovis bacillus Calmette-Guérin (BCG)-mediated TLR2 signaling-induced iNOS/NO expression is obligatory for the suppression of IFN-γ-induced CIITA/MHC-II functions. Significantly, NOTCH/PKC/MAPK-triggered signaling cross-talk was found critical for iNOS/NO production. NO responsive recruitment of a bifunctional transcription factor, KLF4, to the promoter of CIITA during M. bovis BCG infection of macrophages was essential to orchestrate the epigenetic modifications mediated by histone methyltransferase EZH2 or miR-150 and thus calibrate CIITA/MHC-II expression. NO-dependent KLF4 regulated the processing and presentation of ovalbumin by infected macrophages to reactive T cells. Altogether, our study delineates a novel role for iNOS/NO/KLF4 in dictating the mycobacterial capacity to inhibit CIITA/MHC-II-mediated antigen presentation by infected macrophages and thereby elude immune surveillance. PMID:23733190

Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur

PubMed Central

2011-01-01

Background Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB) and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO) affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE) and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs) from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. Results The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3 - 8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa), Rv1926c (BCG1965c, Mpb63) and Rv1886c (BCG1923c, Ag85B) in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2) and Rv0350 (BCG0389, DnaK), show the opposite pattern. Conclusions Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB. PMID:21507239

Effectiveness of Routine BCG Vaccination on Buruli Ulcer Disease: A Case-Control Study in the Democratic Republic of Congo, Ghana and Togo

PubMed Central

Phillips, Richard Odame; Phanzu, Delphin Mavinga; Beissner, Marcus; Badziklou, Kossi; Luzolo, Elysée Kalundieko; Sarfo, Fred Stephen; Halatoko, Wemboo Afiwa; Amoako, Yaw; Frimpong, Michael; Kabiru, Abass Mohammed; Piten, Ebekalisai; Maman, Issaka; Bidjada, Bawimodom; Koba, Adjaho; Awoussi, Koffi Somenou; Kobara, Basile; Nitschke, Jörg; Wiedemann, Franz Xaver; Kere, Abiba Banla; Adjei, Ohene; Löscher, Thomas; Fleischer, Bernhard; Bretzel, Gisela; Herbinger, Karl-Heinz

2015-01-01

Background The only available vaccine that could be potentially beneficial against mycobacterial diseases contains live attenuated bovine tuberculosis bacillus (Mycobacterium bovis) also called Bacillus Calmette-Guérin (BCG). Even though the BCG vaccine is still widely used, results on its effectiveness in preventing mycobacterial diseases are partially contradictory, especially regarding Buruli Ulcer Disease (BUD). The aim of this case-control study is to evaluate the possible protective effect of BCG vaccination on BUD. Methodology The present study was performed in three different countries and sites where BUD is endemic: in the Democratic Republic of the Congo, Ghana, and Togo from 2010 through 2013. The large study population was comprised of 401 cases with laboratory confirmed BUD and 826 controls, mostly family members or neighbors. Principal Findings After stratification by the three countries, two sexes and four age groups, no significant correlation was found between the presence of BCG scar and BUD status of individuals. Multivariate analysis has shown that the independent variables country (p = 0.31), sex (p = 0.24), age (p = 0.96), and presence of a BCG scar (p = 0.07) did not significantly influence the development of BUD category I or category II/III. Furthermore, the status of BCG vaccination was also not significantly related to duration of BUD or time to healing of lesions. Conclusions In our study, we did not observe significant evidence of a protective effect of routine BCG vaccination on the risk of developing either BUD or severe forms of BUD. Since accurate data on BCG strains used in these three countries were not available, no final conclusion can be drawn on the effectiveness of BCG strain in protecting against BUD. As has been suggested for tuberculosis and leprosy, well-designed prospective studies on different existing BCG vaccine strains are needed also for BUD. PMID:25569674

Lactoferrin modulation of BCG-infected dendritic cell functions

PubMed Central

Hwang, Shen-An

2009-01-01

Lactoferrin, an 80-kDa iron-binding protein with immune modulating properties, is a unique adjuvant component able to enhance efficacy of the existing Mycobacterium bovis Bacillus Calmette Guerin (BCG) vaccine to protect against murine model of tuberculosis. Although identified as having effects on macrophage presentation events, lactoferrin's capability to modulate dendritic cells (DCs) function when loaded with BCG antigens has not been previously recognized. In this study, the potential of lactoferrin to modulate surface expression of MHC II, CD80, CD86 and CD40 from bone marrow-derived dendritic cells (BMDCs) was examined. Generally, lactoferrin decreased pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, IL-6 and IL-12p40] and chemokines [macrophage inflammatory protein (MIP)-1α and MIP-2] and increased regulatory cytokine, transforming growth factor-β1 and a T-cell chemotatic factor, monocyte chemotactic protein-1, from uninfected or BCG-infected BMDCs. Culturing BCG-infected BMDCs with lactoferrin also enhanced their ability to respond to IFN-γ activation through up-regulation of maturation markers: MHC I, MHC II and the ratio of CD86:CD80 surface expression. Furthermore, lactoferrin-exposed BCG-infected DCs increased stimulation of BCG-specific CD3+CD4+ splenocytes, as defined by increasing IFN-γ production. Finally, BCG-/lactoferrin-vaccinated mice possessed an increased pool of BCG antigen-specific IFN-γ producing CD3+CD4+CD62L− splenocytes. These studies suggest a mechanism in which lactoferrin may exert adjuvant activity by enhancing DC function to promote generation of antigen-specific T cells. PMID:19692539

Adjuvant Intravesical Bacillus Calmette-Guérin Therapy and Survival Among Elderly Patients With Non–Muscle-Invasive Bladder Cancer

PubMed Central

Spencer, Benjamin A.; McBride, Russell B.; Hershman, Dawn L.; Buono, Donna; Herr, Harry W.; Benson, Mitchell C.; Gupta-Mohile, Supriya; Neugut, Alfred I.

2013-01-01

Purpose: National guidelines recommend adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy for higher-risk non–muscle-invasive bladder cancer (NMIBC). Although a survival benefit has not been demonstrated, randomized trials have shown reduced recurrence and delayed progression after its use. We investigated predictors of BCG receipt and its association with survival for older patients with NMIBC. Patients and Methods: We identified individuals with NMIBC registered in the Surveillance, Epidemiology, and End Results–Medicare database from 1991 to 2003. We used logistic regression to compare those treated with BCG within 6 months of initial diagnosis with those not treated, adjusting for demographic and clinical factors. Cox proportional hazards modeling was used to analyze the association between BCG and overall survival (OS) and bladder cancer–specific survival (BCSS) for the entire cohort and within tumor grades. Results: Of 23,932 patients with NMIBC identified, 22% received adjuvant intravesical BCG. Predictors of receipt were stages Tis and T1, higher grade, and urban residence. Age > 80 years, fewer than two comorbidities, and not being married were associated with decreased use. In the survival analysis, BCG use was associated with better OS (hazard ratio [HR], 0.87; 95% CI, 0.83 to 0.92) in the entire cohort and BCSS among higher-grade cancers (poorly differentiated: HR, 0.78; 95% CI, 0.72 to 0.85; undifferentiated: HR, 0.66; 95% CI, 0.56 to 0.77). Conclusion: Despite guidelines recommending its use, BCG is administered to less than one quarter of eligible patients. This large population-based study found improved OS and BCSS were associated with use of adjuvant intravesical BCG among older patients with NMIBC. Better-designed clinical trials focusing on higher-grade cancers are needed to confirm these findings. PMID:23814517

Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: a systematic review.

PubMed

Zuiverloon, Tahlita C M; Nieuweboer, Annemieke J M; Vékony, Hedvig; Kirkels, Wim J; Bangma, Chris H; Zwarthoff, Ellen C

2012-01-01

Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response. To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies. We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature. If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing. Copyright © 2011 European Association of Urology

Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations.

PubMed

Ritz, Nicole; Mui, Milton; Balloch, Anne; Curtis, Nigel

2013-06-26

Bacille Calmette-Guérin (BCG) is one of the most commonly administered vaccines worldwide. In addition to protection against tuberculosis (TB), evidence suggests that BCG immunisation has a number of additional beneficial non-specific immunological effects. These include a reduction in overall infant and child mortality attributable to causes other than TB in high-mortality regions. The antibody response to immunisations provides an opportunity to investigate the influence of BCG on the immune response to unrelated antigens. This study compared the antibody response to routine immunisations in BCG-immunised and non-BCG-immunised infants. BCG-immunised infants were recruited from a related study in which BCG was given at birth and non-BCG-immunised infants were recruited from immunisation clinics. All infants received their routine immunisations according to the Australian National Immunisation Program. Concentrations of antibodies against pneumococcal (anti-Pn Ps), Haemophilus influenzae type B (anti-Hib), tetanus toxoid (anti-TT) and hepatitis B surface (anti-HBs) antigen were measured four weeks after the last (six month) set of infant immunisations. A total of 127 parents agreed for their infants to take part in the study of which 108 were included in the final analysis (56 BCG-immunised and 52 non-BCG-immunised). The geometric mean concentration (GMC) of anti-Pn Ps IgG for all serotypes, anti-Hib IgG and anti-TT IgG were higher in the BCG-immunised group than the non-BCG-immunised group. This difference reached statistical significance for serotype 9V (p<0.01) and 18C (p=0.04). The GMC of anti-HBs IgG was lower in the BCG-immunised group than the non-BCG-immunised group (p=0.03). The majority of participants in both groups had antibody levels above the protective threshold. BCG immunisation at birth influences the antibody response to routine immunisations administered later in infancy. This has important implications for the introduction of both pneumococcal

Impact of PGL-I Seropositivity on the Protective Effect of BCG Vaccination among Leprosy Contacts: A Cohort Study

PubMed Central

Düppre, Nádia C.; Camacho, Luiz Antonio B.; Sales, Anna M.; Illarramendi, Ximena; Nery, José Augusto C.; Sampaio, Elizabeth P.; Sarno, Euzenir N.; Bührer-Sékula, Samira

2012-01-01

Background Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I) antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied the effect of seropositivity in patient contacts, on the risk of developing leprosy, stratified by Bacille Calmette Guerin (BCG) vaccination after index case diagnosis. Methodology/Principal Findings Leprosy contacts were examined as part of the surveillance programme of the Oswaldo Cruz Institute Leprosy Outpatient Clinic in Rio de Janeiro. Demographic, social, epidemiological and clinical data were collected. The presence of IgM antibodies to PGL-I in sera and BCG vaccination status at the time of index case diagnosis were evaluated in 2,135 contacts. During follow-up, 60 (2.8%; 60/2,135) leprosy cases were diagnosed: 41 among the 1,793 PGL-I-negative contacts and 19 among the 342 PGL-I-positive contacts. Among PGL-I-positive contacts, BCG vaccination after index case diagnosis increased the adjusted rate of developing clinical manifestations of leprosy (Adjusted Rate Ratio (aRR) = 4.1; 95% CI: 1.8–8.2) compared with the PGL-I-positive unvaccinated contacts (aRR = 3.2; 95% CI: 1.2–8.1). The incidence density was highest during the first year of follow-up for the PGL-I-positive vaccinated contacts. However, all of those contacts developed PB leprosy, whereas most MB cases (4/6) occurred in PGL-I-positive unvaccinated contacts. Conclusion Contact examination combined with PGL-I testing and BCG vaccination remain important strategies for leprosy control. The finding that rates of leprosy cases were highest among seropositive contacts justifies targeting this specific group for close monitoring. Furthermore, it is recommended that PGL-I-positive contacts and contacts with a high familial bacteriological index, regardless of

Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

PubMed Central

Aguiló, N; Uranga, S; Marinova, D; Martín, C; Pardo, J

2014-01-01

Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis. PMID:25032866

Exposure to human alveolar lining fluid enhances Mycobacterium bovis BCG vaccine efficacy against Mycobacterium tuberculosis infection in a CD8+ T-cell-dependent manner.

PubMed

Moliva, J I; Hossfeld, A P; Canan, C H; Dwivedi, V; Wewers, M D; Beamer, G; Turner, J; Torrelles, J B

2018-05-01

Current tuberculosis (TB) treatments include chemotherapy and preventative vaccination with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In humans, however, BCG vaccination fails to fully protect against pulmonary TB. Few studies have considered the impact of the human lung mucosa (alveolar lining fluid (ALF)), which modifies the Mycobacterium tuberculosis (M.tb) cell wall, revealing alternate antigenic epitopes on the bacterium surface that alter its pathogenicity. We hypothesized that ALF-induced modification of BCG would induce better protection against aerosol infection with M.tb. Here we vaccinated mice with ALF-exposed BCG, mimicking the mycobacterial cell surface properties that would be present in the lung during M.tb infection. ALF-exposed BCG-vaccinated mice were more effective at reducing M.tb bacterial burden in the lung and spleen, and had reduced lung inflammation at late stages of M.tb infection. Improved BCG efficacy was associated with increased numbers of memory CD8 + T cells, and CD8 + T cells with the potential to produce interferon-γ in the lung in response to M.tb challenge. Depletion studies confirmed an essential role for CD8 + T cells in controlling M.tb bacterial burden. We conclude that ALF modifications to the M.tb cell wall in vivo are relevant in the context of vaccine design.

Role of the private sector in vaccination service delivery in India: evidence from private-sector vaccine sales data, 2009-12.

PubMed

Sharma, Abhishek; Kaplan, Warren A; Chokshi, Maulik; Zodpey, Sanjay P

2016-09-01

India's Universal Immunization Programme (UIP) provides basic vaccines free-of-cost in the public sector, yet national vaccination coverage is poor. The Government of India has urged an expanded role for the private sector to help achieve universal immunization coverage. We conducted a state-by-state analysis of the role of the private sector in vaccinating Indian children against each of the six primary childhood diseases covered under India's UIP. We analyzed IMS Health data on Indian private-sector vaccine sales, 2011 Indian Census data and national household surveys (DHS/NFHS 2005-06 and UNICEF CES 2009) to estimate the percentage of vaccinated children among the 2009-12 birth cohort who received a given vaccine in the private sector in 16 Indian states. We also analyzed the estimated private-sector vaccine shares as function of state-specific socio-economic status. Overall in 16 states, the private sector contributed 4.7% towards tuberculosis (Bacillus Calmette-Guérin (BCG)), 3.5% towards measles, 2.3% towards diphtheria-pertussis-tetanus (DPT3) and 7.6% towards polio (OPV3) overall (both public and private sectors) vaccination coverage. Certain low income states (Uttar Pradesh, Rajasthan, Madhya Pradesh, Orissa, Assam and Bihar) have low private as well as public sector vaccination coverage. The private sector's role has been limited primarily to the high income states as opposed to these low income states where the majority of Indian children live. Urban areas with good access to the private sector and the ability to pay increases the Indian population's willingness to access private-sector vaccination services. In India, the public sector offers vaccination services to the majority of the population but the private sector should not be neglected as it could potentially improve overall vaccination coverage. The government could train and incentivize a wider range of private-sector health professionals to help deliver the vaccines, especially in the low

Effect of the bacillus of Calmette-Guérin, Propionibacter acnes and avridine as immunomodulators in antirabies vaccination of mice using the Fuenzalida-Palacios mouse brain vaccine.

PubMed

Megid, J; Peraçolli, M T; Curi, P R; Zanetti, C R; Cabrera, W H; Vassao, R; Ito, F H

1999-05-14

Using the laboratory mice, Fuenzalida-Palacios mouse brain human rabies vaccine was administered in groups of animals previously inoculated with rabies virus and then submitted to treatments with the immunomodulators onco-BCG, avridine and Propionibacterium acnes. Humoral and cellular immune responses were evaluated through the macrophage inhibition factor (MIF), intra-pad inoculation (IPI) and serum neutralization (SN) tests and by the detection of gamma-interferon (IFN-gamma). The IPI test was not effective in detecting the response of delayed-type hypersensitivity, contrary to MIF, which showed the immune cellular response. Higher levels of IFN-gamma were observed in the groups of mice vaccinated and treated with avridine and P. acnes. Although immunomodulating activities have been detected, the use of adjuvants with the Fuenzalida-Palacios type vaccine in mice did not reveal any encouraging results.

Factors associated with routine immunization coverage of children under one year old in Lao People's Democratic Republic.

PubMed

Phoummalaysith, Bounfeng; Yamamoto, Eiko; Xeuatvongsa, Anonh; Louangpradith, Viengsakhone; Keohavong, Bounxou; Saw, Yu Mon; Hamajima, Nobuyuki

2018-05-03

Routine vaccination is administered free of charge to all children under one year old in Lao People's Democratic Republic (Lao PDR) and the national goal is to achieve at least 95% coverage with all vaccines included in the national immunization program by 2025. In this study, factors related to the immunization system and characteristics of provinces and districts in Lao PDR were examined to evaluate the association with routine immunization coverage. Coverage rates for Bacillus Calmette-Guerin (BCG), Diphtheria-Tetanus-Pertussis-Hepatitis B (DTP-HepB), DTP-HepB-Hib (Haemophilus influenzae type B), polio (OPV), and measles (MCV1) vaccines from 2002 to 2014 collected through regular reporting system, were used to identify the immunization coverage trends in Lao PDR. Correlation analysis was performed using immunization coverage, characteristics of provinces or districts (population, population density, and proportion of poor villages and high-risk villages), and factors related to immunization service (including the proportions of the following: villages served by health facility levels, vaccine session types, and presence of well-functioning cold chain equipment). To determine factors associated with low coverage, provinces were categorized based on 80% of DTP-HepB-Hib3 coverage (<80% = low group; ≥80% = high group). Coverages of BCG, DTP-HepB3, OPV3 and MCV1 increased gradually from 2007 to 2014 (82.2-88.3% in 2014). However, BCG coverage showed the least improvement from 2002 to 2014. The coverage of each vaccine correlated with the coverage of the other vaccines and DTP-HepB-Hib dropout rate in provinces as well as districts. The provinces with low immunization coverage were correlated with higher proportions of poor villages. Routine immunization coverage has been improving in the last 13 years, but the national goal is not yet reached in Lao PDR. The results of this study suggest that BCG coverage and poor villages should be targeted to improve

Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.

PubMed Central

Jouanguy, E; Lamhamedi-Cherradi, S; Altare, F; Fondanèche, M C; Tuerlinckx, D; Blanche, S; Emile, J F; Gaillard, J L; Schreiber, R; Levin, M; Fischer, A; Hivroz, C; Casanova, J L

1997-01-01

Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis. PMID:9389728

Comparative analysis of the immunologic response induced by the Sterne 34F2 live spore Bacillus anthracis vaccine in a ruminant model.

PubMed

Ndumnego, Okechukwu C; Köhler, Susanne M; Crafford, Jannie; van Heerden, Henriette; Beyer, Wolfgang

2016-10-01

The Sterne 34F2 live spore vaccine (SLSV) developed in 1937 is the most widely used veterinary vaccine against anthrax. However, literature on the immunogenicity of this vaccine in a target ruminant host is scarce. In this study, we evaluated the humoral response to the Bacillus anthracis protective antigen (rPA), a recombinant bacillus collagen-like protein of anthracis (rBclA), formaldehyde inactivated spores (FIS) prepared from strain 34F2 and a vegetative antigen formulation prepared from a capsule and toxin deficient strain (CDC 1014) in Boer goats. The toxin neutralizing ability of induced antibodies was evaluated using an in vitro toxin neutralization assay. The protection afforded by the vaccine was also assessed in vaccinates. Anti-rPA, anti-FIS and lethal toxin neutralizing titres were superior after booster vaccinations, compared to single vaccinations. Qualitative analysis of humoral responses to rPA, rBclA and FIS antigens revealed a preponderance of anti-FIS IgG titres following either single or double vaccinations with the SLSV. Antibodies against FIS and rPA both increased by 350 and 300-fold following revaccinations respectively. There was no response to rBclA following vaccinations with the SLSV. Toxin neutralizing titres increased by 80-fold after single vaccination and 700-fold following a double vaccination. Lethal challenge studies in naïve goats indicated a minimum infective dose of 36 B. anthracis spores. Single and double vaccination with the SLSV protected 4/5 and 3/3 of goats challenged with>800 spores respectively. An early booster vaccination following the first immunization is suggested in order to achieve a robust immunity. Results from this study indicate that this crucial second vaccination can be administered as early as 3 months after the initial vaccination. Copyright © 2016 Elsevier B.V. All rights reserved.

Combining blue native polyacrylamide gel electrophoresis with liquid chromatography tandem mass spectrometry as an effective strategy for analyzing potential membrane protein complexes of Mycobacterium bovis bacillus Calmette-Guérin

PubMed Central

2011-01-01

Background Tuberculosis is an infectious bacterial disease in humans caused primarily by Mycobacterium tuberculosis, and infects one-third of the world's total population. Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine has been widely used to prevent tuberculosis worldwide since 1921. Membrane proteins play important roles in various cellular processes, and the protein-protein interactions involved in these processes may provide further information about molecular organization and cellular pathways. However, membrane proteins are notoriously under-represented by traditional two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and little is known about mycobacterial membrane and membrane-associated protein complexes. Here we investigated M. bovis BCG by an alternative proteomic strategy coupling blue native PAGE to liquid chromatography tandem mass spectrometry (LC-MS/MS) to characterize potential protein-protein interactions in membrane fractions. Results Using this approach, we analyzed native molecular composition of protein complexes in BCG membrane fractions. As a result, 40 proteins (including 12 integral membrane proteins), which were organized in 9 different gel bands, were unambiguous identified. The proteins identified have been experimentally confirmed using 2-D SDS PAGE. We identified MmpL8 and four neighboring proteins that were involved in lipid transport complexes, and all subunits of ATP synthase complex in their monomeric states. Two phenolpthiocerol synthases and three arabinosyltransferases belonging to individual operons were obtained in different gel bands. Furthermore, two giant multifunctional enzymes, Pks7 and Pks8, and four mycobacterial Hsp family members were determined. Additionally, seven ribosomal proteins involved in polyribosome complex and two subunits of the succinate dehydrogenase complex were also found. Notablely, some proteins with high hydrophobicity or multiple transmembrane helixes were identified well

Vaccine Adverse Events Reported during the First Ten Years (1998–2008) after Introduction in the State of Rondonia, Brazil

PubMed Central

Cunha, Mônica P. L.; Dórea, José G.; Marques, Rejane C.; Leão, Renata S.

2013-01-01

Despite good safety records, vaccines given to young children can cause adverse events. We investigated the reported adverse events following immunization (AEFI) of vaccines given to children of less than seven years of age during the first ten years (1998 to 2008) in the state of Rondonia, Brazil. We worked with the events related to BCG (Bacillus Calmett-Guérin), HB (hepatitis B), DTwP/Hib (diphtheria-tetanus-pertussis+Hemophillus influenza b), DTP (diphtheria-tetanus-pertussis), MMR (mumps, measles, rubella), and YF (yellow fever) vaccines because they were part of the recommended scheme. The number of doses of vaccines given was 3,231,567 with an average of AEFI of 57.2/year during the studied period. DTwP/Hib was responsible for 298 (57.8%), DTP 114 (22.9%), HB 31 (6%), MMR 28 (5.4%), BCG 24 (4.7%), and YF 20 (3.9%) of the reported AEFI. The combination of the AEFI for DTwP/Hib vaccines showed the highest number of systemic (61.4%) and local events (33.8%). Young children (≤1-year old) were more susceptible to AEFI occurring in the 6 hours (54.2%) following vaccine uptake. This study suggests significant differences in reactogenicity of vaccines and that despite limitations of the AEFI Brazilian registry system we cannot ignore underreporting and should use the system to expand our understanding of adverse events and effects. PMID:23509790

In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin is due principally to trehalose mycolates.

PubMed

Geisel, Rachel E; Sakamoto, Kaori; Russell, David G; Rhoades, Elizabeth R

2005-04-15

The hallmark of Mycobacterium-induced pathology is granulomatous inflammation at the site of infection. Mycobacterial lipids are potent immunomodulators that contribute to the granulomatous response and are released in appreciable quantities by intracellular bacilli. Previously we investigated the granulomagenic nature of the peripheral cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin (BCG) by coating the lipids onto 90-microm diameter microspheres that were mixed into Matrigel matrix with syngeneic bone marrow-derived macrophages and injected i.p. into mice. These studies demonstrated that BCG lipids elicit proinflammatory cytokines and recruit leukocytes. In the current study we determined the lipids responsible for this proinflammatory effect. BCG-derived cell wall lipids were fractionated and purified by liquid chromatography and preparative TLC. The isolated fractions including phosphatidylinositol dimannosides, cardiolipin, phosphatidylglycerol, phosphatidylethanolamine, trehalose monomycolate, trehalose dimycolate, and mycoside B. Trehalose dimycolate, when delivered to bone marrow-derived murine macrophages, induced the greatest secretion of IL-1beta, IL-6, and TNF-alpha in vitro. Trehalose dimycolate similarly induced the greatest secretion of these proinflammatory cytokines in ex vivo matrices over the course of 12 days. Trehalose monomycolate and dimycolate also induced profound neutrophil recruitment in vivo. Experiments with TLR2 or TLR4 gene-deficient mice revealed no defects in responses to trehalose mycolates, although MyD88-deficient mice manifested significantly reduced cell recruitment and cytokine production. These results demonstrate that the trehalose mycolates, particularly trehalose dimycolate, are the most bioactive lipids in the BCG extract, inducing a proinflammatory cascade that influences granuloma formation.

Vaccine Platform for Prevention of Tuberculosis and Mother-to-Child Transmission of Human Immunodeficiency Virus Type 1 through Breastfeeding▿

PubMed Central

Im, Eung-Jun; Saubi, Narcís; Virgili, Goretti; Sander, Clare; Teoh, Denise; Gatell, Jose M.; McShane, Helen; Joseph, Joan; Hanke, Tomáš

2007-01-01

Most children in Africa receive their vaccine against tuberculosis at birth. Those infants born to human immunodeficiency virus type 1 (HIV-1)-positive mothers are at high risk of acquiring HIV-1 infection through breastfeeding in the first weeks of their lives. Thus, the development of a vaccine which would protect newborns against both of these major global killers is a logical yet highly scientifically, ethically, and practically challenging aim. Here, a recombinant lysine auxotroph of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a BCG strain that is safer than those currently used and expresses an African HIV-1 clade-derived immunogen, was generated and shown to be stable and to induce durable, high-quality HIV-1-specific CD4+- and CD8+-T-cell responses. Furthermore, when the recombinant BCG vaccine was used in a priming-boosting regimen with heterologous components, the HIV-1-specific responses provided protection against surrogate virus challenge, and the recombinant BCG vaccine alone protected against aerosol challenge with M. tuberculosis. Thus, inserting an HIV-1-derived immunogen into the scheduled BCG vaccine delivered at or soon after birth may prime HIV-1-specific responses, which can be boosted by natural exposure to HIV-1 in the breast milk and/or by a heterologous vaccine such as recombinant modified vaccinia virus Ankara delivering the same immunogen, and decrease mother-to-child transmission of HIV-1 during breastfeeding. PMID:17596303

Vaccine coverage and adherence to EPI schedules in eight resource poor settings in the MAL-ED cohort study.

PubMed

Hoest, Christel; Seidman, Jessica C; Lee, Gwenyth; Platts-Mills, James A; Ali, Asad; Olortegui, Maribel Paredes; Bessong, Pascal; Chandyo, Ram; Babji, Sudhir; Mohan, Venkata Raghava; Mondal, Dinesh; Mahfuz, Mustafa; Mduma, Estomih R; Nyathi, Emanuel; Abreu, Claudia; Miller, Mark A; Pan, William; Mason, Carl J; Knobler, Stacey L

2017-01-11

Launched in 1974, the Expanded Program on Immunization (EPI) is estimated to prevent two-three million deaths annually from polio, diphtheria, tuberculosis, pertussis, measles, and tetanus. Additional lives could be saved through better understanding what influences adherence to the EPI schedule in specific settings. The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study followed cohorts in eight sites in South Asia, Africa, and South America and monitored vaccine receipt over the first two years of life for the children enrolled in the study. Vaccination histories were obtained monthly from vaccination cards, local clinic records and/or caregiver reports. Vaccination histories were compared against the prescribed EPI schedules for each country, and coverage rates were examined in relation to the timing of vaccination. The influence of socioeconomic factors on vaccine timing and coverage was also considered. Coverage rates for EPI vaccines varied between sites and by type of vaccine; overall, coverage was highest in the Nepal and Bangladesh sites and lowest in the Tanzania and Brazil sites. Bacillus Calmette-Guérin coverage was high across all sites, 87-100%, whereas measles vaccination rates ranged widely, 73-100%. Significant delays between the scheduled administration age and actual vaccination date were present in all sites, especially for measles vaccine where less than 40% were administered on schedule. A range of socioeconomic factors were significantly associated with vaccination status in study children but these results were largely site-specific. Our findings highlight the need to improve measles vaccination rates and reduce delayed vaccination to achieve EPI targets related to the establishment of herd immunity and reduction in disease transmission. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Potential Benefits of Cattle Vaccination as a Supplementary Control for Bovine Tuberculosis

PubMed Central

Conlan, Andrew J. K.; Brooks Pollock, Ellen; McKinley, Trevelyan J.; Mitchell, Andrew P.; Jones, Gareth J.; Vordermeier, Martin; Wood, James L. N.

2015-01-01

Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers’ willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post

Cruciferous vegetables, isothiocyanates, and prevention of bladder cancer

PubMed Central

Veeranki, Omkara L.; Bhattacharya, Arup; Tang, Li; Marshall, James R.; Zhang, Yuesheng

2015-01-01

Approximately 80% of human bladder cancers (BC) are non-muscle invasive when first diagnosed and are usually treated by transurethral tumor resection. But 50–80% of patients experience cancer recurrence. Agents for prevention of primary BC have yet to be identified. Existing prophylactics against BC recurrence, e.g., Bacillus Calmette-Guerin (BCG), have limited efficacy and utility; they engender significant side effects and require urethral catheterization. Many cruciferous vegetables, rich sources of isothiocyanates (ITCs), are commonly consumed by humans. Many ITCs possess promising chemopreventive activities against BC and its recurrence. Moreover, orally ingested ITCs are selectively delivered to bladder via urinary excretion. This review is focused on urinary delivery of ITCs to the bladder, their cellular uptake, their chemopreventive activities in preclinical and epidemiological studies that are particularly relevant to prevention of BC recurrence and progression, and their chemopreventive mechanisms in BC cells and tissues. PMID:26273545

A New Recombinant BCG Vaccine Induces Specific Th17 and Th1 Effector Cells with Higher Protective Efficacy against Tuberculosis

PubMed Central

da Costa, Adeliane Castro; Costa-Júnior, Abadio de Oliveira; de Oliveira, Fábio Muniz; Nogueira, Sarah Veloso; Rosa, Joseane Damaceno; Resende, Danilo Pires; Kipnis, André; Junqueira-Kipnis, Ana Paula

2014-01-01

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that is a major public health problem. The vaccine used for TB prevention is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which provides variable efficacy in protecting against pulmonary TB among adults. Consequently, several groups have pursued the development of a new vaccine with a superior protective capacity to that of BCG. Here we constructed a new recombinant BCG (rBCG) vaccine expressing a fusion protein (CMX) composed of immune dominant epitopes from Ag85C, MPT51, and HspX and evaluated its immunogenicity and protection in a murine model of infection. The stability of the vaccine in vivo was maintained for up to 20 days post-vaccination. rBCG-CMX was efficiently phagocytized by peritoneal macrophages and induced nitric oxide (NO) production. Following mouse immunization, this vaccine induced a specific immune response in cells from lungs and spleen to the fusion protein and to each of the component recombinant proteins by themselves. Vaccinated mice presented higher amounts of Th1, Th17, and polyfunctional specific T cells. rBCG-CMX vaccination reduced the extension of lung lesions caused by challenge with Mtb as well as the lung bacterial load. In addition, when this vaccine was used in a prime-boost strategy together with rCMX, the lung bacterial load was lower than the result observed by BCG vaccination. This study describes the creation of a new promising vaccine for TB that we hope will be used in further studies to address its safety before proceeding to clinical trials. PMID:25398087

Toward Novel Vaccines Against Tuberculosis: Current Hopes and Obstacles

PubMed Central

Thaiss, Christoph A.; Kaufmann, Stefan H.E.

2010-01-01

Approximately 2 million people die of tuberculosis (TB) each year. The current vaccine, Bacille Calmette-Guérin (BCG), albeit widely employed, does not protect against adult pulmonary disease, and new vaccines are urgently needed to reduce the incidence of TB worldwide. New insights into the cellular and molecular mechanisms that underlie the interactions between Mycobacterium tuberculosis and its host have been exploited to develop novel vaccine candidates that recently have entered clinical trials. This review provides a brief overview of different approaches toward a new vaccination strategy and summarizes major challenges for the next decade. PMID:21165340

Next-Generation Bacillus anthracis Live Attenuated Spore Vaccine Based on the htrA- (High Temperature Requirement A) Sterne Strain

PubMed Central

Chitlaru, Theodor; Israeli, Ma’ayan; Bar-Haim, Erez; Elia, Uri; Rotem, Shahar; Ehrlich, Sharon; Cohen, Ofer; Shafferman, Avigdor

2016-01-01

Anthrax is a lethal disease caused by the gram-positive spore-producing bacterium Bacillus anthracis. Live attenuated vaccines, such as the nonencapsulated Sterne strain, do not meet the safety standards mandated for human use in the Western world and are approved for veterinary purposes only. Here we demonstrate that disrupting the htrA gene, encoding the chaperone/protease HtrA (High Temperature Requirement A), in the virulent Bacillus anthracis Vollum strain results in significant virulence attenuation in guinea pigs, rabbits and mice, underlying the universality of the attenuated phenotype associated with htrA knockout. Accordingly, htrA disruption was implemented for the development of a Sterne-derived safe live vaccine compatible with human use. The novel B. anthracis SterneΔhtrA strain secretes functional anthrax toxins but is 10–104-fold less virulent than the Sterne vaccine strain depending on animal model (mice, guinea pigs, or rabbits). In spite of this attenuation, double or even single immunization with SterneΔhtrA spores elicits immune responses which target toxaemia and bacteremia resulting in protection from subcutaneous or respiratory lethal challenge with a virulent strain in guinea pigs and rabbits. The efficacy of the immune-protective response in guinea pigs was maintained for at least 50 weeks after a single immunization. PMID:26732659

Bacillus anthracis virulence in Guinea pigs vaccinated with anthrax vaccine adsorbed is linked to plasmid quantities and clonality.

PubMed

Coker, Pamala R; Smith, Kimothy L; Fellows, Patricia F; Rybachuck, Galena; Kousoulas, Konstantin G; Hugh-Jones, Martin E

2003-03-01

Bacillus anthracis is a bacterial pathogen of great importance, both historically and in the present. This study presents data collected from several investigations and indicates that B. anthracis virulence is associated with the clonality and virulence of plasmids pXO1 and pXO2. Guinea pigs vaccinated with Anthrax Vaccine Adsorbed were challenged with 20 B. anthracis isolates representative of worldwide genetic diversity. These same isolates were characterized with respect to plasmid copy number by using a novel method of quantitative PCR developed for rapid and efficient detection of B. anthracis from environmental samples. We found that the copy numbers for both pXO1 and pXO2 differed from those in previously published reports. By combining the data on survival, plasmid copy numbers, and clonality, we developed a model predicting virulence. This model was validated by using a randomly chosen set of 12 additional B. anthracis isolates. Results from this study will be helpful in future efforts to elucidate the basis for variation in the virulence of this important pathogen.

Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations

PubMed Central

Abdallah, Abdallah M.; Hill-Cawthorne, Grant A.; Otto, Thomas D.; Coll, Francesc; Guerra-Assunção, José Afonso; Gao, Ge; Naeem, Raeece; Ansari, Hifzur; Malas, Tareq B.; Adroub, Sabir A.; Verboom, Theo; Ummels, Roy; Zhang, Huoming; Panigrahi, Aswini Kumar; McNerney, Ruth; Brosch, Roland; Clark, Taane G.; Behr, Marcel A.; Bitter, Wilbert; Pain, Arnab

2015-01-01

Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains. PMID:26487098

Analysis of factors associated with development of Bacille Calmette-Guérin inoculation site change in patients with Kawasaki disease.

PubMed

Araki, Tooru; Kodera, Aya; Kitada, Kunimi; Fujiwara, Michimasa; Muraoka, Michiko; Abe, Yoshiko; Ikeda, Masanori; Tsukahara, Hirokazu

2018-04-01

Objective The present study was performed to identify factors associated with a Bacille Calmette-Guérin (BCG) inoculation site change in patients with Kawasaki disease (KD). Methods Among patients who had received BCG vaccination and treatment for KD at our hospital from 2005 through 2016, 177 patients born in 2005 through 2016 were enrolled. The patients were divided into those with (n = 83, change group) and without (n = 94, no-change group) a BCG site change, and the patient demographics, clinical severity, blood examination results, and echocardiographic findings were compared between the two groups. Results The change group was younger at onset and had a shorter interval from vaccination to onset. A BCG site change was observed in patients who developed the onset of KD symptoms from 31 to 806 days after BCG vaccination. Multivariate analysis showed that the interval from vaccination was closely and positively associated with the BCG site change (hazard ratio = 0.995, 95% confidence interval = 0.993-0.997). Conclusion A BCG site change in patients with KD is most closely associated with the interval from BCG vaccination to onset.

Use of recombinant purified protein derivative (PPD) antigens as specific skin test for tuberculosis.

PubMed

Stavri, Henriette; Bucurenci, Nadia; Ulea, Irina; Costache, Adriana; Popa, Loredana; Popa, Mircea Ioan

2012-11-01

Purified protein derivative (PPD) is currently the only available skin test reagent used worldwide for the diagnosis of tuberculosis (TB). The aim of this study was to develop a Mycobacterium tuberculosis specific skin test reagent, without false positive results due to Bacillus Calmette-Guerin (BCG) vaccination using recombinant antigens. Proteins in PPD IC-65 were analyzed by tandem mass spectrometry and compared to proteins in M. tuberculosis culture filtrate; 54 proteins were found in common. Top candidates MPT64, ESAT 6, and CFP 10 were overexpressed in Escherichia coli expression strains and purified as recombinant proteins. To formulate optimal immunodiagnostic PPD cocktails, the antigens were evaluated by skin testing guinea pigs sensitized with M. tuberculosis H37Rv and BCG. For single antigens and a cocktail mixture of these antigens, best results were obtained using 3 μg/0.1 ml, equivalent to 105 TU (tuberculin units). Each animal was simultaneously tested with PPD IC-65, 2 TU/0.1 ml, as reference. Reactivity of the multi-antigen cocktail was greater than that of any single antigen. The skin test results were between 34.3 and 76.6 per cent the level of reactivity compared to that of the reference when single antigens were tested and 124 per cent the level of reactivity compared to the reference for the multi-antigen cocktail. Our results showed that this specific cocktail could represent a potential candidate for a new skin diagnostic test for TB.

Coverage of childhood vaccination among children aged 12-23 months, Tamil Nadu, 2015, India.

PubMed

Murhekar, Manoj V; Kamaraj, P; Kanagasabai, K; Elavarasu, G; Rajasekar, T Daniel; Boopathi, K; Mehendale, Sanjay

2017-03-01

District-Level Household Survey-4 (DLHS-4) indicated that during 2012-2013, only 56 per cent of children aged 12-23 months in Tamil Nadu were fully vaccinated, which were lesser than those reported in earlier national surveys. We, therefore, conducted cluster surveys to estimate coverage of childhood vaccination in the State, and also to identify the factors associated with low coverage. Cross-sectional surveys were conducted in 15 strata [municipal corporation non-slum (n=1), municipal corporation slum (n=1), hilly (n=1), rural (n=6) and urban (n=6)]. From each stratum, 30 clusters were selected using probability proportional to the population size linear systematic sampling; seven children aged 12-23 months were selected from each cluster and their mothers/care-takers were interviewed to collect information about vaccination status of the child. A child was considered fully vaccinated if he/she received bacillus Calmette-Guérin (BCG), three doses of pentavalent, three doses of oral polio vaccine and one dose of measles vaccine, and appropriately vaccinated if all vaccine doses were given at right age and with right interval. Further, coverage of fully vaccinated children (FVC) as per vaccination cards or mothers' recall, validated coverage of FVC (V-FVC) among those having cards, and coverage of appropriately vaccinated children (AVC) were estimated using survey data analysis module with appropriate sampling weights. A total of 3150 children were surveyed, of them 2528 (80.3%) had vaccination card. The weighted coverage of FVC, V-FVC and AVC in the State was 79.9 per cent [95% confidence interval (CI): 78.2-81.5], 78.8 per cent (95% CI: 76.9-80.5) and 69.7 per cent (95% CI: 67.7-71.7), respectively. The coverage of individual vaccine ranged between 84 per cent (measles) and 99.8 per cent (BCG). About 12 per cent V-FVC were not vaccinated as per the vaccination schedule. The coverage of FVC in Tamil Nadu was high, with about 80 per cent children completing

Vesicular Stomatitis Virus-Vectored Multi-Antigen Tuberculosis Vaccine Limits Bacterial Proliferation in Mice following a Single Intranasal Dose

PubMed Central

Zhang, Ming; Dong, Chunsheng; Xiong, Sidong

2017-01-01

Tuberculosis (TB) remains a serious health problem worldwide, and an urgent need exists to improve or replace the available vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG). Most vaccination protocols adapt two or three doses to induce long-term lasting immunity. Our previous study showed that the naked DNA encoding the triple-antigen fusion TFP846 (Rv3615c-Mtb10.4-Rv2660c) induced robust T cellular immune responses accompanying four inoculations against mycobacteria infection. However, a number of compliance issues exist in some areas lacking the appropriate medical infrastructure with multiple administrations. In this study, a novel vesicular stomatitis virus expressing TFP846 (VSV-846) was developed and the immune responses elicited by VSV-846 were evaluated. We observed that intranasal delivery of VSV-846 induced a potent antigen-specific T cell response following a single dose and VSV-846 efficiently controlled bacterial growth to levels ~10-fold lower than that observed in the mock group 6 weeks post-infection in BCG-infected mice. Importantly, mice immunized with VSV-846 provided long-term protection against mycobacteria infection compared with those receiving p846 or BCG immunization. Increased memory T cells were also observed in the spleens of VSV-846-vaccinated mice, which could be a potential mechanism associated with long-term protective immune response. These findings supported the use of VSV as an antigen delivery vector with the potential for TB vaccine development. PMID:28224119

Immunological changes in canine peripheral blood leukocytes triggered by immunization with first or second generation vaccines against canine visceral leishmaniasis.

PubMed

Araújo, Márcio Sobreira Silva; de Andrade, Renata Aline; Sathler-Avelar, Renato; Magalhães, Camila Paula; Carvalho, Andréa Teixeira; Andrade, Mariléia Chaves; Campolina, Sabrina Sidney; Mello, Maria Norma; Vianna, Leonardo Rocha; Mayrink, Wilson; Reis, Alexandre Barbosa; Malaquias, Luiz Cosme Cotta; Rocha, Luciana Morais; Martins-Filho, Olindo Assis

2011-05-15

In this study, we summarized the major phenotypic/functional aspects of circulating leukocytes following canine immunization with Leishvaccine and Leishmune®. Our findings showed that Leishvaccine triggered early changes in the innate immunity (neutrophils and eosinophils) with late alterations on monocytes. Conversely, Leishmune(®) induced early phenotypic changes in both, neutrophils and monocytes. Moreover, Leishvaccine triggered mixed activation-related phenotypic changes on T-cells (CD4+ and CD8+ and B-lymphocytes, whereas Leishmune(®) promoted a selective response, mainly associated with CD8+ T-cell activation. Mixed cytokine profile (IFN-γ/IL-4) was observed in Leishvaccine immunized dogs whereas a selective pro-inflammatory pattern (IFN-γ/NO) was induced by Leishmune® vaccination. The distinct immunological profile triggered by Leishvaccine and Leishmune® may be a direct consequence of the distinct biochemical composition of these immunobiological, i.e. complex versus purified Leishmania antigen along with Bacillus Calmette-Guérin (BCG) versus saponin adjuvant. Both immunobiologicals are able to activate phagocytes and CD8+ T-cells and therefore could be considered as a putative vaccines against canine visceral leishmaniasis (CVL). Copyright © 2011 Elsevier B.V. All rights reserved.

Over-Expression of the Mycobacterial Trehalose-Phosphate Phosphatase OtsB2 Results in a Defect in Macrophage Phagocytosis Associated with Increased Mycobacterial-Macrophage Adhesion

PubMed Central

Li, Hao; Wu, Mei; Shi, Yan; Javid, Babak

2016-01-01

Trehalose-6-phosphate phosphatase (OtsB2) is involved in the OtsAB trehalose synthesis pathway to produce free trehalose and is strictly essential for mycobacterial growth. We wished to determine the effects of OtsB2 expression on mycobacterial phenotypes such as growth, phagocytosis and survival in macrophages. Mycobacterium bovis-bacillus calmette-guerin (BCG) over-expressing OtsB2 were able to better survive in stationary phase. Over-expression of OtsB2 led to a decrease in phagocytosis but not survival in THP-1 macrophage-like cells, and this was not due to a decrease in general macrophage phagocytic activity. Surprisingly, when we investigated macrophage–mycobacterial interactions by flow cytometry and atomic force microscopy, we discovered that BCG over-expressing OtsB2 have stronger binding to THP-1 cells than wild-type BCG. These results suggest that altering OtsB2 expression has implications for mycobacterial host–pathogen interactions. Macrophage–mycobacteria phagocytic interactions are complex and merit further study. PMID:27867377

Intravital Fluorescence Excitation in Whole-Animal Optical Imaging.

PubMed

Nooshabadi, Fatemeh; Yang, Hee-Jeong; Bixler, Joel N; Kong, Ying; Cirillo, Jeffrey D; Maitland, Kristen C

2016-01-01

Whole-animal fluorescence imaging with recombinant or fluorescently-tagged pathogens or cells enables real-time analysis of disease progression and treatment response in live animals. Tissue absorption limits penetration of fluorescence excitation light, particularly in the visible wavelength range, resulting in reduced sensitivity to deep targets. Here, we demonstrate the use of an optical fiber bundle to deliver light into the mouse lung to excite fluorescent bacteria, circumventing tissue absorption of excitation light in whole-animal imaging. We present the use of this technology to improve detection of recombinant reporter strains of tdTomato-expressing Mycobacterium bovis BCG (Bacillus Calmette Guerin) bacteria in the mouse lung. A microendoscope was integrated into a whole-animal fluorescence imager to enable intravital excitation in the mouse lung with whole-animal detection. Using this technique, the threshold of detection was measured as 103 colony forming units (CFU) during pulmonary infection. In comparison, the threshold of detection for whole-animal fluorescence imaging using standard epi-illumination was greater than 106 CFU.

Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge.

PubMed

Sivko, G S; Stark, G V; Tordoff, K P; Taylor, K L; Glaze, E; VanRaden, M; Schiffer, J M; Hewitt, J A; Quinn, C P; Nuzum, E O

2016-12-12

Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD 50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment of different formulations of oral Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine in rodent models for immunogenicity and protection against aerosol challenge with M. bovis.

PubMed

Clark, Simon; Cross, Martin L; Smith, Alan; Court, Pinar; Vipond, Julia; Nadian, Allan; Hewinson, R Glyn; Batchelor, Hannah K; Perrie, Yvonne; Williams, Ann; Aldwell, Frank E; Chambers, Mark A

2008-10-29

Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Meles meles) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guérin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery

Proteomic profiling and identification of immunodominant spore antigens of Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis.

PubMed

Delvecchio, Vito G; Connolly, Joseph P; Alefantis, Timothy G; Walz, Alexander; Quan, Marian A; Patra, Guy; Ashton, John M; Whittington, Jessica T; Chafin, Ryan D; Liang, Xudong; Grewal, Paul; Khan, Akbar S; Mujer, Cesar V

2006-09-01

Differentially expressed and immunogenic spore proteins of the Bacillus cereus group of bacteria, which includes Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis, were identified. Comparative proteomic profiling of their spore proteins distinguished the three species from each other as well as the virulent from the avirulent strains. A total of 458 proteins encoded by 232 open reading frames were identified by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis for all the species. A number of highly expressed proteins, including elongation factor Tu (EF-Tu), elongation factor G, 60-kDa chaperonin, enolase, pyruvate dehydrogenase complex, and others exist as charge variants on two-dimensional gels. These charge variants have similar masses but different isoelectric points. The majority of identified proteins have cellular roles associated with energy production, carbohydrate transport and metabolism, amino acid transport and metabolism, posttranslational modifications, and translation. Novel vaccine candidate proteins were identified using B. anthracis polyclonal antisera from humans postinfected with cutaneous anthrax. Fifteen immunoreactive proteins were identified in B. anthracis spores, whereas 7, 14, and 7 immunoreactive proteins were identified for B. cereus and in the virulent and avirulent strains of B. thuringiensis spores, respectively. Some of the immunodominant antigens include charge variants of EF-Tu, glyceraldehyde-3-phosphate dehydrogenase, dihydrolipoamide acetyltransferase, Delta-1-pyrroline-5-carboxylate dehydrogenase, and a dihydrolipoamide dehydrogenase. Alanine racemase and neutral protease were uniquely immunogenic to B. anthracis. Comparative analysis of the spore immunome will be of significance for further nucleic acid- and immuno-based detection systems as well as next-generation vaccine development.

Proteomic Profiling and Identification of Immunodominant Spore Antigens of Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis‡

PubMed Central

DelVecchio, Vito G.; Connolly, Joseph P.; Alefantis, Timothy G.; Walz, Alexander; Quan, Marian A.; Patra, Guy; Ashton, John M.; Whittington, Jessica T.; Chafin, Ryan D.; Liang, Xudong; Grewal, Paul; Khan, Akbar S.; Mujer, Cesar V.

2006-01-01

Differentially expressed and immunogenic spore proteins of the Bacillus cereus group of bacteria, which includes Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis, were identified. Comparative proteomic profiling of their spore proteins distinguished the three species from each other as well as the virulent from the avirulent strains. A total of 458 proteins encoded by 232 open reading frames were identified by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis for all the species. A number of highly expressed proteins, including elongation factor Tu (EF-Tu), elongation factor G, 60-kDa chaperonin, enolase, pyruvate dehydrogenase complex, and others exist as charge variants on two-dimensional gels. These charge variants have similar masses but different isoelectric points. The majority of identified proteins have cellular roles associated with energy production, carbohydrate transport and metabolism, amino acid transport and metabolism, posttranslational modifications, and translation. Novel vaccine candidate proteins were identified using B. anthracis polyclonal antisera from humans postinfected with cutaneous anthrax. Fifteen immunoreactive proteins were identified in B. anthracis spores, whereas 7, 14, and 7 immunoreactive proteins were identified for B. cereus and in the virulent and avirulent strains of B. thuringiensis spores, respectively. Some of the immunodominant antigens include charge variants of EF-Tu, glyceraldehyde-3-phosphate dehydrogenase, dihydrolipoamide acetyltransferase, Δ-1-pyrroline-5-carboxylate dehydrogenase, and a dihydrolipoamide dehydrogenase. Alanine racemase and neutral protease were uniquely immunogenic to B. anthracis. Comparative analysis of the spore immunome will be of significance for further nucleic acid- and immuno-based detection systems as well as next-generation vaccine development. PMID:16957262

Surface display of Clonorchis sinensis enolase on Bacillus subtilis spores potentializes an oral vaccine candidate.

PubMed

Wang, Xiaoyun; Chen, Wenjun; Tian, Yanli; Mao, Qiang; Lv, Xiaoli; Shang, Mei; Li, Xuerong; Yu, Xinbing; Huang, Yan

2014-03-10

Clonorchis sinensis (C. sinensis) infections remain the common public health problem in freshwater fish consumption areas. New effective prevention strategies are still the urgent challenges to control this kind of foodborne infectious disease. The biochemical importance and biological relevance render C. sinensis enolase (Csenolase) as a potential vaccine candidate. In the present study, we constructed Escherichia coli/Bacillus subtilis shuttle genetic engineering system and investigated the potential of Csenolase as an oral vaccine candidate for C. sinensis prevention in different immunization routes. Our results showed that, compared with control groups, both recombinant Csenolase protein and nucleic acid could induce a mixed IgG1/IgG2a immune response when administrated subcutaneously (P<0.001), intraperitoneally (P<0.01) and intramuscularly (P<0.001) with worm reduction rate of 56.29%, 15.38% and 37.42%, respectively. More importantly, Csenolase could be successfully expressed as a fusion protein (55kDa) on B. subtilis spore indicated by immunoblot and immunofluorescence assays. Killed spores triggered reactive Th1/Th2 immune response and exhibited protective efficacy against C. sinensis infection. Csenolase derived oral vaccine conferred worm reduction rate and egg reduction rate at 60.07% (P<0.001) and 80.67% (P<0.001), respectively. The shuttle genetic engineering system facilitated the development of oral vaccine with B. subtilis stably overexpressing target protein. Comparably vaccinal trails with Csenolase in different immunization routes potentialize Csenolase an oral vaccine candidate in C. sinensis prevention. Copyright © 2014 Elsevier Ltd. All rights reserved.

A plant-produced protective antigen vaccine confers protection in rabbits against a lethal aerosolized challenge with Bacillus anthracis Ames spores.

PubMed

Chichester, Jessica A; Manceva, Slobodanka D; Rhee, Amy; Coffin, Megan V; Musiychuk, Konstantin; Mett, Vadim; Shamloul, Moneim; Norikane, Joey; Streatfield, Stephen J; Yusibov, Vidadi

2013-03-01

The potential use of Bacillus anthracis as a bioterrorism weapon threatens the security of populations globally, requiring the immediate availability of safe, efficient and easily delivered anthrax vaccine for mass vaccination. Extensive research efforts have been directed toward the development of recombinant subunit vaccines based on protective antigen (PA), the principal virulence factor of B. anthracis. Among the emerging technologies for the production of these vaccine antigens is our launch vector-based plant transient expression system. Using this system, we have successfully engineered, expressed, purified and characterized full-length PA (pp-PA83) in Nicotiana benthamiana plants using agroinfiltration. This plant-produced antigen elicited high toxin neutralizing antibody titers in mice and rabbits after two vaccine administrations with Alhydrogel. In addition, immunization with this vaccine candidate protected 100% of rabbits from a lethal aerosolized B. anthracis challenge. The vaccine effects were dose-dependent and required the presence of Alhydrogel adjuvant. In addition, the vaccine antigen formulated with Alhydrogel was stable and retained immunogenicity after two-week storage at 4°C, the conditions intended for clinical use. These results support the testing of this vaccine candidate in human volunteers and the utility of our plant expression system for the production of a recombinant anthrax vaccine.

A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

PubMed Central

Minhinnick, Alice; Satti, Iman; Harris, Stephanie; Wilkie, Morven; Sheehan, Sharon; Stockdale, Lisa; Thomas, Zita-Rose Manjaly; Lopez-Ramon, Raquel; Poulton, Ian; Lawrie, Alison; Vermaak, Samantha; Le Vert, Alexandre; Del Campo, Judith; Hill, Fergal; Moss, Paul; McShane, Helen

2016-01-01

Introduction There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. Methods In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. Results The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. Conclusion MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163. PMID:26854906

Timeliness of Childhood Primary Immunization and Risk Factors Related with Delays: Evidence from the 2014 Zhejiang Provincial Vaccination Coverage Survey

PubMed Central

Hu, Yu; Li, Qian; Chen, Yaping

2017-01-01

Background: this study aimed to assess both immunization coverage and timeliness, as well as reasons for non-vaccination, and identity the risk factors of delayed immunization, for the vaccines scheduled during the first year of life, in Zhejiang province, east China. Methods: A cluster survey among children aged 24–35 months was conducted. Demographic information and socio-economic characteristics of the selected child, the mother, and the household were collected. Immunization data were transcribed from immunization cards. Timeliness was assessed with Kaplan–Meier analysis for each vaccine given before 12 months of age, based on the time frame stipulated by the expanded program on immunization of China. Cox proportional hazard regression was applied to identify risk factors of delayed immunization. Results: A total of 2772 eligible children were surveyed. The age-appropriate coverage ranged from 25.4% (95% CI: 23.7–27.0%) for Bacillus Calmette–Guerin (BCG) to 91.3% (95% CI: 90.2–92.3%) for the first dose of oral poliomyelitis vaccine (OPV1). The most frequent reason for non-vaccination was parent’s fear of adverse events of immunization. Delayed immunizations were associated with mother having a lower education level, mother having a job, delivery at home, increasing number of children per household, and having a lower household income. Conclusions: Although the timeliness of immunization has improved since 2011, necessary steps are still needed to achieve further improvement. Timeliness of immunization should be considered as another important indicator of expanded program on immunization (EPI) performance. Future interventions on vaccination coverage should take into consideration demographic and socio-economic risk factors identified in this study. The importance of adhering to the recommended schedule should be explained to parents. PMID:28930165

A New Screen for Tuberculosis Drug Candidates Utilizing a Luciferase-Expressing Recombinant Mycobacterium bovis Bacillus Calmette-Guéren.

PubMed

Ozeki, Yuriko; Igarashi, Masayuki; Doe, Matsumi; Tamaru, Aki; Kinoshita, Naoko; Ogura, Yoshitoshi; Iwamoto, Tomotada; Sawa, Ryuichi; Umekita, Maya; Enany, Shymaa; Nishiuchi, Yukiko; Osada-Oka, Mayuko; Hayashi, Tetsuya; Niki, Mamiko; Tateishi, Yoshitaka; Hatano, Masaki; Matsumoto, Sohkichi

2015-01-01

Tuberculosis (TB) is a serious infectious disease caused by a bacterial pathogen. Mortality from tuberculosis was estimated at 1.5 million deaths worldwide in 2013. Development of new TB drugs is needed to not only to shorten the medication period but also to treat multi-drug resistant and extensively drug-resistant TB. Mycobacterium tuberculosis (Mtb) grows slowly and only multiplies once or twice per day. Therefore, conventional drug screening takes more than 3 weeks. Additionally, a biosafety level-3 (BSL-3) facility is required. Thus, we developed a new screening method to identify TB drug candidates by utilizing luciferase-expressing recombinant Mycobacterium bovis bacillus Calmette-Guéren (rBCG). Using this method, we identified several candidates in 4 days in a non-BSL-3 facility. We screened 10,080 individual crude extracts derived from Actinomyces and Streptomyces and identified 137 extracts which possessed suppressive activity to the luciferase of rBCG. Among them, 41 compounds inhibited the growth of both Mtb H37Rv and the extensively drug-resistant Mtb (XDR-Mtb) strains. We purified the active substance of the 1904-1 extract, which possessed strong activity toward rBCG, Mtb H37Rv, and XDR-Mtb but was harmless to the host eukaryotic cells. The MIC of this substance was 0.13 μg/ml, 0.5 μg/ml, and 2.0-7.5 μg/ml against rBCG, H37Rv, and 2 XDR-strains, respectively. Its efficacy was specific to acid-fast bacterium except for the Mycobacterium avium intracellular complex. Mass spectrometry and nuclear magnetic resonance analyses revealed that the active substance of 1904-1 was cyclomarin A. To confirm the mode of action of the 1904-1-derived compound, resistant BCG clones were used. Whole genome DNA sequence analysis showed that these clones contained a mutation in the clpc gene which encodes caseinolytic protein, an essential component of an ATP-dependent proteinase, and the likely target of the active substance of 1904-1. Our method provides a rapid and

Influence of Bacille Calmette-Guérin on tuberculin skin testing in Venezuelan Amerindians in high tuberculosis burden areas.

PubMed

Maes, Mailis; Verhagen, Lilly M; Ortega, Dagmarys; Sánchez, Gregorio L; Segovia, Yajaira; del Nogal, Berenice; de Waard, Jacobus H

2014-02-13

Extraordinarily high tuberculosis (TB) prevalence rates have been reported in Venezuelan Amerindians. Amerindian populations often live in geographically isolated villages where they receive little medical attention and live under precarious sanitary conditions. TB prevalence varies by ethnicity and geographic location and is generally higher in Amerindians than in non-indigenous (Creole) people. Between January 1, 1998 and December 31, 2009, the tuberculin skin test (TST) was administered during field operations to 9,538 Amerindian and Creole people between 0 and 94 years of age living in Venezuela. In 6,979 individuals (73%), Bacille Calmette-Guérin (BCG) vaccination status, age, and ethnicity were recorded. Univariate and multivariate analyses were performed to determine the influence of previous BCG vaccination, age, and ethnicity on TST outcomes. Age, ethnicity, and the number of BCG vaccinations administered each had a significant influence on TST outcomes (p < 0.001). The influence of BCG vaccination on TST outcomes varied by ethnicity and was only significant in children aged between 0 and 3 years. The utility of TST in the diagnosis of TB infection in high TB burden settings with widespread BCG vaccination should be evaluated locally and individually as this depends on ethnicity, age, and the number of BCG vaccinations administered. In Venezuelan children 4 years of age and older, the TST remains a useful tool for the detection of TB infection, independent of BCG vaccination status.

A Novel Immunogenic Spore Coat-Associated Protein in Bacillus Anthracis: Characterization via Proteomics Approaches and a Vector-Based Vaccine System

PubMed Central

Liu, Yu-Tsueng; Lin, Shwu-Bin; Huang, Cheng-Po; Huang, Chun-Ming

2007-01-01

New generation anthrax vaccines have been actively explored with the aim of enhancing efficacies and decreasing undesirable side effects that could be caused by licensed vaccines. Targeting novel antigens and/or eliminating the requirements for multiple needle injections and adjuvants are major objectives in the development of new anthrax vaccines. Using proteomics approaches, we identified a spore coat-associated protein (SCAP) in Bacillus anthracis. An E. coli vector-based vaccine system was used to determine the immunogenicity of SCAP. Mice generated detectable SCAP antibodies three weeks after intranasal immunization with an intact particle of ultraviolet (UV)-irradiated E. coli vector overproducing SCAP. The production of SCAP antibodies was detected via western blotting and SCAP-spotted antigen-arrays. The adjuvant effect of a UV-irradiated E. coli vector eliminates the necessity of boosting and the use of other immunomodulators which will foster the screening and manufacturing of new generation anthrax vaccines. More importantly, the immunogenic SCAP may potentially be a new candidate for the development of anthrax vaccines. PMID:18029197

Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial.

PubMed

Nankabirwa, Victoria; Tumwine, James K; Namugga, Olive; Tylleskär, Thorkild; Ndeezi, Grace; Robberstad, Bjarne; Netea, Mihai G; Sommerfelt, Halvor

2017-03-31

Bacillus Calmette-Guérin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants. This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1β, IL-6 and interferon-γ in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda. A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants. ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015.

Isolation, purification and chemical composition of insoluble collagen from Guerin epithelioma.

PubMed

Bańkowski, E; Galasiński, W; Gindzieẃski, A; Rzeczycki, W

1975-01-01

1. The insoluble collagen from Guerin epithelioma was isolated and its chemical composition was determined. The unusually high histidine content is accompanied in tumour collagen by a relatively small amount of lysine and arginine. 2. The isolated protein was strongly bound to glycoprotein, which could not be removed by EDTA treatment unless this procedure was preceded by digestion of the complex with trypsin.

The Québec BCG Vaccination Registry (1956-1992): assessing data quality and linkage with administrative health databases.

PubMed

Rousseau, Marie-Claude; Conus, Florence; Li, Jun; Parent, Marie-Élise; El-Zein, Mariam

2014-01-09

Vaccination registries have undoubtedly proven useful for estimating vaccination coverage as well as examining vaccine safety and effectiveness. However, their use for population health research is often limited. The Bacillus Calmette-Guérin (BCG) Vaccination Registry for the Canadian province of Québec comprises some 4 million vaccination records (1926-1992). This registry represents a unique opportunity to study potential associations between BCG vaccination and various health outcomes. So far, such studies have been hampered by the absence of a computerized version of the registry. We determined the completeness and accuracy of the recently computerized BCG Vaccination Registry, as well as examined its linkability with demographic and administrative medical databases. Two systematically selected verification samples, each representing ~0.1% of the registry, were used to ascertain accuracy and completeness of the electronic BCG Vaccination Registry. Agreement between the paper [listings (n = 4,987 records) and vaccination certificates (n = 4,709 records)] and electronic formats was determined along several nominal and BCG-related variables. Linkage feasibility with the Birth Registry (probabilistic approach) and provincial Healthcare Registration File (deterministic approach) was examined using nominal identifiers for a random sample of 3,500 individuals born from 1961 to 1974 and BCG vaccinated between 1970 and 1974. Exact agreement was observed for 99.6% and 81.5% of records upon comparing, respectively, the paper listings and vaccination certificates to their corresponding computerized records. The proportion of successful linkage was 77% with the Birth Registry, 70% with the Healthcare Registration File, 57% with both, and varied by birth year. Computerization of this Registry yielded excellent results. The registry was complete and accurate, and linkage with administrative databases was highly feasible. This study represents the first step towards

Clinical and economic impact of a specific BCG vaccination program implemented in Prato, central Italy, involving foreign newborns on hospitalizations.

PubMed

Bellini, Irene; Nastasi, Antonino; Boccalini, Sara

2016-09-01

In Tuscany (Central Italy), the average annual notification rate of tuberculosis (TB) in the years 2007-2012 was 7.5-9.8 per 100,000 people, with the Local Health Unit of Prato (LHU4) showing the highest rate compared to the other regional area. Therefore, in order to reduce the burden of TB, foreign newborns in the LHU4 are being given the Bacillus Calmette-Guérin (BCG) vaccine since 2000. The aim of this study is to assess the impact of BCG vaccination in Prato, in terms of TB-related hospitalizations and costs. The regional archive containing all TB-related discharges and costs in the period 2007-2014 was consulted. Data regarding foreigners living in the LHU4 who have been vaccinated since 2000 were compared with those living in the other Tuscan LHUs and never vaccinated. These populations were then disaggregated by a threshold age of 15 y. After calculating the standardized hospitalization rates, the expected number of hospitalizations for TB among unvaccinated adults (in both populations) was found to be similar in the LHU4 and the other LHUs (165 vs. 156). However, expected number of hospitalizations among children in the other Tuscan LHUs (67) was double that of the LHU4 (34). If the same vaccine had been administrated everywhere, each year 29 hospitalizations could have been avoided and EUR 343,525 saved. Overall, BCG vaccinations cost EUR 14,879 in the LHU4, but 69 hospitalizations were avoided and EUR 107,435 saved. The introduction of the BCG immunization program in the LHU4 of Prato has led to significant reductions in the clinical and economic impact of TB.

The Québec BCG Vaccination Registry (1956–1992): assessing data quality and linkage with administrative health databases

PubMed Central

2014-01-01

Background Vaccination registries have undoubtedly proven useful for estimating vaccination coverage as well as examining vaccine safety and effectiveness. However, their use for population health research is often limited. The Bacillus Calmette-Guérin (BCG) Vaccination Registry for the Canadian province of Québec comprises some 4 million vaccination records (1926-1992). This registry represents a unique opportunity to study potential associations between BCG vaccination and various health outcomes. So far, such studies have been hampered by the absence of a computerized version of the registry. We determined the completeness and accuracy of the recently computerized BCG Vaccination Registry, as well as examined its linkability with demographic and administrative medical databases. Methods Two systematically selected verification samples, each representing ~0.1% of the registry, were used to ascertain accuracy and completeness of the electronic BCG Vaccination Registry. Agreement between the paper [listings (n = 4,987 records) and vaccination certificates (n = 4,709 records)] and electronic formats was determined along several nominal and BCG-related variables. Linkage feasibility with the Birth Registry (probabilistic approach) and provincial Healthcare Registration File (deterministic approach) was examined using nominal identifiers for a random sample of 3,500 individuals born from 1961 to 1974 and BCG vaccinated between 1970 and 1974. Results Exact agreement was observed for 99.6% and 81.5% of records upon comparing, respectively, the paper listings and vaccination certificates to their corresponding computerized records. The proportion of successful linkage was 77% with the Birth Registry, 70% with the Healthcare Registration File, 57% with both, and varied by birth year. Conclusions Computerization of this Registry yielded excellent results. The registry was complete and accurate, and linkage with administrative databases was highly feasible. This

Coverage of childhood vaccination among children aged 12-23 months, Tamil Nadu, 2015, India

PubMed Central

Murhekar, Manoj V.; Kamaraj, P.; Kanagasabai, K.; Elavarasu, G.; Rajasekar, T. Daniel; Boopathi, K.; Mehendale, Sanjay

2017-01-01

Background & objectives: District-Level Household Survey-4 (DLHS-4) indicated that during 2012-2013, only 56 per cent of children aged 12-23 months in Tamil Nadu were fully vaccinated, which were lesser than those reported in earlier national surveys. We, therefore, conducted cluster surveys to estimate coverage of childhood vaccination in the State, and also to identify the factors associated with low coverage. Methods: Cross-sectional surveys were conducted in 15 strata [municipal corporation non-slum (n=1), municipal corporation slum (n=1), hilly (n=1), rural (n=6) and urban (n=6)]. From each stratum, 30 clusters were selected using probability proportional to the population size linear systematic sampling; seven children aged 12-23 months were selected from each cluster and their mothers/care-takers were interviewed to collect information about vaccination status of the child. A child was considered fully vaccinated if he/she received bacillus Calmette-Guérin (BCG), three doses of pentavalent, three doses of oral polio vaccine and one dose of measles vaccine, and appropriately vaccinated if all vaccine doses were given at right age and with right interval. Further, coverage of fully vaccinated children (FVC) as per vaccination cards or mothers’ recall, validated coverage of FVC (V-FVC) among those having cards, and coverage of appropriately vaccinated children (AVC) were estimated using survey data analysis module with appropriate sampling weights. Results: A total of 3150 children were surveyed, of them 2528 (80.3%) had vaccination card. The weighted coverage of FVC, V-FVC and AVC in the State was 79.9 per cent [95% confidence interval (CI): 78.2-81.5], 78.8 per cent (95% CI: 76.9-80.5) and 69.7 per cent (95% CI: 67.7-71.7), respectively. The coverage of individual vaccine ranged between 84 per cent (measles) and 99.8 per cent (BCG). About 12 per cent V-FVC were not vaccinated as per the vaccination schedule. Interpretation & conclusions: The coverage of

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

PubMed Central

Beierlein, J.M.; Anderson, A.C.

2013-01-01

Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics. PMID:22050756

A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation.

PubMed

Ma, Jilei; Teng, Xindong; Wang, Xiaochun; Fan, Xionglin; Wu, Yaqi; Tian, Maopeng; Zhou, Zijie; Li, Longmeng

2017-08-01

Adult tuberculosis (TB) is the main cause of TB epidemic and death. The infection results mainly by endogenous reactivation of latent TB infection and secondarily transmitted by exogenous infection. There is no vaccine for adult TB. To this end, we first chose antigens from a potential antigenic reservoir. The antigens strongly recognized T cells from latent and active TB infections that responded to antigens expressed by Mycobacterium tuberculosis cultured under different metabolic states. Fusions of single-stage polyprotein CTT3H, two-stage polyprotein A1D4, and multistage CMFO were constructed. C57BL/6 mice vaccinated with DMT adjuvant ed CMFO (CMFO-DMT) were protected more significantly than by CTT3H-DMT, and efficacy was similar to that of the only licensed vaccine, Bacillus Calmette-Guérin (BCG) and A1D4-DMT in the M. tuberculosis primary infection model. In the setting of BCG priming and latent TB infection, M. tuberculosis in the lung and spleen was eliminated more effectively in mice boosted with CMFO-DMT rather than with BCG, A1D4-DMT, or CTT3H-DMT. In particular, sterile immunity was only conferred by CMFO-DMT, which was associated with expedited homing of interferon-gamma + CD4 + T EM and interleukin-2 + T CM cells from the spleen to the infected lung. CMFO-DMT represents a promising candidate to prevent the occurrence of adult TB through both prophylactic and therapeutic methods, and warrants assessment in preclinical and clinical trials. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Recombinant Invasive Lactococcus lactis Carrying a DNA Vaccine Coding the Ag85A Antigen Increases INF-γ, IL-6, and TNF-α Cytokines after Intranasal Immunization.

PubMed

Mancha-Agresti, Pamela; de Castro, Camila Prosperi; Dos Santos, Janete S C; Araujo, Maíra A; Pereira, Vanessa B; LeBlanc, Jean G; Leclercq, Sophie Y; Azevedo, Vasco

2017-01-01

Tuberculosis (TB) remains a major threat throughout the world and in 2015 it caused the death of 1.4 million people. The Bacillus Calmette-Guérin is the only existing vaccine against this ancient disease; however, it does not provide complete protection in adults. New vaccines against TB are eminently a global priority. The use of bacteria as vehicles for delivery of vaccine plasmids is a promising vaccination strategy. In this study, we evaluated the use of, an engineered invasive Lactococcus lactis (expressing Fibronectin-Binding Protein A from Staphylococcus aureus ) for the delivery of DNA plasmid to host cells, especially to the mucosal site as a new DNA vaccine against tuberculosis. One of the major antigens documented that offers protective responses against Mycobacterium tuberculosis is the Ag85A. L. lactis FnBPA + (pValac: Ag85A) which was obtained and used for intranasal immunization of C57BL/6 mice and the immune response profile was evaluated. In this study we observed that this strain was able to produce significant increases in the amount of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6) in the stimulated spleen cell supernatants, showing a systemic T helper 1 (Th1) cell response. Antibody production (IgG and sIgA anti-Ag85A) was also significantly increased in bronchoalveolar lavage, as well as in the serum of mice. In summary, these findings open new perspectives in the area of mucosal DNA vaccine, against specific pathogens using a Lactic Acid Bacteria such as L. lactis.

Anthrax vaccine antigen-adjuvant formulations completely protect New Zealand white rabbits against challenge with Bacillus anthracis Ames strain spores.

PubMed

Peachman, Kristina K; Li, Qin; Matyas, Gary R; Shivachandra, Sathish B; Lovchik, Julie; Lyons, Rick C; Alving, Carl R; Rao, Venigalla B; Rao, Mangala

2012-01-01

In an effort to develop an improved anthrax vaccine that shows high potency, five different anthrax protective antigen (PA)-adjuvant vaccine formulations that were previously found to be efficacious in a nonhuman primate model were evaluated for their efficacy in a rabbit pulmonary challenge model using Bacillus anthracis Ames strain spores. The vaccine formulations include PA adsorbed to Alhydrogel, PA encapsulated in liposomes containing monophosphoryl lipid A, stable liposomal PA oil-in-water emulsion, PA displayed on bacteriophage T4 by the intramuscular route, and PA mixed with Escherichia coli heat-labile enterotoxin administered by the needle-free transcutaneous route. Three of the vaccine formulations administered by the intramuscular or the transcutaneous route as a three-dose regimen induced 100% protection in the rabbit model. One of the formulations, liposomal PA, also induced significantly higher lethal toxin neutralizing antibodies than PA-Alhydrogel. Even 5 months after the second immunization of a two-dose regimen, rabbits vaccinated with liposomal PA were 100% protected from lethal challenge with Ames strain spores. In summary, the needle-free skin delivery and liposomal formulation that were found to be effective in two different animal model systems appear to be promising candidates for next-generation anthrax vaccine development.

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

PubMed Central

Moliva, Juan I.; Turner, Joanne; Torrelles, Jordi B.

2017-01-01

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the current leading cause of death due to a single infectious organism. Although curable, the broad emergence of multi-, extensive-, extreme-, and total-drug resistant strains of M.tb has hindered eradication efforts of this pathogen. Furthermore, computational models predict a quarter of the world’s population is infected with M.tb in a latent state, effectively serving as the largest reservoir for any human pathogen with the ability to cause significant morbidity and mortality. The World Health Organization has prioritized new strategies for improved vaccination programs; however, the lack of understanding of mycobacterial immunity has made it difficult to develop new successful vaccines. Currently, Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the only vaccine approved for use to prevent TB. BCG is highly efficacious at preventing meningeal and miliary TB, but is at best 60% effective against the development of pulmonary TB in adults and wanes as we age. In this review, we provide a detailed summary on the innate immune response of macrophages, dendritic cells, and neutrophils in response to BCG vaccination. Additionally, we discuss adaptive immune responses generated by BCG vaccination, emphasizing their specific contributions to mycobacterial immunity. The success of future vaccines against TB will directly depend on our understanding of mycobacterial immunity. PMID:28424703

Molecular Characterization of Heterologous HIV-1gp120 Gene Expression Disruption in Mycobacterium bovis BCG Host Strain: A Critical Issue for Engineering Mycobacterial Based-Vaccine Vectors

PubMed Central

Joseph, Joan; Fernández-Lloris, Raquel; Pezzat, Elías; Saubi, Narcís; Cardona, Pere-Joan; Mothe, Beatriz; Gatell, Josep Maria

2010-01-01

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) as a live vector of recombinant bacterial vaccine is a promising system to be used. In this study, we evaluate the disrupted expression of heterologous HIV-1gp120 gene in BCG Pasteur host strain using replicative vectors pMV261 and pJH222. pJH222 carries a lysine complementing gene in BCG lysine auxotrophs. The HIV-1 gp120 gene expression was regulated by BCG hsp60 promoter (in plasmid pMV261) and Mycobacteria spp. α-antigen promoter (in plasmid pJH222). Among 14 rBCG:HIV-1gp120 (pMV261) colonies screened, 12 showed a partial deletion and two showed a complete deletion. However, deletion was not observed in all 10 rBCG:HIV-1gp120 (pJH222) colonies screened. In this study, we demonstrated that E. coli/Mycobacterial expression vectors bearing a weak promoter and lysine complementing gene in a recombinant lysine auxotroph of BCG could prevent genetic rearrangements and disruption of HIV 1gp120 gene expression, a key issue for engineering Mycobacterial based vaccine vectors. PMID:20617151

Neutralizing antibody and functional mapping of Bacillus anthracis protective antigen-The first step toward a rationally designed anthrax vaccine.

PubMed

McComb, Ryan C; Martchenko, Mikhail

2016-01-02

Anthrax is defined by the Centers for Disease Control and Prevention as a Category A pathogen for its potential use as a bioweapon. Current prevention treatments include Anthrax Vaccine Adsorbed (AVA). AVA is an undefined formulation of Bacillus anthracis culture supernatant adsorbed to aluminum hydroxide. It has an onerous vaccination schedule, is slow and cumbersome to produce and is slightly reactogenic. Next-generation vaccines are focused on producing recombinant forms of anthrax toxin in a well-defined formulation but these vaccines have been shown to lose potency as they are stored. In addition, studies have shown that a proportion of the antibody response against these vaccines is focused on non-functional, non-neutralizing regions of the anthrax toxin while some essential functional regions are shielded from eliciting an antibody response. Rational vaccinology is a developing field that focuses on designing vaccine antigens based on structural information provided by neutralizing antibody epitope mapping, crystal structure analysis, and functional mapping through amino acid mutations. This information provides an opportunity to design antigens that target only functionally important and conserved regions of a pathogen in order to make a more optimal vaccine product. This review provides an overview of the literature related to functional and neutralizing antibody epitope mapping of the Protective Antigen (PA) component of anthrax toxin. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Systematic review on conservative treatment options in non-muscle-invasive bladder cancer patients refractory to Bacillus Calmette-Guérin instillation therapy].

PubMed

Martini, Thomas; Wezel, Felix; Löbig, Niklas; Mitterberger, Michael J; Colleselli, Daniela

2017-08-01

Background Adjuvant Bacillus Calmette-Guérin (BCG) intravesical instillation is the recommended standard treatment in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). However, a significant proportion of patients fail treatment, and radical cystectomy (RC) is the subsequent gold standard. On the other hand, there is an unmet need for conservative alternatives for patients who are unfit or unwilling to undergo surgery. This study aimed to identify conservative treatment options in NMIBC patients after BCG failure. Material and Methods We performed a systematic search in the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, including all randomised controlled trials (RCTs), quasi-RCTs and single-arm studies, in which patients with NMIBC were treated with second-line intravesical or systemic therapy after BCG failure. A minimum of eight patients were included in each treatment arm. Full papers were restricted to English language. Literature research and data analysis were assessed independently by two reviewers. Data on treatment response, recurrence, time to recurrence, progression and rate of cystectomy were collected and analysed. Results  This systematic review included 42 publications with a total of 3521 patients (2371 BCG failures). Valrubicin, taxanes, gemcitabine, combination chemotherapy, thermochemotherapy, photodynamic therapy, combination of BCG and interferon and immunotherapies or targeted therapies were identified as conservative treatment options. For taxanes, gemcitabine and thermochemotherapy there is the highest evidence for a clinical meaningful response with minor toxicities. Conclusions Despite some promising response rates for taxanes, gemcitabine or thermochemotherapy, an evidence-based recommendation for treatment options superior to RC in patients failing BCG therapy cannot be made. The definition of BCG failure is still inconsistent and heterogeneous outcomes in patients with BCG

Tuberculosis vaccine development at a divide.

PubMed

Kaufmann, Stefan H E

2014-05-01

Tuberculosis (TB) remains a major health threat that will only be defeated by a combination of better drugs, diagnostics and vaccines. The only licensed TB vaccine, bacille Calmette-Guérin (BCG), protects against extrapulmonary TB in infants. Novel vaccine candidates that could protect against pulmonary TB either in TB naïve or in latent TB-infected healthy individuals have been developed and are currently being assessed in clinical trials. Subunit booster vaccines are either based on viral vectors expressing TB-specific antigens or on TB-protein antigens in adjuvants. Subunit vaccines are administered on top of BCG. Replacement vaccines for BCG are recombinant viable BCG or Mycobacterium tuberculosis. Several candidates are undergoing, or will soon start, phase IIb assessment for efficacy. The first vaccine candidate, MVA85A, to complete a phase IIb trial, unfortunately failed to show protection against TB in infants. Therapeutic vaccines composed of killed mycobacterial preparations target patients with complicated TB in adjunct to drug treatment. With increasing numbers of TB vaccine candidates in clinical trials, financial, regulatory and infrastructural issues arise, which would be best tackled by a global strategy. In addition, selection of the most promising vaccine candidates for further clinical development gains increasing importance.

Immunisation coverage and its determinants among children aged 12-23 months in Atakumosa-west district, Osun State Nigeria: a cross-sectional study.

PubMed

Adedire, Elizabeth B; Ajayi, Ikeoluwapo; Fawole, Olufunmilayo I; Ajumobi, Olufemi; Kasasa, Simon; Wasswa, Peter; Nguku, Patrick

2016-08-30

Routine immunisation (RI) contributes immensely to reduction in mortality from vaccine preventable diseases (VPD) among children. The Nigerian Demographic and Health Survey, 2008 revealed that only 58 % of children in Osun State had received all recommended vaccines, which is far below World Health Organization (WHO) target of 80 %. We therefore, assessed RI uptake and its determinants among children in Atakumosa-west district of Osun State. Atakumosa-west district has an estimated population of 90,525 inhabitants. We enrolled 750 mothers of children aged 12-23 months in this cross-sectional study. Semi-structured questionnaires were used to obtain data on socio-demographic characteristics, knowledge of mothers on RI, history of RI in children and factors associated with full RI uptake. A fully-immunised child was defined as a child who had received one dose of Bacillus-Calmette-Guerin, three doses of Oral-Polio-Vaccine, three doses of Diptheria-Pertusis-Tetanus vaccine and one dose of measles vaccine by 12 months of age. We tested for the association between immunisation uptake and its likely determinants using multivariable logistic regression at 0.05 level of significance and 95 % confidence Interval (CI). Mean ± (SD) age of the mothers and children were 27.9 ± 6.1 years and 17.2 ± 4.0 months, respectively. About 94 % (703/750) of mothers had received antenatal care (ANC) and 63.3 % (475) of the children possessed vaccination cards. Seventy-six percent (571/750) had good knowledge of RI and VPD. About 58 % (275/475) of children who possessed vaccination card were fully-immunised. Mothers antenatal care attendance (aOR = 3.3, 95 % CI = 1.1-8.3), maternal tetanus toxoid immunisation (aOR = 3.2, 95 % CI = 1.1-10.0) access to immunisation information (aOR = 1.8, 95 % CI = 1.1-2.5) and mothers having good knowledge of immunisation (aOR = 2.4, 95 % CI = 1.6-3.8) were significant determinants of full

The current status, challenges, and future developments of new tuberculosis vaccines.

PubMed

Gong, Wenping; Liang, Yan; Wu, Xueqiong

2018-03-30

Mycobacterium tuberculosis complex causes tuberculosis (TB), one of the top 10 causes of death worldwide. TB results in more fatalities than multi-drug resistant (MDR) HIV strain related coinfection. Vaccines play a key role in the prevention and control of infectious diseases. Unfortunately, the only licensed preventive vaccine against TB, bacilli Calmette-Guérin (BCG), is ineffective for prevention of pulmonary TB in adults. Therefore, it is very important to develop novel vaccines for TB prevention and control. This literature review provides an overview of the innate and adaptive immune response during M. tuberculosis infection, and presents current developments and challenges to novel TB vaccines. A comprehensive understanding of vaccines in preclinical and clinical studies provides extensive insight for the development of safer and more efficient vaccines, and may inspire new ideas for TB prevention and treatment.

Biomimetically Engineered Demi-Bacteria Potentiate Vaccination against Cancer.

PubMed

Ni, Dezhi; Qing, Shuang; Ding, Hui; Yue, Hua; Yu, Di; Wang, Shuang; Luo, Nana; Su, Zhiguo; Wei, Wei; Ma, Guanghui

2017-10-01

Failure in enhancing antigen immunogenicity has limited the development of cancer vaccine. Inspired by effective immune responses toward microorganisms, demi-bacteria (DB) from Bacillus are engineered as carriers for cancer vaccines. The explored hydrothermal treatment enables the Bacillus to preserve optimal pathogen morphology with intrinsic mannose receptor agonist. Meanwhile, the treated Bacillus can be further endowed with ideal hollow/porous structure for efficient accommodation of antigen and adjuvant, such as CpG. Therefore, this optimal engineered nanoarchitecture allows multiple immunostimulatory elements integrate in a pattern closely resembling that of bacterial pathogens. Such pathogen mimicry greatly enhances antigen uptake and cross-presentation, resulting in stronger immune activation suitable for cancer vaccines. Indeed, DB-based biomimetic vaccination in mice induces synergistic cellular and humoral immune responses, achieving potent therapeutic and preventive effects against cancer. Application of microorganism-sourced materials thus presents new opportunities for potent cancer therapy.

Biomimetically Engineered Demi‐Bacteria Potentiate Vaccination against Cancer

PubMed Central

Ni, Dezhi; Qing, Shuang; Ding, Hui; Yue, Hua; Yu, Di; Wang, Shuang; Luo, Nana; Su, Zhiguo

2017-01-01

Abstract Failure in enhancing antigen immunogenicity has limited the development of cancer vaccine. Inspired by effective immune responses toward microorganisms, demi‐bacteria (DB) from Bacillus are engineered as carriers for cancer vaccines. The explored hydrothermal treatment enables the Bacillus to preserve optimal pathogen morphology with intrinsic mannose receptor agonist. Meanwhile, the treated Bacillus can be further endowed with ideal hollow/porous structure for efficient accommodation of antigen and adjuvant, such as CpG. Therefore, this optimal engineered nanoarchitecture allows multiple immunostimulatory elements integrate in a pattern closely resembling that of bacterial pathogens. Such pathogen mimicry greatly enhances antigen uptake and cross‐presentation, resulting in stronger immune activation suitable for cancer vaccines. Indeed, DB‐based biomimetic vaccination in mice induces synergistic cellular and humoral immune responses, achieving potent therapeutic and preventive effects against cancer. Application of microorganism‐sourced materials thus presents new opportunities for potent cancer therapy. PMID:29051851

Immunopathological evaluation of recombinant mycobacterial antigen Hsp65 expressed in Lactococcus lactis as a novel vaccine candidate

PubMed Central

Herrera Ramírez, J. C.; De la Mora, A. Ch.; De la Mora Valle, A.; Lopez-Valencia, G.; Hurtado, R. M. B.; Rentería Evangelista, T. B.; Rodríguez Castillo, J. L.; Rodríguez Gardea, A.; Gómez Gómez, S. D.; Medina-Basulto, G. E.

2017-01-01

Bovine tuberculosis (TBB) is a zoonotic disease distributed worldwide and is of great importance for public health and the livestock industry. Several experimental vaccines against this disease have been evaluated in recent years, yielding varying results. An example is the Bacillus Calmette-Guérin (BCG) vaccine, which has been used extensively in humans and tested in cattle showing mixed results related to protection (0-80%) against Mycobacterium bovis. In this study, we used the food-grade bacterium Lactococcus lactis as an expression system for production of mycobacterial protein Hsp65. For this purpose, the construction of a replicable plasmid in strain NZ9000 L. lactis (pVElepr) was conducted, which expressed the Mycobacterium leprae Hsp65 antigen, and was recognized by traded anti-Hsp65 antibodies. The strain NZ9000-pVElepr was applied to calves that were negative to tuberculin test and the immune response was monitored. The results showed that immune response was not significantly increased in calves with NZ9000-pVElepr with respect to control groups, and no injury was observed in any lung or lymph of the calves. Finally, this study suggest that the recombinant NZ9000 strain of L. lactis may protect against the development of M. bovis infection, although studies with longer exposure to this pathogen are necessary to conclude the matter. PMID:29163649

Quantitative Determination of Lethal Toxin Proteins in Culture Supernatant of Human Live Anthrax Vaccine Bacillus anthracis A16R

PubMed Central

Zai, Xiaodong; Zhang, Jun; Liu, Ju; Liu, Jie; Li, Liangliang; Yin, Ying; Fu, Ling; Xu, Junjie; Chen, Wei

2016-01-01

Bacillus anthracis (B. anthracis) is the etiological agent of anthrax affecting both humans and animals. Anthrax toxin (AT) plays a major role in pathogenesis. It includes lethal toxin (LT) and edema toxin (ET), which are formed by the combination of protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. The currently used human anthrax vaccine in China utilizes live-attenuated B. anthracis spores (A16R; pXO1+, pXO2−) that produce anthrax toxin but cannot produce the capsule. Anthrax toxins, especially LT, have key effects on both the immunogenicity and toxicity of human anthrax vaccines. Thus, determining quantities and biological activities of LT proteins expressed by the A16R strain is meaningful. Here, we explored LT expression patterns of the A16R strain in culture conditions using another vaccine strain Sterne as a control. We developed a sandwich ELISA and cytotoxicity-based method for quantitative detection of PA and LF. Expression and degradation of LT proteins were observed in culture supernatants over time. Additionally, LT proteins expressed by the A16R and Sterne strains were found to be monomeric and showed cytotoxic activity, which may be the main reason for side effects of live anthrax vaccines. Our work facilitates the characterization of anthrax vaccines components and establishment of a quality control standard for vaccine production which may ultimately help to ensure the efficacy and safety of the human anthrax vaccine A16R. PMID:26927174

Quantitative Determination of Lethal Toxin Proteins in Culture Supernatant of Human Live Anthrax Vaccine Bacillus anthracis A16R.

PubMed

Zai, Xiaodong; Zhang, Jun; Liu, Ju; Liu, Jie; Li, Liangliang; Yin, Ying; Fu, Ling; Xu, Junjie; Chen, Wei

2016-02-25

Bacillus anthracis (B. anthracis) is the etiological agent of anthrax affecting both humans and animals. Anthrax toxin (AT) plays a major role in pathogenesis. It includes lethal toxin (LT) and edema toxin (ET), which are formed by the combination of protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. The currently used human anthrax vaccine in China utilizes live-attenuated B. anthracis spores (A16R; pXO1+, pXO2-) that produce anthrax toxin but cannot produce the capsule. Anthrax toxins, especially LT, have key effects on both the immunogenicity and toxicity of human anthrax vaccines. Thus, determining quantities and biological activities of LT proteins expressed by the A16R strain is meaningful. Here, we explored LT expression patterns of the A16R strain in culture conditions using another vaccine strain Sterne as a control. We developed a sandwich ELISA and cytotoxicity-based method for quantitative detection of PA and LF. Expression and degradation of LT proteins were observed in culture supernatants over time. Additionally, LT proteins expressed by the A16R and Sterne strains were found to be monomeric and showed cytotoxic activity, which may be the main reason for side effects of live anthrax vaccines. Our work facilitates the characterization of anthrax vaccines components and establishment of a quality control standard for vaccine production which may ultimately help to ensure the efficacy and safety of the human anthrax vaccine A16R.

Field Trial of an Aerially-Distributed Tuberculosis Vaccine in a Low-Density Wildlife Population of Brushtail Possums (Trichosurus vulpecula).

PubMed

Nugent, Graham; Yockney, Ivor J; Whitford, E Jackie; Cross, Martin L; Aldwell, Frank E; Buddle, Bryce M

2016-01-01

Oral-delivery Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine in a lipid matrix has been shown to confer protection against M. bovis infection and reduce the severity of tuberculosis (TB) when fed to brushtail possums (Trichosurus vulpecula), the major wildlife vector of bovine TB in New Zealand. Here we demonstrate the feasibility of aerial delivery of this live vaccine in bait form to an M. bovis-infected wild possum population, and subsequently assess vaccine uptake and field efficacy. Pre-trial studies indicated a resident possum population at very low density (<0.6 possums/ha) at the field site, with a 5.1% prevalence of macroscopic TB lesions. Pilot studies indicated that flavoured lipid matrix baits in weather-proof sachets could be successfully sown aerially via helicopter and were palatable to, and likely to be consumed by, a majority of wild possums under free-choice conditions. Subsequently, sachet-held lipid baits containing live BCG vaccine were sown at 3 baits/ha over a 1360 ha area, equating to >5 baits available per possum. Blood sampling conducted two months later provided some evidence of vaccine uptake. A necropsy survey conducted one year later identified a lower prevalence of culture-confirmed M. bovis infection and/or gross TB lesions among adult possums in vaccinated areas (1.1% prevalence; 95% CI, 0-3.3%, n = 92) than in unvaccinated areas (5.6%; 0.7-10.5%, n = 89); P = 0.098. Although not statistically different, the 81% efficacy in protecting possums against natural infection calculated from these data is within the range of previous estimates of vaccine efficacy in trials where BCG vaccine was delivered manually. We conclude that, with further straightforward refinement to improve free-choice uptake, aerial delivery of oral BCG vaccine is likely to be effective in controlling TB in wild possums. We briefly discuss contexts in which this could potentially become an important complementary tool in achieving national eradication

Field Trial of an Aerially-Distributed Tuberculosis Vaccine in a Low-Density Wildlife Population of Brushtail Possums (Trichosurus vulpecula)

PubMed Central

Nugent, Graham; Yockney, Ivor J.; Whitford, E. Jackie; Cross, Martin L.; Aldwell, Frank E.; Buddle, Bryce M.

2016-01-01

Oral-delivery Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine in a lipid matrix has been shown to confer protection against M. bovis infection and reduce the severity of tuberculosis (TB) when fed to brushtail possums (Trichosurus vulpecula), the major wildlife vector of bovine TB in New Zealand. Here we demonstrate the feasibility of aerial delivery of this live vaccine in bait form to an M. bovis-infected wild possum population, and subsequently assess vaccine uptake and field efficacy. Pre-trial studies indicated a resident possum population at very low density (<0.6 possums/ha) at the field site, with a 5.1% prevalence of macroscopic TB lesions. Pilot studies indicated that flavoured lipid matrix baits in weather-proof sachets could be successfully sown aerially via helicopter and were palatable to, and likely to be consumed by, a majority of wild possums under free-choice conditions. Subsequently, sachet-held lipid baits containing live BCG vaccine were sown at 3 baits/ha over a 1360 ha area, equating to >5 baits available per possum. Blood sampling conducted two months later provided some evidence of vaccine uptake. A necropsy survey conducted one year later identified a lower prevalence of culture-confirmed M. bovis infection and/or gross TB lesions among adult possums in vaccinated areas (1.1% prevalence; 95% CI, 0–3.3%, n = 92) than in unvaccinated areas (5.6%; 0.7–10.5%, n = 89); P = 0.098. Although not statistically different, the 81% efficacy in protecting possums against natural infection calculated from these data is within the range of previous estimates of vaccine efficacy in trials where BCG vaccine was delivered manually. We conclude that, with further straightforward refinement to improve free-choice uptake, aerial delivery of oral BCG vaccine is likely to be effective in controlling TB in wild possums. We briefly discuss contexts in which this could potentially become an important complementary tool in achieving national

p53 Status correlates with the risk of recurrence in non-muscle invasive bladder cancers treated with Bacillus Calmette-Guérin: a meta-analysis.

PubMed

Zhou, Xiaofeng; Zhang, Guan; Tian, Ye

2015-01-01

Published studies have yielded inconsistent results on the relationship between p53 status and the prognosis of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) intravesical therapy. Therefore, we performed a meta-analysis to evaluate the prognostic value of p53 in NMIBC treated with BCG. We systematically searched for relevant literature in PubMed, EMBASE, CNKI, and Chinese Wanfang databases. Hazard ratios (HRs) with 95% confidence intervals (CIs) were combined as the effect size (ES) across studies for recurrence-free survival (RFS) and progression-free survival (PFS). A total of 11 studies, consisting of 1,049 participants, met the criteria. Overall, there was no clear relationship between p53 status and RFS or PFS for NMIBC patients treated with BCG (HR: 1.40, 95% CI: 0.91-2.16; HR: 1.37, 95% CI: 0.90-2.09, respectively). Obvious heterogeneity was observed across the studies (I2 = 69.5%, P = 0.001; I2 = 44.7%, P = 0.081, respectively). In stratified analysis by region, p53 overexpression was a predictor of poor RFS in Asian populations (HR: 1.57, 95% CI: 1.08-2.27). In addition, after excluding the studies that possibly contributed to the heterogeneity by the Galbraith plot, the overall association for RFS became statistically significant (HR: 1.38 95% CI: 1.08-1.77) without evidence of heterogeneity (I2 = 0.0%, P = 0.499). This meta-analysis suggests that p53 overexpression in NMIBC patients treated with BCG may be associated with RFS, especially in Asian populations. Because of the heterogeneity and other limitations, further studies with rigid criteria and large populations are still warranted to confirm our findings.

Protective effect of a lipid-based preparation from Mycobacterium smegmatis in a murine model of progressive pulmonary tuberculosis.

PubMed

García, Maria de los Angeles; Borrero, Reinier; Lanio, Maria E; Tirado, Yanely; Alvarez, Nadine; Puig, Alina; Aguilar, Alicia; Canet, Liem; Mata Espinoza, Dulce; Barrios Payán, Jorge; Sarmiento, María Elena; Hernández-Pando, Rogelio; Norazmi, Mohd-Nor; Acosta, Armando

2014-01-01

A more effective vaccine against tuberculosis (TB) is urgently needed. Based on its high genetic homology with Mycobacterium tuberculosis (Mtb), the nonpathogenic mycobacteria, Mycobacterium smegmatis (Ms), could be an attractive source of potential antigens to be included in such a vaccine. We evaluated the capability of lipid-based preparations obtained from Ms to provide a protective response in Balb/c mice after challenge with Mtb H37Rv strain. The intratracheal model of progressive pulmonary TB was used to assess the level of protection in terms of bacterial load as well as the pathological changes in the lungs of immunized Balb/c mice following challenge with Mtb. Mice immunized with the lipid-based preparation from Ms either adjuvanted with Alum (LMs-AL) or nonadjuvanted (LMs) showed significant reductions in bacterial load (P < 0.01) compared to the negative control group (animals immunized with phosphate buffered saline (PBS)). Both lipid formulations showed the same level of protection as Bacille Calmette and Guerin (BCG). Regarding the pathologic changes in the lungs, mice immunized with both lipid formulations showed less pneumonic area when compared with the PBS group (P < 0.01) and showed similar results compared with the BCG group. These findings suggest the potential of LMs as a promising vaccine candidate against TB.

Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines

PubMed Central

Libraty, Daniel H.; Zhang, Lei; Woda, Marcia; Acosta, Luz P.; Obcena, AnaMae; Brion, Job D.; Capeding, Rosario Z.

2014-01-01

Neonatal Bacille Calmette Guérin (BCG) vaccination has been reported to have beneficial effects beyond preventing infantile tuberculous meningitis and miliary disease. We hypothesized that BCG vaccine given at birth would enhance T-helper 1 (Th1) immune responses to the first vaccines given later in infancy. We conducted a nested case-control study of neonatal BCG vaccination and its heterologous Th1 immune effects in 2–3 months old infants. BCG vaccination at birth was associated with an increased frequency of interferon-γ (IFN-γ) producing spot-forming cells (SFC) to tetanus toxoid 2–3 months later. The frequency of IFN-γ producing SFC to polioviruses 1–3 also trended higher among infants who received BCG vaccination at birth. The frequency of IFN-γ+/tumor necrosis factor-α (TNF-α)+CD45RO+CD4+ T-cells upon stimulation with phorbol myristate acetate (PMA)/Ionomycin was higher in 2–3 months old infants who received BCG vaccination at birth compared to those who did not. The circulating frequency of forkhead box P3 (FoxP3)+ CD45RO+ regulatory CD4+ T-cells also trended lower in these infants. Neonatal BCG vaccination is associated with heterologous Th1 immune effects 2–3 months later. PMID:24611083

Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines.

PubMed

Libraty, Daniel H; Zhang, Lei; Woda, Marcia; Acosta, Luz P; Obcena, Anamae; Brion, Job D; Capeding, Rosario Z

2014-01-01

Neonatal Bacille Calmette Guérin (BCG) vaccination has been reported to have beneficial effects beyond preventing infantile tuberculous meningitis and miliary disease. We hypothesized that BCG vaccine given at birth would enhance T-helper 1 (Th1) immune responses to the first vaccines given later in infancy. We conducted a nested case-control study of neonatal BCG vaccination and its heterologous Th1 immune effects in 2-3 months old infants. BCG vaccination at birth was associated with an increased frequency of interferon-γ (IFN-γ) producing spot-forming cells (SFC) to tetanus toxoid 2-3 months later. The frequency of IFN-γ producing SFC to polioviruses 1-3 also trended higher among infants who received BCG vaccination at birth. The frequency of IFN-γ+/tumor necrosis factor-α (TNF-α)+CD45RO+CD4+ T-cells upon stimulation with phorbol myristate acetate (PMA)/Ionomycin was higher in 2-3 months old infants who received BCG vaccination at birth compared to those who did not. The circulating frequency of forkhead box P3 (FoxP3)+ CD45RO+ regulatory CD4+ T-cells also trended lower in these infants. Neonatal BCG vaccination is associated with heterologous Th1 immune effects 2-3 months later.

Bacillus subtilis Spores as Vaccine Adjuvants: Further Insights into the Mechanisms of Action

PubMed Central

de Souza, Renata Damásio; Batista, Milene Tavares; Luiz, Wilson Barros; Cavalcante, Rafael Ciro Marques; Amorim, Jaime Henrique; Bizerra, Raíza Sales Pereira; Martins, Eduardo Gimenes; de Souza Ferreira, Luís Carlos

2014-01-01

Bacillus subtilis spores have received growing attention regarding potential biotechnological applications, including the use as probiotics and in vaccine formulations. B. subtilis spores have also been shown to behave as particulate vaccine adjuvants, promoting the increase of antibody responses after co-administration with antigens either admixed or adsorbed on the spore surface. In this study, we further evaluated the immune modulatory properties of B. subtilis spores using a recombinant HIV gag p24 protein as a model antigen. The adjuvant effects of B. subtilis spores were not affected by the genetic background of the mouse lineage and did not induce significant inflammatory or deleterious effects after parenteral administration. Our results demonstrated that co-administration, but not adsorption to the spore surface, enhanced the immunogenicity of that target antigen after subcutaneous administration to BALB/c and C57BL/6 mice. Spores promoted activation of antigen presenting cells as demonstrated by the upregulation of MHC and CD40 molecules and enhanced secretion of pro-inflammatory cytokines by murine dendritic cells. In addition, in vivo studies indicated a direct role of the innate immunity on the immunomodulatory properties of B. subtilis spores, as demonstrated by the lack of adjuvant effects on MyD88 and TLR2 knockout mouse strains. PMID:24475289

Intravital Fluorescence Excitation in Whole-Animal Optical Imaging

PubMed Central

Bixler, Joel N.; Kong, Ying; Cirillo, Jeffrey D.; Maitland, Kristen C.

2016-01-01

Whole-animal fluorescence imaging with recombinant or fluorescently-tagged pathogens or cells enables real-time analysis of disease progression and treatment response in live animals. Tissue absorption limits penetration of fluorescence excitation light, particularly in the visible wavelength range, resulting in reduced sensitivity to deep targets. Here, we demonstrate the use of an optical fiber bundle to deliver light into the mouse lung to excite fluorescent bacteria, circumventing tissue absorption of excitation light in whole-animal imaging. We present the use of this technology to improve detection of recombinant reporter strains of tdTomato-expressing Mycobacterium bovis BCG (Bacillus Calmette Guerin) bacteria in the mouse lung. A microendoscope was integrated into a whole-animal fluorescence imager to enable intravital excitation in the mouse lung with whole-animal detection. Using this technique, the threshold of detection was measured as 103 colony forming units (CFU) during pulmonary infection. In comparison, the threshold of detection for whole-animal fluorescence imaging using standard epi-illumination was greater than 106 CFU. PMID:26901051

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

PubMed

Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

2014-06-16

Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

Effects of increased dietary protein and energy on composition and functional capacities of blood mononuclear cells from vaccinated, neonatal calves.

PubMed

Foote, Monica R; Nonnecke, Brian J; Waters, W Ray; Palmer, Mitchell V; Beitz, Donald C; Fowler, Mike A; Miller, Bill L; Johnson, Tom E; Perry, H Bruce

2005-09-01

Effects of increased protein and energy provided by an intensified milk replacer on the antigen-specific, cell-mediated immune response of the neonatal calf were examined. Calves were fed a standard (0.45 kg/day of a 20% crude protein, 20% fat milk replacer; n=11) or intensified (1.14 kg/day of a 28% crude protein, 20% fat milk replacer; n=11) diet from 0 to 6 weeks of age. All calves were vaccinated with Mycobacterium bovis bacillus Calmette-Guerin (BCG) at 1 week of age. The daily weight gain of intensified-diet calves (0.62 kg/day) was greater than the weight gain of standard-diet calves (0.29 kg/day). Liver, kidney, heart, thymus, and subcervical lymph nodes from intensified-diet calves were heavier than the same organs from standard-diet calves. Flow cytometric analysis of peripheral blood mononuclear cell (PBMC) populations indicated that CD4+ cells, gamma delta TCR+ cells, and monocyte percentages, although unaffected by diet during the first 5 weeks of the study, were higher in intensified-diet calves at week 6. The decline in gamma delta TCR+ cell percentages and increase in B cell percentages with increasing age seen in all calves are characteristic of the maturing immune system of the calf. CD8+ T cell or B cell percentages were not affected by diet. In intensified-diet calves, percentages of CD4+ expressing interleukin-2 receptor increased and percentages of gamma delta TCR+ cells expressing interleukin-2 receptor decreased with time. The same populations in standard-diet calves did not change with time. Percentages of CD4+ and CD8+ T cells, and B cells expressing MHC class II antigen, were unaffected by diet or age. Although mitogen-induced interferon (IFN)-gamma and nitric oxide (NO) secretion increased with age for all calves, PBMC from intensified-diet calves produced less IFN-gamma and more NO than did cells from standard-diet calves at week 6 of the study. Antigen-induced secretion of IFN-gamma and NO also increased with age but was unaffected by

A proposed national strategy for tuberculosis vaccine development.

PubMed

Ginsberg, A M

2000-06-01

The global tuberculosis epidemic causes approximately 5% of deaths worldwide. Despite recent concerted and largely successful tuberculosis control efforts, the incidence of tuberculosis in the United States remains 74-fold higher than the stated elimination goal of <1 case per million population by the year 2010. Current bacille Calmette-Guérin vaccines, although efficacious in preventing extrapulmonary tuberculosis in young children, have shown widely variable efficacy in preventing adult pulmonary tuberculosis, confound skin test screening, and are not recommended for use in the United States. The Advisory Council for Elimination of Tuberculosis recently stated that tuberculosis would not be eliminated from the United States without a more effective vaccine. Recent scientific advances have created unprecedented opportunity for tuberculosis vaccine development. Therefore, members of the broad tuberculosis research and control communities have recently created and proposed a national strategy, or blueprint, for tuberculosis vaccine development, which is presented here.

Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization.

PubMed

Qi, Fangfang; Zuo, Zejie; Yang, Junhua; Hu, Saisai; Yang, Yang; Yuan, Qunfang; Zou, Juntao; Guo, Kaihua; Yao, Zhibin

2017-02-10

The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. Here, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively. Together, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.

Altered cord blood γδ T cell repertoire in Nigeria: possible impacts of environmental factors on neonatal immunity

PubMed Central

Cairo, Cristiana; Propp, Nadia; Auricchio, Giovanni; Armstrong, Cheryl L.; Abimiku, Alash’le; Mancino, Giorgio; Colizzi, Vittorio; Blattner, William; Pauza, C. David

2008-01-01

Infectious diseases during pregnancy can impact the development of fetal immunity, leading to reduced neonatal resistance to infection and decreased responses to pediatric vaccines. P. falciparum causes placental infection in low parity pregnant women and is among the pathogens that affect fetal immunity. Recognizing the relationship between malaria and γδ T lymphocytes in adults, we asked whether neonatal γδ T cells would be altered in malaria-endemic regions as a marker for changes in fetal immunity. Our initial studies compared cord blood γδ T cells from deliveries to HIV- mothers in Jos (Nigeria) where malaria is endemic, or in Rome (Italy). We noted substantial differences in the Vγ2 repertoire for cord blood collected in Jos or Rome; differences were consistent with a negative selection mechanism operating on the fetal Vγ2 chain repertoire in neonates from Jos. A specific disruption affected the fraction of γδ T cells that we expect will respond to Bacille Calmette-Guerin (BCG). Fetal γδ T cell depletion might be a mechanism for impaired neonatal immunity and lowered responses to pediatric vaccines. PMID:18440637

Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010.

PubMed

Rieckmann, Andreas; Villumsen, Marie; Sørup, Signe; Haugaard, Line Klingen; Ravn, Henrik; Roth, Adam; Baker, Jennifer Lyn; Benn, Christine Stabell; Aaby, Peter

2017-04-01

When vaccinations with vaccinia against smallpox and Bacillus Calmette-Guérin (BCG) against tuberculosis were phased out in some high-income countries around 1980, the impact on overall mortality was not examined. Recent studies from low-income countries have suggested that these vaccines are associated with mortality reductions, not explained by specific disease protection. We examined whether vaccinia and BCG administered in childhood were associated with long-term mortality reductions in a high-income population. In this case-cohort study, we followed 47 622 schoolchildren from Copenhagen, Denmark, born 1965 to 1976, from their first health examination to 2010. This cohort experienced the phase-out of vaccinia and BCG vaccination programmes. A sub-cohort of 5 316 individuals (699 excluded) was followed for 164 450 person-years (0.2% were lost to follow-up), and 401 deaths due to natural causes (841 deaths in total) occurred in the full cohort. Compared with individuals who had not received vaccinia or BCG, those who had received both vaccinia and BCG had an adjusted hazard ratio (aHR) of 0.54 [95% confidence interval (CI): 0.36-0.81] for mortality due to natural causes of death; those who only received BCG had an aHR of 0.58 (95% CI: 0.39-0.85). Vaccinia and BCG were not associated with any protection against deaths by accidents, suicide or murder, the combined aHR being 0.94 (95% CI: 0.62-1.42). Vaccinia and BCG vaccinations were associated with better long-term survival, which was not explained by specific protection. Vaccines with beneficial non-specific effects may reduce overall mortality even after the target diseases are eradicated. © The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association

Probiotics Bacillus toyonensis and Saccharomyces boulardii improve the vaccine immune response to Bovine herpesvirus type 5 in sheep.

PubMed

Roos, Talita Bandeira; de Moraes, Carina Martins; Sturbelle, Régis Tuchtenhagen; Dummer, Luana Alves; Fischer, Geferson; Leite, Fábio Pereira Leivas

2018-04-01

There have been significant efforts toward the development of more efficient vaccines for animal health. A strategy that may be used to improve vaccine efficacy is the use of probiotics. Bovine herpesvirus 5 (BoHV-5) is an example of an important animal pathogen for which vaccines have provided only limited protection. In this study, we examined the use of the probiotics Bacillus toyonensis and Saccharomyces boulardii as a potential immune modulator to improve vaccine efficiency. Thirty, 5-month-old lambs were randomly grouped in three lots of 10 each and vaccinated at days 0, 21 and 42 of the experiment. They grazed on the same pasture and were fed ad libitum twice a day with commercial sheep feed supplemented with either B. toyonensis (1×10 6 CFU/g of feed) or S. boulardii (1×10 7 CFU/g of feed), or non-supplemented feed. The probiotic supplementation was suspended day 28; thereafter, the next 35days, they were fed with the same commercial feed as control group. Animals supplemented with probiotics showed a significant (p>0.001) increased seroconversions against BoHV-5, and higher neutralizing antibodies titres (p>0.05) to BoHV-5 than non-supplemented animals. At 63days of experiment, splenocytes from the supplemented sheep had higher mRNA transcription levels of cytokines IL-10 and IL-17A. These results suggest that these probiotics could provide a promising means of improving vaccine efficacy. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Bivalent Anthrax–Plague Vaccine That Can Protect against Two Tier-1 Bioterror Pathogens, Bacillus anthracis and Yersinia pestis

PubMed Central

Tao, Pan; Mahalingam, Marthandan; Zhu, Jingen; Moayeri, Mahtab; Kirtley, Michelle L.; Fitts, Eric C.; Andersson, Jourdan A.; Lawrence, William S.; Leppla, Stephen H.; Chopra, Ashok K.; Rao, Venigalla B.

2017-01-01

Bioterrorism remains as one of the biggest challenges to global security and public health. Since the deadly anthrax attacks of 2001 in the United States, Bacillus anthracis and Yersinia pestis, the causative agents of anthrax and plague, respectively, gained notoriety and were listed by the CDC as Tier-1 biothreat agents. Currently, there is no Food and Drug Administration-approved vaccine against either of these threats for mass vaccination to protect general public, let alone a bivalent vaccine. Here, we report the development of a single recombinant vaccine, a triple antigen consisting of all three target antigens, F1 and V from Y. pestis and PA from B. anthracis, in a structurally stable context. Properly folded and soluble, the triple antigen retained the functional and immunogenicity properties of all three antigens. Remarkably, two doses of this immunogen adjuvanted with Alhydrogel® elicited robust antibody responses in mice, rats, and rabbits and conferred complete protection against inhalational anthrax and pneumonic plague. No significant antigenic interference was observed. Furthermore, we report, for the first time, complete protection of animals against simultaneous challenge with Y. pestis and the lethal toxin of B. anthracis, demonstrating that a single biodefense vaccine can protect against a bioterror attack with weaponized B. anthracis and/or Y. pestis. This bivalent anthrax–plague vaccine is, therefore, a strong candidate for stockpiling, after demonstration of its safety and immunogenicity in human clinical trials, as part of national preparedness against two of the deadliest bioterror threats. PMID:28694806

A Bivalent Anthrax-Plague Vaccine That Can Protect against Two Tier-1 Bioterror Pathogens, Bacillus anthracis and Yersinia pestis.

PubMed

Tao, Pan; Mahalingam, Marthandan; Zhu, Jingen; Moayeri, Mahtab; Kirtley, Michelle L; Fitts, Eric C; Andersson, Jourdan A; Lawrence, William S; Leppla, Stephen H; Chopra, Ashok K; Rao, Venigalla B

2017-01-01

Bioterrorism remains as one of the biggest challenges to global security and public health. Since the deadly anthrax attacks of 2001 in the United States, Bacillus anthracis and Yersinia pestis , the causative agents of anthrax and plague, respectively, gained notoriety and were listed by the CDC as Tier-1 biothreat agents. Currently, there is no Food and Drug Administration-approved vaccine against either of these threats for mass vaccination to protect general public, let alone a bivalent vaccine. Here, we report the development of a single recombinant vaccine, a triple antigen consisting of all three target antigens, F1 and V from Y. pestis and PA from B. anthracis , in a structurally stable context. Properly folded and soluble, the triple antigen retained the functional and immunogenicity properties of all three antigens. Remarkably, two doses of this immunogen adjuvanted with Alhydrogel ® elicited robust antibody responses in mice, rats, and rabbits and conferred complete protection against inhalational anthrax and pneumonic plague. No significant antigenic interference was observed. Furthermore, we report, for the first time, complete protection of animals against simultaneous challenge with Y. pestis and the lethal toxin of B. anthracis , demonstrating that a single biodefense vaccine can protect against a bioterror attack with weaponized B. anthracis and/or Y. pestis . This bivalent anthrax-plague vaccine is, therefore, a strong candidate for stockpiling, after demonstration of its safety and immunogenicity in human clinical trials, as part of national preparedness against two of the deadliest bioterror threats.

Do childhood vaccines have non-specific effects on mortality?

PubMed Central

Cooper, William O.; Boyce, Thomas G.; Wright, Peter F.; Griffin, Marie R.

2003-01-01

A recent article by Kristensen et al. suggested that measles vaccine and bacille Calmette-Gu rin (BCG) vaccine might reduce mortality beyond what is expected simply from protection against measles and tuberculosis. Previous reviews of the potential effects of childhood vaccines on mortality have not considered methodological features of reviewed studies. Methodological considerations play an especially important role in observational assessments, in which selection factors for vaccination may be difficult to ascertain. We reviewed 782 English language articles on vaccines and childhood mortality and found only a few whose design met the criteria for methodological rigor. The data reviewed suggest that measles vaccine delivers its promised reduction in mortality, but there is insufficient evidence to suggest a mortality benefit above that caused by its effect on measles disease and its sequelae. Our review of the available data in the literature reinforces how difficult answering these considerations has been and how important study design will be in determining the effect of specific vaccines on all-cause mortality. PMID:14758409

[BCG vaccines for the prevention of tuberculosis in the world].

PubMed

Hashimoto, T

1997-11-01

The BCG vaccines will celebrate the 100th anniversary of their discovery in a decade at the beginning of the next century since Albert Calmette and Camille Guerin had presented it before the Academie des Sciences in 1908. At present tuberculosis kills more people than any other infectious disease about 3 million people a year, including almost 300,000 children under 15, and is producing over 7,000 deaths and over 24,000 new cases every day. Therefore, WHO declared a global health emergency in 1993. More worse, recently multi-drug resistant tubercle bacilli are emerging rapidly making TB patients incurable. Under these situations we need a potent anti-tuberculosis vaccine. So first of all, we must check the century-old BCG before proceeding further. At moment, the BCG vaccines are being used worldwide in the largest quantities in the world, but still most controversial vaccines anywhere. I would like to describe here their success and failure in the combat against the white plague. 1. The Expanded Programme on Immunization (EPI). In 1974, when the EPI was launched by WHO, less than 5% of the world children were immunized against six infectious diseases including tuberculosis. In 1995 statistics, BCG gave the highest vaccination coverage, 87% higher than any other 5 vaccines of EPI for children. The BCG in EPI must have saved a lot of infants as the vaccine, has been proved to be most effective against the blood-born tuberculosis of child type. 2. The efficacy of BCG vaccination against tuberculosis. Results of each 10 of randomized controlled trials (RCT) and Case-control studies (CCS) showed the protective efficacy against tuberculosis as uncertain, unpredictable, as protective efficacy varied from 80% to 0%. More recently, a Meta-analysis of selected papers on BCG field trials which were so far collected. They recalculated vaccine protective effect separately for pulmonary TB and for meningeal/miliary TB in the trials. As the result, it was found that protective

Guerin versus Malgaigne: a precedent for the free criticism of scientific papers.

PubMed

Peltier, L F

1983-01-01

The right to publish data and opinions which are critical of the theories and practices of our colleagues is taken for granted. This right was not gained without a struggle, both moral and legal. The case of Guerin versus Malgaigne established a significant precedent in this regard. Since the protagonists were both orthopaedic pioneers and the case involved the first surgical approach to the treatment of scoliosis, it is of great interest.

Estimating the costs of the vaccine supply chain and service delivery for selected districts in Kenya and Tanzania.

PubMed

Mvundura, Mercy; Lorenson, Kristina; Chweya, Amos; Kigadye, Rosemary; Bartholomew, Kathryn; Makame, Mohammed; Lennon, T Patrick; Mwangi, Steven; Kirika, Lydia; Kamau, Peter; Otieno, Abner; Murunga, Peninah; Omurwa, Tom; Dafrossa, Lyimo; Kristensen, Debra

2015-05-28

Having data on the costs of the immunization system can provide decision-makers with information to benchmark the costs when evaluating the impact of new technologies or programmatic innovations. This paper estimated the supply chain and immunization service delivery costs and cost per dose in selected districts in Kenya and Tanzania. We also present operational data describing the supply chain and service delivery points (SDPs). To estimate the supply chain costs, we collected resource-use data for the cold chain, distribution system, and health worker time and per diems paid. We also estimated the service delivery costs, which included the time cost of health workers to provide immunization services, and per diems and transport costs for outreach sessions. Data on the annual quantities of vaccines distributed to each facility, and the occurrence and duration of stockouts were collected from stock registers. These data were collected from the national store, 2 regional and 4 district stores, and 12 SDPs in each country for 2012. Cost per dose for the supply chain and immunization service delivery were estimated. The average annual costs per dose at the SDPs were $0.34 (standard deviation (s.d.) $0.18) for Kenya when including only the vaccine supply chain costs, and $1.33 (s.d. $0.82) when including immunization service delivery costs. In Tanzania, these costs were $0.67 (s.d. $0.35) and $2.82 (s.d. $1.64), respectively. Both countries experienced vaccine stockouts in 2012, bacillus Calmette-Guérin vaccine being more likely to be stocked out in Kenya, and oral poliovirus vaccine in Tanzania. When stockouts happened, they usually lasted for at least one month. Tanzania made investments in 2011 in preparation for planned vaccine introductions, and their supply chain cost per dose is expected to decline with the new vaccine introductions. Immunization service delivery costs are a significant portion of the total costs at the SDPs. Copyright © 2015 Elsevier Ltd. All

The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

PubMed Central

Lin, Philana Ling; Dietrich, Jes; Tan, Esterlina; Abalos, Rodolfo M.; Burgos, Jasmin; Bigbee, Carolyn; Bigbee, Matthew; Milk, Leslie; Gideon, Hannah P.; Rodgers, Mark; Cochran, Catherine; Guinn, Kristi M.; Sherman, David R.; Klein, Edwin; Janssen, Christopher; Flynn, JoAnne L.; Andersen, Peter

2011-01-01

It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56. PMID:22133873

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

PubMed Central

Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

2014-01-01

Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

Novel Recombinant Mycobacterium bovis BCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques▿

PubMed Central

Rosario, Maximillian; Hopkins, Richard; Fulkerson, John; Borthwick, Nicola; Quigley, Máire F.; Joseph, Joan; Douek, Daniel C.; Greenaway, Hui Yee; Venturi, Vanessa; Gostick, Emma; Price, David A.; Both, Gerald W.; Sadoff, Jerald C.; Hanke, Tomáš

2010-01-01

Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA401 as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA401 was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA401 and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration. PMID:20375158

Genetic Characterization of Bacillus anthracis 17 JB strain.

PubMed

Seyed-Mohamadi, Sakineh; Moradi Bidhendi, Soheila; Tadayon, Keyvan; Ghaderi, Rainak

2015-06-01

Bacillus anthracis is one of the most homogenous bacteria ever described. Some level of diversity. Bacillus anthracis 17JB is a laboratory strain It is broadly used as a challenge strain in guinea pigs for potency test of anthrax vaccine. This work describes genetic characterization of B. anthracis 17 JB strain using the SNPs and MLVA genotyping. In SNPs typing, the originally French 17JB strain represented the A.Br. 008/009 subgroup. In Levy's genotyping method, 843, 451 and 864 bp long fragments were identified at AA03, AJ03 and AA07 loci, respectively. In the vaccine manufacturer perspective these findings are much valuable on their own account, but similar research is required to extend molecular knowledge of B. anthracis epidemiology in Persia.

Alteration in lipid composition of plasma membranes of sensitive and resistant Guerin carcinoma cells due to the action of free and liposomal form of cisplatin.

PubMed

Naleskina, L A; Todor, I N; Nosko, M M; Lukianova, N Y; Pivnyuk, V M; Chekhun, V F

2013-09-01

To study in vivo changes of lipid composition of plasma membranes of sensitive and resistant to cisplatin Guerin carcinoma cells under influence of free and liposomal cisplatin forms. The isolation of plasma membranes from parental (sensitive) and resistant to cisplatin Guerin carcinoma cells was by differential ultracentrifugation in sucrose density gradient. Lipids were detected by method of thin-layer chromatography. It was determined that more effective action of cisplatin liposomal form on resistant cells is associated with essential abnormalities of conformation of plasma membrane due to change of lipid components and architectonics of rafts. It results in the increase of membrane fluidity. Reconstructions in lipid composition of plasma membranes of cisplatin-resistant Guerin carcinoma cells provide more intensive delivery of drug into the cells, increase of its concentration and more effective interaction with cellular structural elements.

Selection of a new Mycobacterium tuberculosis H37Rv aptamer and its application in the construction of a SWCNT/aptamer/Au-IDE MSPQC H37Rv sensor.

PubMed

Zhang, XiaoQing; Feng, Ye; Yao, QiongQiong; He, Fengjiao

2017-12-15

A rapid and accurate detection method for Mycobacterium tuberculosis (M. tuberculosis) is essential for effectively treating tuberculosis. However, current detection methods cannot meet these clinical requirements because the methods are slow or of low specificity. Consequently, a new highly specific ssDNA aptamer against M. tuberculosis reference strain H37Rv was selected by using the whole-cell systematic evolution of ligands by exponential enrichment technique. The selected aptamer was used to construct a fast and highly specific H37Rv sensor. The probe was produced by immobilizing thiol-modified aptamer on an Au interdigital electrode (Au-IDE) of a multichannel series piezoelectric quartz crystal (MSPQC) through Au-S bonding, and then single-walled carbon nanotubes (SWCNTs) were bonded on the aptamer by π-π stacking. SWCNTs were used as a signal indicator because of their considerable difference in conductivity compared with H37Rv. When H37Rv is present, it replaces the SWCNTs because it binds to the aptamer much more strongly than SWCNTs do. The replacement of SWCNTs by H37Rv resulted in a large change in the electrical properties, and this change was detected by the MSPQC. The proposed sensor is highly selective and can distinguish H37Rv from Mycobacterium smegmatis (M. smegmatis) and Bacillus Calmette-Guerin vaccine (BCG). The detection time was 70min and the detection limit was 100cfu/mL. Compared with conventional methods, this new SWCNT/aptamer/Au-IDE MSPQC H37Rv sensor was specific, rapid, and sensitive, and it holds great potential for the early detection of H37Rv in clinical diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Paid maternity leave and childhood vaccination uptake: Longitudinal evidence from 20 low-and-middle-income countries.

PubMed

Hajizadeh, Mohammad; Heymann, Jody; Strumpf, Erin; Harper, Sam; Nandi, Arijit

2015-09-01

The availability of maternity leave might remove barriers to improved vaccination coverage by increasing the likelihood that parents are available to bring a child to the clinic for immunizations. Using information from 20 low-and-middle-income countries (LMICs) we estimated the effect of paid maternity leave policies on childhood vaccination uptake. We used birth history data collected via Demographic and Health Surveys (DHS) to assemble a multilevel panel of 258,769 live births in 20 countries from 2001 to 2008; these data were merged with longitudinal information on the number of full-time equivalent (FTE) weeks of paid maternity leave guaranteed by each country. We used Logistic regression models that included country and year fixed effects to estimate the impact of increases in FTE paid maternity leave policies in the prior year on the receipt of the following vaccines: Bacillus Calmette-Guérin (BCG) commonly given at birth, diphtheria, tetanus, and pertussis (DTP, 3 doses) commonly given in clinic visits and Polio (3 doses) given in clinic visits or as part of campaigns. We found that extending the duration of paid maternity leave had a positive effect on immunization rates for all three doses of the DTP vaccine; each additional FTE week of paid maternity leave increased DTP1, 2 and 3 coverage by 1.38 (95% CI = 1.18, 1.57), 1.62 (CI = 1.34, 1.91) and 2.17 (CI = 1.76, 2.58) percentage points, respectively. Estimates were robust to adjustment for birth characteristics, household-level covariates, attendance of skilled health personnel at birth and time-varying country-level covariates. We found no evidence for an effect of maternity leave on the probability of receiving vaccinations for BCG or Polio after adjustment for the above-mentioned covariates. Our findings were consistent with the hypothesis that more generous paid leave policies have the potential to improve DTP immunization coverage. Further work is needed to understand the health effects of

Acetalated Dextran Microparticulate Vaccine Formulated via Coaxial Electrospray Preserves Toxin Neutralization and Enhances Murine Survival Following Inhalational Bacillus Anthracis Exposure.

PubMed

Gallovic, Matthew D; Schully, Kevin L; Bell, Matthew G; Elberson, Margaret A; Palmer, John R; Darko, Christian A; Bachelder, Eric M; Wyslouzil, Barbara E; Keane-Myers, Andrea M; Ainslie, Kristy M

2016-10-01

Subunit formulations are regarded as the safest type of vaccine, but they often contain a protein-based antigen that can result in significant challenges, such as preserving antigenicity during formulation and administration. Many studies have demonstrated that encapsulation of protein antigens in polymeric microparticles (MPs) via emulsion techniques results in total IgG antibody titers comparable to alum formulations, however, the antibodies themselves are non-neutralizing. To address this issue, a coaxial electrohydrodynamic spraying (electrospray) technique is used to formulate a microparticulate-based subunit anthrax vaccine under conditions that minimize recombinant protective antigen (rPA) exposure to harsh solvents and high shear stress. rPA and the adjuvant resiquimod are encapsulated either in separate or the same acetalated dextran MPs. Using a murine model, the electrospray formulations lead to higher IgG2a subtype titers as well as comparable total IgG antibody titers and toxin neutralization relative to the FDA-approved vaccine (BioThrax). BioThrax provides no protection against a lethal inhalational challenge of the highly virulent Ames Bacillus anthracis anthrax strain, whereas 50% of the mice vaccinated with separately encapsulated electrospray MPs survive. Overall, this study demonstrates the potential use of electrospray for encapsulating protein antigens in polymeric MPs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mycobacterium tuberculosis, but not vaccine BCG, specifically upregulates matrix metalloproteinase-1.

PubMed

Elkington, Paul T G; Nuttall, Robert K; Boyle, Joseph J; O'Kane, Cecilia M; Horncastle, Donna E; Edwards, Dylan R; Friedland, Jon S

2005-12-15

Pulmonary cavitation is fundamental to the global success of Mycobacterium tuberculosis. However, the mechanisms of this lung destruction are poorly understood. The biochemistry of lung matrix predicts matrix metalloproteinase (MMP) involvement in immunopathology. We investigated gene expression of all MMPs, proteins with a disintegrin and metalloproteinase domain, and tissue inhibitors of metalloproteinases in M. tuberculosis-infected human macrophages by real-time polymerase chain reaction. MMP secretion was measured by zymography and Western analysis, and expression in patients with pulmonary tuberculosis was localized by immunohistochemistry. MMP-1 and MMP-7 gene expression and secretion are potently upregulated by M. tuberculosis, and no increase in tissue inhibitor of metalloproteinase expression occurs to oppose their activity. Dexamethasone completely suppresses MMP-1 but not MMP-7 gene expression and secretion. In patients with active tuberculosis, macrophages express MMP-1 and MMP-7 adjacent to areas of tissue destruction. MMP-1 but not MMP-7 expression and secretion are relatively M. tuberculosis specific, are not upregulated by tuberculosis-associated cytokines, and are prostaglandin dependent. In contrast, the vaccine M. bovis bacillus Calmette-Guérin (BCG) does not stimulate MMP-1 secretion from human macrophages, although M. tuberculosis and BCG do upregulate MMP-7 equally. BCG-infected macrophages secrete reduced prostaglandin E2 concentrations compared with M. tuberculosis-infected macrophages, and prostaglandin pathway supplementation augments MMP-1 secretion from BCG-infected cells. M. tuberculosis specifically upregulates MMP-1 in a cellular model of human infection and in patients with tuberculosis. In contrast, vaccine BCG, which does not cause lung cavitation, does not upregulate prostaglandin E2-dependent MMP-1 secretion.

Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

PubMed

Miyake, Makito; Tatsumi, Yoshihiro; Matsumoto, Hiroaki; Nagao, Kazuhiro; Matsuyama, Hideyasu; Inamoto, Teruo; Azuma, Haruhito; Yasumoto, Hiroaki; Shiina, Hiroaki; Fujimoto, Kiyohide

2018-05-01

To describe the clinicopathological characteristics and prognosis of subsequent non-muscle-invasive bladder cancer (NMIBC) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC), and particularly its response to intravesical Bacillus Calmette-Guérin (BCG). An observational study was conducted in 1463 patients with UTUC who had undergone RNU and in 1555 patients with primary NMIBC. Of the 1463 patients with UTUC, 256 (17%) subsequently developed NMIBC (UTUC-NMIBC group) and were available for the analysis. The clinicopathological background and outcomes, including intravesical recurrence-free survival and bladder progression-free survival, were compared between the patients with UTUC-NMIBC and the patients with primary NMIBC treated with intravesical BCG. Propensity score matching was performed to adjust for the potential differences in the backgrounds of the two groups. To validate the utility of the CUETO scoring model in the UTUC-NMIBC group, risk scores were calculated and compared with the published probabilities for recurrence and progression. Compared with the unadjusted primary NMIBC group (n = 352), the UTUC-NMIBC group (n = 75) were found to have a worse prognosis for intravesical recurrence and progression, before propensity score matching. After propensity score matching for potential confounding factors, however, a worse prognosis was observed only for intravesical recurrence. The validation test of the CUETO scoring model for the UTUC-NMIBC group showed a significant difference in the rate of intravesical recurrence and progression for the 0-4 and 5-6 score groups between the UTUC-NMIBC group and the CUETO risk table reference data. Compared with the primary NMIBC group, the UTUC-NMIBC group had a worse prognosis after intravesical BCG, especially with regard to intravesical recurrence. This suggests that patients with UTUC-NMIBC are inherently poor responders to BCG exposure. An optimal treatment strategy and risk

A Reduced Antigen Load In Vivo, Rather Than Weak Inflammation, Causes a Substantial Delay in CD8+ T Cell Priming against Mycobacterium bovis (Bacillus Calmette-Guérin)1

PubMed Central

Russell, Marsha S.; Iskandar, Monica; Mykytczuk, Oksana L.; Nash, John H. E.; Krishnan, Lakshmi; Sad, Subash

2014-01-01

Regardless of the dose of Ag, Ag presentation occurs rapidly within the first few days which results in rapid expansion of the CD8+ T cell response that peaks at day 7. However, we have previously shown that this rapid priming of CD8+ T cells is absent during infection of mice with Mycobacterium bovis (bacillus Calmette-Guérin (BCG)). In this study, we have evaluated the mechanisms responsible for the delayed CD8+ T cell priming. Because BCG replicates poorly and survives within phagosomes we considered whether 1) generation of reduced amounts of Ag or 2) weaker activation by pathogen-associated molecular patterns (PAMPs) during BCG infection is responsible for the delay in CD8+ T cell priming. Using rOVA-expressing bacteria, our results indicate that infection of mice with BCG-OVA generates greatly reduced levels of OVA, which are 70-fold lower in comparison to the levels generated during infection of mice with Listeria monocytogenes-expressing OVA. Furthermore, increasing the dose of OVA, but not PAMP signaling during BCG-OVA infection resulted in rapid Ag presentation and consequent expansion of the CD8+ T cell response, indicating that the generation of reduced Ag levels, not lack of PAMP-associated inflammation, was responsible for delayed priming of CD8+ T cells. There was a strong correlation between the relative timing of Ag presentation and the increase in the level of OVA in vivo. Taken together, these results reveal that some slowly replicating pathogens, such as mycobacteria, may facilitate their chronicity by generating reduced Ag levels which causes a substantial delay in the development of acquired immune responses. PMID:17579040

Dendritic Cell Activity Driven by Recombinant Mycobacterium bovis BCG Producing Human IL-18, in Healthy BCG Vaccinated Adults.

PubMed

Szpakowski, Piotr; Biet, Franck; Locht, Camille; Paszkiewicz, Małgorzata; Rudnicka, Wiesława; Druszczyńska, Magdalena; Allain, Fabrice; Fol, Marek; Pestel, Joël; Kowalewicz-Kulbat, Magdalena

2015-01-01

Tuberculosis remains an enormous global burden, despite wide vaccination coverage with the Bacillus Calmette-Guérin (BCG), the only vaccine available against this disease, indicating that BCG-driven immunity is insufficient to protect the human population against tuberculosis. In this study we constructed recombinant BCG producing human IL-18 (rBCGhIL-18) and investigated whether human IL-18 produced by rBCGhIL-18 modulates DC functions and enhances Th1 responses to mycobacterial antigens in humans. We found that the costimulatory CD86 and CD80 molecules were significantly upregulated on rBCGhIL-18-infected DCs, whereas the stimulation of DCs with nonrecombinant BCG was less effective. In contrast, both BCG strains decreased the DC-SIGN expression on human DCs. The rBCGhIL-18 increased IL-23, IL-10, and IP-10 production by DCs to a greater extent than nonrecombinant BCG. In a coculture system of CD4(+) T cells and loaded DCs, rBCGhIL-18 favoured strong IFN-γ but also IL-10 production by naive T cells but not by memory T cells. This was much less the case for nonrecombinant BCG. Thus the expression of IL-18 by recombinant BCG increases IL-23, IP-10, and IL-10 expression by human DCs and enhances their ability to induce IFN-γ and IL-10 expression by naive T cells, without affecting the maturation phenotype of the DCs.

Dendritic Cell Activity Driven by Recombinant Mycobacterium bovis BCG Producing Human IL-18, in Healthy BCG Vaccinated Adults

PubMed Central

Biet, Franck; Rudnicka, Wiesława; Druszczyńska, Magdalena; Fol, Marek; Pestel, Joël

2015-01-01

Tuberculosis remains an enormous global burden, despite wide vaccination coverage with the Bacillus Calmette-Guérin (BCG), the only vaccine available against this disease, indicating that BCG-driven immunity is insufficient to protect the human population against tuberculosis. In this study we constructed recombinant BCG producing human IL-18 (rBCGhIL-18) and investigated whether human IL-18 produced by rBCGhIL-18 modulates DC functions and enhances Th1 responses to mycobacterial antigens in humans. We found that the costimulatory CD86 and CD80 molecules were significantly upregulated on rBCGhIL-18-infected DCs, whereas the stimulation of DCs with nonrecombinant BCG was less effective. In contrast, both BCG strains decreased the DC-SIGN expression on human DCs. The rBCGhIL-18 increased IL-23, IL-10, and IP-10 production by DCs to a greater extent than nonrecombinant BCG. In a coculture system of CD4+ T cells and loaded DCs, rBCGhIL-18 favoured strong IFN-γ but also IL-10 production by naive T cells but not by memory T cells. This was much less the case for nonrecombinant BCG. Thus the expression of IL-18 by recombinant BCG increases IL-23, IP-10, and IL-10 expression by human DCs and enhances their ability to induce IFN-γ and IL-10 expression by naive T cells, without affecting the maturation phenotype of the DCs. PMID:26339658

Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells.

PubMed

Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G

2000-10-31

We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer.

PubMed

Buss, Julieti Huch; Begnini, Karine Rech; Bender, Camila Bonemann; Pohlmann, Adriana R; Guterres, Silvia S; Collares, Tiago; Seixas, Fabiana Kömmling

2017-01-01

Mycobacterium bovis bacillus Calmette-Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

Oral administration of a Salmonella enterica-based vaccine expressing Bacillus anthracis protective antigen confers protection against aerosolized B. anthracis.

PubMed

Stokes, Margaret G M; Titball, Richard W; Neeson, Brendan N; Galen, James E; Walker, Nicola J; Stagg, Anthony J; Jenner, Dominic C; Thwaite, Joanne E; Nataro, James P; Baillie, Leslie W J; Atkins, Helen S

2007-04-01

Bacillus anthracis is the causative agent of anthrax, a disease that affects wildlife, livestock, and humans. Protection against anthrax is primarily afforded by immunity to the B. anthracis protective antigen (PA), particularly PA domains 4 and 1. To further the development of an orally delivered human vaccine for mass vaccination against anthrax, we produced Salmonella enterica serovar Typhimurium expressing full-length PA, PA domains 1 and 4, or PA domain 4 using codon-optimized PA DNA fused to the S. enterica serovar Typhi ClyA and under the control of the ompC promoter. Oral immunization of A/J mice with Salmonella expressing full-length PA protected five of six mice against a challenge with 10(5) CFU of aerosolized B. anthracis STI spores, whereas Salmonella expressing PA domains 1 and 4 provided only 25% protection (two of eight mice), and Salmonella expressing PA domain 4 or a Salmonella-only control afforded no measurable protection. However, a purified recombinant fusion protein of domains 1 and 4 provided 100% protection, and purified recombinant 4 provided protection in three of eight immunized mice. Thus, we demonstrate for the first time the efficacy of an oral S. enterica-based vaccine against aerosolized B. anthracis spores.

The Effect of Oral Vaccination with Mycobacterium bovis BCG on the Development of Tuberculosis in Captive European Badgers (Meles meles).

PubMed

Chambers, Mark A; Aldwell, Frank; Williams, Gareth A; Palmer, Si; Gowtage, Sonya; Ashford, Roland; Dalley, Deanna J; Davé, Dipesh; Weyer, Ute; Salguero, Francisco J; Nunez, Alejandro; Nadian, Allan K; Crawshaw, Timothy; Corner, Leigh A L; Lesellier, Sandrine

2017-01-01

The European badger ( Meles meles ) is a reservoir host of Mycobacterium bovis and responsible for a proportion of the tuberculosis (TB) cases seen in cattle in the United Kingdom and Republic of Ireland. An injectable preparation of the bacillus Calmette-Guérin (BCG) vaccine is licensed for use in badgers in the UK and its use forms part of the bovine TB eradication plans of England and Wales. However, there are practical limitations to the widespread application of an injectable vaccine for badgers and a research priority is the development of an oral vaccine deliverable to badgers in bait. Previous studies reported the successful vaccination of badgers with oral preparations of 10 8 colony forming units (CFU) of both Pasteur and Danish strains of BCG contained within a lipid matrix composed of triglycerides of fatty acids. Protection against TB in these studies was expressed as a reduction in the number and apparent progression of visible lesions, and reductions in the bacterial load and dissemination of infection. To reduce the cost of an oral vaccine and reduce the potential for environmental contamination with BCG, it is necessary to define the minimal efficacious dose of oral BCG for badgers. The objectives of the two studies reported here were to compare the efficacy of BCG Danish strain in a lipid matrix with unformulated BCG given orally, and to evaluate the efficacy of BCG Danish in a lipid matrix at a 10-fold lower dose than previously evaluated in badgers. In the first study, both BCG unformulated and in a lipid matrix reduced the number and apparent progression of visible lesions and the dissemination of infection from the lung. In the second study, vaccination with BCG in the lipid matrix at a 10-fold lower dose produced a similar outcome, but with greater intra-group variability than seen with the higher dose in the first study. Further research is needed before we are able to recommend a final dose of BCG for oral vaccination of badgers against TB

The Effect of Oral Vaccination with Mycobacterium bovis BCG on the Development of Tuberculosis in Captive European Badgers (Meles meles)

PubMed Central

Chambers, Mark A.; Aldwell, Frank; Williams, Gareth A.; Palmer, Si; Gowtage, Sonya; Ashford, Roland; Dalley, Deanna J.; Davé, Dipesh; Weyer, Ute; Salguero, Francisco J.; Nunez, Alejandro; Nadian, Allan K.; Crawshaw, Timothy; Corner, Leigh A. L.; Lesellier, Sandrine

2017-01-01

The European badger (Meles meles) is a reservoir host of Mycobacterium bovis and responsible for a proportion of the tuberculosis (TB) cases seen in cattle in the United Kingdom and Republic of Ireland. An injectable preparation of the bacillus Calmette-Guérin (BCG) vaccine is licensed for use in badgers in the UK and its use forms part of the bovine TB eradication plans of England and Wales. However, there are practical limitations to the widespread application of an injectable vaccine for badgers and a research priority is the development of an oral vaccine deliverable to badgers in bait. Previous studies reported the successful vaccination of badgers with oral preparations of 108 colony forming units (CFU) of both Pasteur and Danish strains of BCG contained within a lipid matrix composed of triglycerides of fatty acids. Protection against TB in these studies was expressed as a reduction in the number and apparent progression of visible lesions, and reductions in the bacterial load and dissemination of infection. To reduce the cost of an oral vaccine and reduce the potential for environmental contamination with BCG, it is necessary to define the minimal efficacious dose of oral BCG for badgers. The objectives of the two studies reported here were to compare the efficacy of BCG Danish strain in a lipid matrix with unformulated BCG given orally, and to evaluate the efficacy of BCG Danish in a lipid matrix at a 10-fold lower dose than previously evaluated in badgers. In the first study, both BCG unformulated and in a lipid matrix reduced the number and apparent progression of visible lesions and the dissemination of infection from the lung. In the second study, vaccination with BCG in the lipid matrix at a 10-fold lower dose produced a similar outcome, but with greater intra-group variability than seen with the higher dose in the first study. Further research is needed before we are able to recommend a final dose of BCG for oral vaccination of badgers against TB or

Immunological correlates for protection against intranasal challenge of Bacillus anthracis spores conferred by a protective antigen-based vaccine in rabbits.

PubMed

Weiss, Shay; Kobiler, David; Levy, Haim; Marcus, Hadar; Pass, Avi; Rothschild, Nili; Altboum, Zeev

2006-01-01

Correlates between immunological parameters and protection against Bacillus anthracis infection in animals vaccinated with protective antigen (PA)-based vaccines could provide surrogate markers to evaluate the putative protective efficiency of immunization in humans. In previous studies we demonstrated that neutralizing antibody levels serve as correlates for protection in guinea pigs (S. Reuveny et al., Infect. Immun. 69:2888-2893, 2001; H. Marcus et al., Infect. Immun. 72:3471-3477, 2004). In this study we evaluated similar correlates for protection by active and passive immunization of New Zealand White rabbits. Full immunization and partial immunization were achieved by single and multiple injections of standard and diluted doses of a PA-based vaccine. Passive immunization was carried out by injection of immune sera from rabbits vaccinated with PA-based vaccine prior to challenge with B. anthracis spores. Immunized rabbits were challenged by intranasal spore instillation with one of two virulent strains (strains Vollum and ATCC 6605). The immune competence was estimated by measuring the level of total anti-PA antibodies, the neutralizing antibody titers, and the conferred protective immunity. The results indicate that total anti-PA antibody titers greater than 1 x 10(5) conferred protection, whereas lower titers (between 10(4) and 10(5)) provided partial protection but failed to predict protection. Neutralizing antibody titers between 500 and 800 provided partial protection, while titers higher than 1,000 conferred protection. In conclusion, this study emphasizes that regardless of the immunization regimen or the time of challenge, neutralizing antibody titers are better predictors of protection than total anti-PA titers.

Comparative performance of public and private sector delivery of BCG vaccination: evidence from Sub-Saharan Africa.

PubMed

Wagner, Zachary; Szilagyi, Peter G; Sood, Neeraj

2014-07-31

The private sector is an important source of health care in the developing world. However, there is limited evidence on how private providers compare to public providers, particularly for preventive services such as immunizations. We used data from Sub-Saharan Africa (SSA) to assess public-private differences in Bacillus Calmette-Guérin (BCG) vaccine delivery. We used demographic and health surveys from 102,629 children aged 0-59 months from 29 countries across SSA to measure differences in BCG status for children born at private versus public health facilities (BCG is recommended at birth). We used a probit model to estimate public-private differences in BCG delivery, while controlling for key confounders. Next, we estimated how differences in BCG status evolved over time for children born at private versus public facilities. Finally, we estimated heterogeneity in public-private differences based on wealth and rural-urban residency. We found that children born at a private facility were 7.1 percentage points less likely to receive BCG vaccine in the same month as birth than children born at a public facility (95% CI 6.3-8.0; p<0.001). Most of this difference was driven by for-profit private providers (as opposed to NGOs) where the BCG provision rate was 10.0 percentage points less than public providers (95% CI 9.0-11.2; p<0.001) compared to only 2.4 percentage points for NGOs (95% CI 1.0-3. 8; p<0.01). Moreover, children born at private for-profit facilities remained less likely to be vaccinated up to 59 months after birth. Finally, public-private differences were more pronounced for poorer children and children in rural areas. The for-profit private sector performed substantially worse than the public sector in providing BCG vaccine to newborns, resulting in a longer duration of vulnerability to tuberculosis. This disparity was greater for poorer children and children in rural areas. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tuberculin Skin-Test Reactions Are Unaffected by the Severity of Hyperendemic Intestinal Helminth Infections and Co-Infections

PubMed Central

Zevallos, Karine; Vergara, Katherine C.; Vergara, Antonio; Vidal, Carlos; Garcia, Hector H.; Evans, Carlton A.

2010-01-01

The tuberculin skin test (TST) quantifies cell-mediated immunity to tuberculosis antigens. Helminths suppress cell-mediated immunity, so we studied the effect of helminth infection and deworming on the TST in a randomized, double-blind, placebo-controlled study in an indigenous Amazon community (N = 195). Stool microscopy diagnosed helminths in 98% and co-infection with multiple species in 24% of study subjects. The TST was positive (≥ 10 mm) for 49%, and responses increased with age (P < 0.001), Bacille Calmette Guerin (BCG) vaccination (P = 0.01), and tuberculosis contact (P = 0.05). TST results had no association with helminth-egg concentrations, species, or co-infections (all P > 0.1). One month after deworming with albendazole (three daily 400-mg doses), helminths were reduced, but 63% remained infected with helminths. Albendazole did not cause a change in TST size (P = 0.8) or positivity (P = 0.9) relative to placebo. Thus, TST reactions were unaffected by albendazole therapy that partially cured intestinal helminth infections, and TST interpretation was unaffected by high-burden helminth infections and co-infection with multiple helminth species. PMID:20682875

Destruction of Various Kinds of Mycobacteria in Milk by Pasteurization

PubMed Central

Harrington, Rube; Karlson, Alfred G.

1965-01-01

Various strains of unclassified mycobacteria, Mycobacterium tuberculosis (including H37Rv strains), M. bovis, M. avium, M. fortuitum, and bacille Calmette-Guerin, were exposed to the temperature and time of pasteurization in skim milk in test tubes. Of the 195 strains tested, there were a few surviving colonies among 6 of 33 skotochromogens, 1 of 26 photochromogens, 10 of 79 nonchromogens, and 1 of 9 rapid growers. Subcultures of the surviving colonies failed to resist the pasteurization tests on subsequent trials. PMID:14325295

Bacillus anthracis

PubMed Central

Spencer, R C

2003-01-01

The events of 11 September 2001 and the subsequent anthrax outbreaks have shown that the West needs to be prepared for an increasing number of terrorist attacks, which may include the use of biological warfare. Bacillus anthracis has long been considered a potential biological warfare agent, and this review will discuss the history of its use as such. It will also cover the biology of this organism and the clinical features of the three disease forms that it can produce: cutaneous, gastrointestinal, and inhalation anthrax. In addition, treatment and vaccination strategies will be reviewed. PMID:12610093

Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen.

PubMed

Oscherwitz, Jon; Quinn, Conrad P; Cease, Kemp B

2015-05-11

Epitope-focused immunogens can elicit antibody against the loop neutralizing determinant (LND), a neutralizing epitope found within the 2β2-2β3 loop of protective antigen (PA), which can protect rabbits from high-dose inhalation challenge with Bacillus anthracis Ames strain. Interestingly, data suggests that this epitope is relatively immunosilent in rabbits and non-human primates immunized with full length PA. To determine whether the LND is immunosilent among humans vaccinated with PA, we screened antisera from AVA- or placebo-vaccinees from a clinical trial for antibody reactive with the LND. AVA-vaccinee sera had significant PA-specific antibody compared to placebo-vaccinee sera; however, sera from the two cohorts were indistinguishable with regard to the frequency of individuals with antibody specific for the LND. AVA-vaccinees have a low frequency of antibody reactive with the LND. As with rabbits and non-human primates, the elicitation of LND-specific antibody in humans appears to require immunization with an epitope-focused vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of delayed anthrax vaccine dose on Bacillus anthracis protective antigen IgG response and lethal toxin neutralization activity.

PubMed

Pittman, Phillip R; Fisher, Diana; Quinn, Xiaofei; Schmader, Trevor; Barrera-Oro, Julio G

2013-10-17

We describe the Bacillus anthracis protective antigen IgG antibody response and the B. anthracis lethal toxin neutralization activity to a delayed dose of anthrax vaccine adsorbed (AVA, BioThrax(®)) using validated assays. 373 individuals received 1, 2, or 3 priming doses, 18-24 months afterward, they received a delayed dose of AVA. Overall, 23.6% of subjects showed detectable anti-PA IgG before the boost, compared to 99.2% (P<0.0001) 28 days after the boost. Geometric mean anti-PA IgG concentration (GMC) was 1.66 μg/mL before and 887.82 μg/mL after the boost (P<0.0001). The proportion of individuals with four-fold increase in GMC following the boost ranged from 93.8% to 100%. Robust anti-PA IgG levels and B. anthracis lethal toxin neutralization activity are induced when an AVA dose is delayed as long as two years. These data support continuing with the vaccination schedule when a dose is delayed as long as two years rather than restarting the series. Published by Elsevier Ltd.

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge with Bacillus cereus G9241.

PubMed

Palmer, John; Bell, Matt; Darko, Christian; Barnewall, Roy; Keane-Myers, Andrea

2014-11-01

In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid-borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen-specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model. Published 2014. This article is a US Government work and is in the public domain in the USA.

Comparing an Interferon Gamma Release Assay with the Tuberculin Skin Test During Pregnancy: Implications for Tuberculosis Screening During Prenatal Care.

PubMed

Molina, Rose; Venkatesh, Kartik; Schantz-Dunn, Julianna; Meadows, Audra; Nour, Nawal; Diouf, Khady

2016-06-01

Background Currently there are no guidelines regarding optimal screening for latent tuberculosis infection during pregnancy. Objective This study measures completion rates and the concordance between the TSPOT.TB, a commercially available interferon gamma release assay (IGRA), and the traditional tuberculin skin test (TST) in a predominantly urban minority obstetrics practice. Design This is an observational cohort study of 141 pregnant women enrolled from an obstetrics practice with a large immigrant population. Women with a history of a positive TST result were excluded. Demographic and clinical risk factors for tuberculosis were assessed. Enrolled women underwent a T-SPOT.TB test and placement of TST, and returned in 48-72 h for TST interpretation. We calculated the completion rate and frequency of a positive result for each test, as well as the concordance between the T-SPOT.TB and TST. Results Among the 141 women enrolled, 75 % were either Latina or African-American, 44 % were born in a country with a high TB prevalence, and 52 % had received the Bacillus Calmette-Guerin vaccine. Seven women (5 %) had a positive screening test, a total of 3 positive T-SPOT.TB results and 6 positive TST results, and all were from countries with a high TB prevalence. The concordance of the two tests was 96.3 %. The completion rate for the T-SPOT.TB was 98 %, while the completion rate for the TST was 63 %. The IGRA test had a markedly higher completion rate in addition to maintaining high concordance with the two-step TST in this population of pregnant women with a high prevalence of prior TB exposure. Targeted screening of women from countries with a high prevalence of tuberculosis may be warranted during prenatal care.

Influence of ESAT-6 secretion system 1 (RD1) of Mycobacterium tuberculosis on the interaction between mycobacteria and the host immune system.

PubMed

Majlessi, Laleh; Brodin, Priscille; Brosch, Roland; Rojas, Marie-Jésus; Khun, Huot; Huerre, Michel; Cole, Stewart T; Leclerc, Claude

2005-03-15

The chromosomal locus encoding the early secreted antigenic target, 6 kDa (ESAT-6) secretion system 1 of Mycobacterium tuberculosis, also referred to as "region of difference 1 (RD1)," is absent from Mycobacterium bovis bacillus Calmette-Guerin (BCG). In this study, using low-dose aerosol infection in mice, we demonstrate that BCG complemented with RD1 (BCG::RD1) displays markedly increased virulence which albeit does not attain that of M. tuberculosis H37Rv. Nevertheless, phenotypic and functional analyses of immune cells at the site of infection show that the capacity of BCG::RD1 to initiate recruitment/activation of immune cells is comparable to that of fully virulent H37Rv. Indeed, in contrast to the parental BCG, BCG::RD1 mimics H37Rv and induces substantial influx of activated (CD44highCD45RB(-)CD62L(-)) or effector (CD45RB(-)CD27(-)) T cells and of activated CD11c(+)CD11bhigh cells to the lungs of aerosol-infected mice. For the first time, using in vivo analysis of transcriptome of inflammatory cytokines and chemokines of lung interstitial CD11c+ cells, we show that in a low-dose aerosol infection model, BCG::RD1 triggered an activation/inflammation program comparable to that induced by H37Rv while parental BCG, due to its overattenuation, did not initiate the activation program in lung interstitial CD11c+ cells. Thus, products encoded by the ESAT-6 secretion system 1 of M. tuberculosis profoundly modify the interaction between mycobacteria and the host innate and adaptive immune system. These modifications can explain the previously described improved protective capacity of BCG::RD1 vaccine candidate against M. tuberculosis challenge.

Immunization dropout rate and data quality among children 12-23 months of age in Ghana.

PubMed

Baguune, Benjamin; Ndago, Joyce Aputere; Adokiya, Martin Nyaaba

2017-01-01

Immunization against diseases is one of the most important public health interventions with cost effective means to preventing childhood morbidity, mortality and disability. However, a proportion of children particularly in Africa are not fully immunized with the recommended vaccines. Thus, many children are still susceptible to the Expanded Program on Immunization (EPI) targeted diseases. The objective of this study was to determine the immunization dropout rate and data quality among children aged 12-23 months in Techiman Municipality, Ghana. A cross-sectional cluster survey was conducted among 600 children. Data was collected using semi-structured questionnaire through face-to-face interviews. Before the main data collection, the tools were pre-tested in three different communities in the Municipality. The mothers/caregivers were interviewed, extracted information from the child immunization cards and observation employed to confirm the presence of Bacillus Calmette-Guerin (BCG) scar on each child. Routine immunization data was also extracted from immunization registers and annual reports in the Municipality. I mmunization coverage for each of the fifteen vaccines doses is above 90.0% while full childhood immunized status is 89.5%. Immunization dropout rate was 5.6% (using BCG and Measles as proxy vaccines). This is lower than the 10.0% cutoff point by World Health Organization. However, routine administrative data was characterized by some discrepancies (e.g. > 100.0% immunization coverage for each of the vaccines) and high dropout rate (BCG - Measles = 31.5%). Binary regression was performed to determine predictors of dropout rate. The following were statistically significant: married (OR = 0.31; 95% = CI 0.15-0.62; and p  = 0.001), Christianity (OR = 0.27; 95% CI = 0.13-0.91; and p  < 0.001), female child (OR = 0.50; 95% CI = 0.26-0.91; and p  = 0.024) and possession of immunization card (OR = 50.3; 95% CI = 14.40-175.92; and p

New drug candidates and therapeutic targets for tuberculosis therapy.

PubMed

Zhang, Ying; Post-Martens, Katrin; Denkin, Steven

2006-01-01

Despite advances in chemotherapy and the BCG (Bacillus Calmette-Guérin) vaccine, tuberculosis remains a significant infectious disease. Although it can be cured, the therapy takes at least 6-9 months, and the laborious and lengthy treatment brings with it dangers of noncompliance, significant toxicity and drug resistance. The increasing emergence of drug resistance and the problem of mycobacterial persistence highlight the need to develop novel TB drugs that are active against drug resistant bacteria but, more importantly, kill persistent bacteria and shorten the length of treatment. Recent new and exciting developments in tuberculosis drug discovery show good promise of a possible revolution in the chemotherapy of tuberculosis.

Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study.

PubMed

Villumsen, Marie; Sørup, Signe; Jess, Tine; Ravn, Henrik; Relander, Thomas; Baker, Jennifer L; Benn, Christine Stabell; Sørensen, Thorkild I A; Aaby, Peter; Roth, Adam

2009-11-16

Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N=47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N=20) and lymphoma (N=51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N=2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR=0.49 (95% CI: 0.26-0.93)), whereas smallpox vaccination did not (HR=1.32 (0.56-3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR=0.81 (0.31-2.16); smallpox vaccination HR=1.32 (0.49-3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.

PROTECTION AGAINST TYPHOID-LIKE INFECTIONS BY VACCINATION

PubMed Central

Nichols, Henry J.; Stimmel, Clarence O.

1923-01-01

1. A natural infection of guinea pigs with the "mutton" strain of Bacillus aertrycke was used to test the protective power of vaccination against the typhoid group of infections. 2. Under the conditions of the experiment, complete protection was secured by vaccination with full strength fresh saline vaccine, while 100 per cent of deaths occurred among the controls. 3. The immunity acquired is variable and depends on the number of organisms injected. 4. Vaccine kept 10 to 14 months gave less protection than vaccine 8 months old and under. 5. Saline vaccine was more effective than lipovaccine, sensitized vaccine, or supernatant fluid vaccine. 6. Resuspended vaccine was as effective as the original vaccine. 7. In one experiment, group vaccine, made of typhoid Para A and Para B bacilli, was as effective as the original specific vaccine. PMID:19868790

Comparative performance of a licensed anthrax vaccine versus electroporation based delivery of a PA encoding DNA vaccine in rhesus macaques.

PubMed

Livingston, Brian D; Little, Stephen F; Luxembourg, Alain; Ellefsen, Barry; Hannaman, Drew

2010-01-22

DNA vaccination is a promising immunization strategy that could be applied in the development of vaccines for a variety of prophylactic and therapeutic indications. Utilizing anthrax protective antigen as a model antigen, we demonstrate that electroporation mediated delivery enhanced the immunogenicity of DNA vaccines in nonhuman primates over 100-fold as compared to conventional intramuscular injection. Two administrations of a DNA vaccine with electroporation elicited anthrax toxin neutralizing antibody responses in 100% of rhesus macaques. Toxin neutralizing antibodies were sustained for the nearly 1-year study duration and were correlated with protection against subsequent lethal Bacillus anthracis spore challenge. Collectively, electroporation mediated DNA vaccination conferred protection comparable to that observed following vaccination with an FDA approved anthrax vaccine.

Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine.

PubMed

Hansen, Scott G; Zak, Daniel E; Xu, Guangwu; Ford, Julia C; Marshall, Emily E; Malouli, Daniel; Gilbride, Roxanne M; Hughes, Colette M; Ventura, Abigail B; Ainslie, Emily; Randall, Kurt T; Selseth, Andrea N; Rundstrom, Parker; Herlache, Lauren; Lewis, Matthew S; Park, Haesun; Planer, Shannon L; Turner, John M; Fischer, Miranda; Armstrong, Christina; Zweig, Robert C; Valvo, Joseph; Braun, Jackie M; Shankar, Smitha; Lu, Lenette; Sylwester, Andrew W; Legasse, Alfred W; Messerle, Martin; Jarvis, Michael A; Amon, Lynn M; Aderem, Alan; Alter, Galit; Laddy, Dominick J; Stone, Michele; Bonavia, Aurelio; Evans, Thomas G; Axthelm, Michael K; Früh, Klaus; Edlefsen, Paul T; Picker, Louis J

2018-02-01

Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)-which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4 + and CD8 + memory T cell responses-can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.

Vaccines and bioterrorism: smallpox and anthrax.

PubMed

Kimmel, Sanford R; Mahoney, Martin C; Zimmerman, Richard K

2003-01-01

Because of the success of vaccination and the ring strategy in eradicating smallpox from the world, smallpox vaccine has not been recommended for the United States civilian populations for decades. Given the low but possible threat of bioterrorism, smallpox vaccination is now recommended for those teams investigating potential smallpox cases and for selected personnel of acute-care hospitals who would be needed to care for victims in the event of a terrorist attack. Treatment and post-exposure prophylaxis for anthrax are ciprofloxacin or doxycycline. Anthrax vaccine alone is not effective for post-exposure prevention of anthrax; vaccination is accompanied by 60 days of antibiotic therapy. In addition to military use, anthrax vaccine is recommended for pre-exposure use in those persons whose work involves repeated exposure to Bacillus anthracis spores.

Tuberculin reactivity and tuberculosis epidemiology in the Pakaanóva (Wari') Indians of Rondônia, south-western Brazilian Amazon.

PubMed

Escobar, A L; Coimbra, C E A; Camacho, L A B; Santos, R V

2004-01-01

To investigate the characteristics of tuberculin skin test reactivity in the Pakaanóva Indians, in Amazonia, Brazil, after revaccination of all study participants with bacille Calmette-Guerin (BCG). The investigation was designed as a post-BCG vaccination purified protein derivative (PPD) survey. Data included PPD readings, age, sex, nutritional status, place of residence, previous tuberculosis, physical examinations and BCG status. Bivariate and multivariate logistic regression analyses were conducted. About 90% (n = 505) of the total population participated. One third (32.1%) of the subjects presented induration > or = 10 mm at 72 h. Induration sizes showed weak linear correlation with age; differences between sexes were not observed. Skin reaction was not associated with nutritional status. Individuals with a history of tuberculosis were six times more likely to test positive. History of tuberculosis, age, and previous BCG vaccination were significantly associated with PPD reactivity in the multivariate analyses. The Pakaanóva showed a high proportion (58.4%) of non-reactors, even with a recent BCG booster. Sex differences in PPD reactivity were either not present or could not be demonstrated. The association between age and PPD reactivity resembles that observed in other Amazonian populations. The authors discuss the potential of PPD testing as a screening tool to enhance tuberculosis detection, especially in indigenous populations in Amazonia with limited access to health services.

Anthrax vaccination strategies

PubMed Central

Cybulski, Robert J.; Sanz, Patrick; O'Brien, Alison D.

2009-01-01

The biological attack conducted through the U.S. postal system in 2001 broadened the threat posed by anthrax from one pertinent mainly to soldiers on the battlefield to one understood to exist throughout our society. The expansion of the threatened population placed greater emphasis on the reexamination of how we vaccinate against Bacillus anthracis. The currently-licensed Anthrax Vaccine, Adsorbed (AVA) and Anthrax Vaccine, Precipitated (AVP) are capable of generating a protective immune response but are hampered by shortcomings that make their widespread use undesirable or infeasible. Efforts to gain U.S. Food and Drug Administration (FDA) approval for licensure of a second generation recombinant protective antigen (rPA)-based anthrax vaccine are ongoing. However, this vaccine's reliance on the generation of a humoral immune response against a single virulence factor has led a number of scientists to conclude that the vaccine is likely not the final solution to optimal anthrax vaccine design. Other vaccine approaches, which seek a more comprehensive immune response targeted at multiple components of the B. anthracis organism, are under active investigation. This review seeks to summarize work that has been done to build on the current PA-based vaccine methodology and to evaluate the search for future anthrax prophylaxis strategies. PMID:19729034

The Canonical Wnt Pathway Drives Macropinocytosis in Cancer.

PubMed

Redelman-Sidi, Gil; Binyamin, Anna; Gaeta, Isabella; Palm, Wilhelm; Thompson, Craig B; Romesser, Paul B; Lowe, Scott W; Bagul, Mukta; Doench, John G; Root, David E; Glickman, Michael S

2018-06-05

Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the beta catenin-dependent canonical Wnt pathway, was Pak1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation. Copyright ©2018, American Association for Cancer Research.

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154.

PubMed

Kunnath-Velayudhan, Shajo; Goldberg, Michael F; Saini, Neeraj K; Johndrow, Christopher T; Ng, Tony W; Johnson, Alison J; Xu, Jiayong; Chan, John; Jacobs, William R; Porcelli, Steven A

2017-10-01

Analysis of Ag-specific CD4 + T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. Although several methods exist for identifying Ag-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC class II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live Ag-specific CD4 + T cells, but this approach remains underexplored and, to our knowledge, has not previously been applied in mycobacteria-infected animals. In this article, we show that CD154 expression identifies adoptively transferred or endogenous Ag-specific CD4 + T cells induced by Mycobacterium bovis bacillus Calmette-Guérin vaccination. We confirmed that Ag-specific cytokine production was positively correlated with CD154 expression by CD4 + T cells from bacillus Calmette-Guérin-vaccinated mice and show that high-quality microarrays can be performed from RNA isolated from CD154 + cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of CD4 + CD154 + cells was distinct from that of CD154 - cells and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4 + T cells that is characterized by the production of IL-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live Ag-specific CD4 + T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts. Copyright © 2017 by The American Association of Immunologists, Inc.

An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon.

PubMed

Sousa, A O; Salem, J I; Lee, F K; Verçosa, M C; Cruaud, P; Bloom, B R; Lagrange, P H; David, H L

1997-11-25

A survey of an emerging tuberculosis epidemic among the Yanomami Indians of the Amazonian rain forest provided a unique opportunity to study the impact of tuberculosis on a population isolated from contact with the tubercle bacillus for millennia until the mid-1960s. Within the Yanomami population, an extraordinary high prevalence of active tuberculosis (6.4% of 625 individuals clinically examined) was observed, indicating a high susceptibility to disease, even among bacille Calmette-Guérin-vaccinated individuals. Observational studies on cell-mediated and humoral immune responses of the Yanomami Indians compared with contemporary residents of the region suggest profound differences in immunological responsiveness to Mycobacterium tuberculosis infection. Among the Yanomami, a very high prevalence of tuberculin skin test anergy was found. Of patients with active tuberculosis, 46% had purified protein derivative of tuberculosis reactions <10 mm; similarly 58% of recent bacillus Calmette-Guérin vaccines exhibited skin test reactions <5 mm. The Yanomami also had higher titers of antibodies against M. tuberculosis glycolipid antigens (>70%) than the control subjects comprised of Brazilians of European descent (14%). The antibodies were mostly of the IgM isotype. Among the tuberculosis patients who also produced IgG antibodies, the titers of IgG4 were significantly higher among the Yanomami than in the control population. Although it was not possible to analyze T-cell responses or patterns of lymphokine production in vitro because of the remoteness of the villages from laboratory facilities, the results suggest that the first encounter of the Yanomami Indian population with tuberculosis engenders a diminished cell-mediated immune response and an increased production antibody responses, relative to other populations with extensive previous contact with the pathogen. These findings suggest that tuberculosis may represent a powerful selective pressure on human evolution

Pros and cons of BCG vaccination in countries with low incidence of tuberculosis.

PubMed

Tala, E O; Tala-Heikkilä, M M

1994-07-01

Preventive bacille Calmette-Guérin (BCG) vaccination, together with case finding and effective chemotherapy, has formed an integral part of the tuberculosis (TB) control program in most countries. In some low-incidence countries the balance of prevention has been more on the side of chemoprophylaxis than of BCG vaccination. The time clearly has come when the strategy of mass BCG vaccination no longer is indicated medically, nor is it cost-effective. The pros and cons of the programs need to be critically evaluated against the present epidemiological background, taking into account the facts that TB, the killer disease, is recovering strength, human immunodeficiency virus infection is on the increase, and multidrug-resistant TB has changed the outcome of this previously fully curable disease. Although no longer appropriate for mass programs, BCG vaccination still should be considered for the protection of selected risk groups in low-incidence countries. The overall efficacy may be of the order 50% to 80%, but the variation is great. Therefore, further research urgently is needed on the effectiveness of BCG as an intervention in local TB programs.

A Young Man With Hemoptysis and Cavitary Lung Lesions.

PubMed

Brady, Virginia A; Zinchuk, Andrey V; Siegel, Mark D; Possick, Jennifer D

2018-04-01

A man in his 20s presented with 2 months of mild fatigue and intermittent hemoptysis of less than a tablespoon per episode. He was previously healthy and was on no medications. He denied fevers, night sweats, weight loss, wheezing, dyspnea, musculoskeletal symptoms, and rashes. He had emigrated from a South American country to the United States 3 years earlier. He worked as a groundskeeper but had no exposures to animals, mold, or dusts. He reported rare prior cigarette smoking with no history of alcohol or drug use. He was unsure whether he had received the Bacillus Calmette-Guérin vaccine. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Genetic and Physiological Studies of Bacillus anthracis Related to Development of an Improved Vaccine

DTIC Science & Technology

1987-07-01

nontransformable Bacillus species such as B. anthracis. Our results suggest that plasmid pLS20 of Bacillus subtilis ( natto ), which promotes transfer of the...mobilizing pBC16, pLS20 mediates transfer of the B. subtills ( natto ) plasmid pLS19 and the Staphylococcus aureus plasmid pUB110. To facilitate direct...and (v) transformation of B. cereus and B. anthracis with plasmid DNA. The 55-kb plasmid, pLS20, of Bacillus subtilis ( natto ) 3335 promotes tr msfer

Passive vaccination with a human monoclonal antibody: generation of antibodies and studies for efficacy in Bacillus anthracis infections.

PubMed

vor dem Esche, Ulrich; Huber, Maria; Zgaga-Griesz, Andrea; Grunow, Roland; Beyer, Wolfgang; Hahn, Ulrike; Bessler, Wolfgang G

2011-07-01

A major difficulty in creating human monoclonal antibodies is the lack of a suitable myeloma cell line to be used for fusion experiments. In order to create fully human monoclonal antibodies for passive immunization, the human mouse heteromyeloma cell line CB-F7 was evaluated. Using this cell line, we generated human monoclonal antibodies against Bacillus anthracis toxin components. Antibodies against protective antigen (PA) and against lethal factor (LF) were obtained using peripheral blood lymphocytes (PBLs) from persons vaccinated with the UK anthrax vaccine. PBL were fused with the cell line CB-F7. We obtained several clones producing PA specific Ig and one clone (hLF1-SAN) producing a monoclonal antibody (hLF1) directed against LF. The LF binding antibody was able to neutralize Anthrax toxin activity in an in vitro neutralization assay, and preliminary in vivo studies in mice also indicated a trend towards protection. We mapped the epitope of the antibody binding to LF by dot blot analysis and ELIFA using 80 synthetic LF peptides of 20 amino acid lengths with an overlapping range of 10 amino acids. Our results suggest the binding of the monoclonal antibody to the peptide regions 121-150 or 451-470 of LF. The Fab-fragment of the antibody hLF1 was cloned in Escherichia coli and could be useful as part of a fully human monoclonal antibody for the treatment of Anthrax infections. In general, our studies show the applicability of the CB-F7 line to create fully human monoclonal antibodies for vaccination. Copyright © 2010 Elsevier GmbH. All rights reserved.

Efficacy of parenteral vaccination against tuberculosis with heat-inactivated Mycobacterium bovis in experimentally challenged goats.

PubMed

Arrieta-Villegas, Claudia; Perálvarez, Tania; Vidal, Enric; Puighibet, Zoë; Moll, Xavier; Canturri, Albert; Sevilla, Iker A; Espada, Yvonne; Juste, Ramón A; Domingo, Mariano; Pérez de Val, Bernat

2018-01-01

Tuberculosis (TB) in animals is a re-emerging disease with a wide range of hosts that causes large economic losses in livestock. Goats are particularly susceptible to TB and, in endemic areas, vaccination may be a valuable measure to control the disease. The main aim of this study was to evaluate the efficacy of parenteral vaccination of goats with a heat-inactivated Mycobacterium bovis (HIMB) vaccine, and compare it to M. bovis Bacille Calmette-Guérin (BCG) vaccine. Twenty-four goat kids were divided in 3 groups as following: HIMB vaccinated group (n = 8), BCG vaccinated group (n = 8) and unvaccinated group (n = 8). Afterwards, goats were experimentally challenged with Mycobacterium caprae by the endobronchial route. Antigen specific interferon-γ release assays and serology were performed after vaccination and challenge. Pathological and bacteriological parameters were evaluated after necropsy at 9 weeks post-challenge (p.c.). HIMB vaccine showed similar levels of protection to BCG in terms of volume reduction of thoracic TB lesions, presence of extra-pulmonary lesions, as well as a slight reduction of bacterial load in pulmonary lymph nodes. Moreover, HIMB vaccine did not induce interferences on the interferon-γ release assay based on reagents previously developed to differentiate infected from BCG vaccinated individuals. The results indicate that HIMB is a suitable vaccine candidate for further larger-scale trials under field conditions in goats.

Leprosy: a review of laboratory and therapeutic aspects - Part 2*

PubMed Central

Lastória, Joel Carlos; de Abreu, Marilda Aparecida Milanez Morgado

2014-01-01

Leprosy is a chronic infectious condition caused by Mycobacterium leprae(M. leprae). It is endemic in many regions of the world and a public health problem in Brazil. Additionally, it presents a wide spectrum of clinical manifestations, which are dependent on the interaction between M. leprae and host, and are related to the degree of immunity to the bacillus. The diagnosis of this disease is a clinical one. However, in some situations laboratory exams are necessary to confirm the diagnosis of leprosy or classify its clinical form. This article aims to update dermatologists on leprosy, through a review of complementary laboratory techniques that can be employed for the diagnosis of leprosy, including Mitsuda intradermal reaction, skin smear microscopy, histopathology, serology, immunohistochemistry, polymerase chain reaction, imaging tests, electromyography, and blood tests. It also aims to explain standard multidrug therapy regimens, the treatment of reactions and resistant cases, immunotherapy with bacillus Calmette-Guérin (BCG) vaccine and chemoprophylaxis. PMID:24937811

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

PubMed Central

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A.; Lozza, Laura; Saikali, Philippe; Sander, Leif E.; Vogelzang, Alexis; Kupz, Andreas

2016-01-01

ABSTRACT Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. PMID:27879332

Comparison of QuantiFERON-TB gold in-tube test with tuberculin skin test in children who had no contact with active tuberculosis case.

PubMed

Metin Timur, Özge; Tanir, Gönül; Öz, Fatma Nur; Bayhan, Gülsüm İclal; Aydin Teke, Türkan; Tuygun, Nilden

2014-01-01

In this study, we aimed to compare QuantiFERON-TB gold in-tube test (QFT-GIT) and tuberculin skin test (TST) as a diagnosis of latent tuberculosis infection in the children with Bacille Calmette-Guerin (BCG) vaccine. We evaluated 81 children in the study who have positive TST result without a known history of tuberculosis contact from 2008 to 2011 prospectively. Patients were separated into groups according to their ages, the reason of TST application, number of BCG vaccination scars and diameter of TST induration. Posteroanterior, lateral chest radiographies and computerized tomography, if necessary, were performed. The study consists of 48 (59.3%) boys and 33 (40.7%) girls with a mean age of 94.8 ± 51.9 months (ranged from 6 to 193 months). Sixty nine (85.2%) children had one and 12 (14.8%) had two BCG vaccination scars. The TST induration diameters were 15-19 mm in 65 (80.2%) children and ≥ 20 mm in 16 (19.8%) children. QFT-GIT positivity was found in 12 (14.8%) of the evaluated patients. QFT-GIT positive patients were treated with triple anti-tuberculosis regime or isoniazid (INH). In three years period of study, there were no tuberculosis disease observed among the children who had not been treated with anti-tuberculosis drugs. As a result of the study it is suggested to confirm positive TST results with tests based on interferon-gamma (IFN-γ) because it can reduce false positive diagnosis and treatment of latent tuberculosis infection, thus adverse reactions of drugs, in countries where BCG vaccination is routinely recommended especially for low risk children.

Effects of low birth weight on time to BCG vaccination in an urban poor settlement in Nairobi, Kenya: an observational cohort study.

PubMed

Mutua, Martin Kavao; Ochako, Rhoune; Ettarh, Remare; Ravn, Henrik; Echoka, Elizabeth; Mwaniki, Peter

2015-04-18

The World Health Organization recommends Bacillus Calmette-Guérin (BCG) vaccination against tuberculosis be given at birth. However, in many developing countries, pre-term and low birth weight infants get vaccinated only after they gain the desired weight. In Kenya, the ministry of health recommends pre-term and low birth weight infants to be immunized at the time of discharge from hospital irrespective of their weight. This paper seeks to understand the effects of birth weight on timing of BCG vaccine. The study was conducted in two Nairobi urban informal settlements, Korogocho and Viwandani which hosts the Nairobi Urban Health and Demographic Surveillance system. All infants born in the study area since September 2006 were included in the study. Data on immunization history and birth weight of the infant were recorded from child's clinic card. Follow up visits were done every four months to update immunization status of the child. A total of 3,602 infants were included in this analysis. Log normal accelerated failure time parametric model was used to assess the association between low birth weight infants and time to BCG immunization. In total, 229 (6.4%) infants were low birth weight. About 16.6% of the low birth weight infants weighed less than 2000 grams and 83.4% weighed between 2000 and 2490 grams. Results showed that, 60% of the low birth weight infants received BCG vaccine after more than five weeks of life. Private health facilities were less likely to administer a BCG vaccine on time compared to public health facilities. The effects of low birth weight on females was 0.60 and 0.97-times that of males for infants weighing 2000-2499 grams and for infants weighing <2000 grams respectively. The effect of low birth weight among infants born in public health facilities was 1.52 and 3.94-times that of infants delivered in private health facilities for infants weighing 2000-2499 grams and those weighing < 2000 grams respectively. Low birth weight infants

BCG vaccination reaction in low birth weight infants.

PubMed

Kaur, S; Faridi, M M A; Agarwal, K N

2002-08-01

About 30 per cent newborns (preterm and term) weigh < 2500 g at birth. The immunological system is less mature in low birth weight (LBW) babies compared to term and normal birth weight (NBW) babies. Bacille Calmettee Guerin (BCG) vaccine is given at birth under the national immunization programme. There is a paucity of information on the immunogenicity of BCG vaccine in preterm and LBW babies. It was, therefore, proposed to study the reaction of BCG vaccination in LBW, preterm and normal birth weight newborns. A total of 143 newborns (90 term and 53 preterm; of these 78 were LBW) received during March to September 1998, 0.1 ml of BCG vaccine (Danish 1331 strain) intradermally on the left arm just above the insertion of the deltoid muscle within 7 days of life. At the same time trivalent oral polio vaccine was administered as per the national immunization programme. These babies were followed up in the immunization clinic at 4, 6, 8, 10 and 12 +/- 1 wk to observe reactions at the BCG vaccination site. After 4 wk reaction at the vaccination site was significantly (P < 0.001) delayed in preterm babies as compared to term infants, and in the LBW babies (P < 0.05) as compared to NBW babies. The reaction at the site of vaccination was not found to be different at 6, 8, 10, 12 wk. BCG scar was seen in 47.5 per cent infants (45.4% in < 2500 g birth weight and 50% in > or = 2500 g birth weight infants) at 12 wk. But 33 (42.3%) LBW and 24 (36.9%) NBW infants also showed papule, pustule, ulceration or scab at the BCG vaccination site. The BCG reaction was seen in the sequential order from papule to scar formation. No significant difference was seen in the scar formation in infants studied with varying gestation and birth weights after 12 wk of BCG vaccination. Fifty seven (40.4%) babies still showed different stages of BCG reaction at 12 wk. BCG vaccine along with OPV administered in early neonatal life showed successful BCG reaction in 95.5 per cent infants.

Evaluation of Immunogenicity and Protective Efficacy Elicited by Mycobacterium bovis BCG Overexpressing Ag85A Protein against Mycobacterium tuberculosis Aerosol Infection.

PubMed

Xu, Zheng Zhong; Chen, Xiang; Hu, Ting; Meng, Chuang; Wang, Xiao Bo; Rao, Yan; Zhang, Xiao Ming; Yin, Yue Lan; Pan, Zhi Ming; Jiao, Xin An

2016-01-01

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide-MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.

Evolving role of immunotherapy in the treatment of refractory warts

PubMed Central

Thappa, Devinder M; Chiramel, Minu J

2016-01-01

Cutaneous and genital warts are common dermatological conditions caused by the human papilloma virus (HPV). Although it is a benign condition, it causes disfigurement, has a tendency to koebnerize, and can be transmitted to others. This makes adequate and timely treatment important. There are several conventional treatments available with variable response. Topical and systemic immunotherapy has now found a significant place in the treatment of warts because of its nondestructive action, ease of use, and promising results. Through this review, we would like to present a brief overview of the various immunotherapeutic agents used. These include more established agents such as imiquimod, Mycobacterium w vaccine, bacillus Calmette-Guérin vaccine, measles, mumps, and rubella vaccine, Candida antigen, trichophyton antigen, tuberculin, zinc, cimetidine, levamisole, HPV vaccine, and autoimplantation therapy. Other agents such as contact immunotherapy which is sparsely used now than before and newer agents such as Corynebacterium parvum, sinecatechins, echinacea, propolis, glycyrrizinic acid, and Vitamin D have also been discussed. The mechanism of action of these agents, along with their dosage, mode of administration, duration of use, expected outcomes and comparative efficacy, evidence for their use, and expected side effects, if any, are reviewed. PMID:27730031

A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes.

PubMed

Chitlaru, Theodor; Israeli, Ma'ayan; Rotem, Shahar; Elia, Uri; Bar-Haim, Erez; Ehrlich, Sharon; Cohen, Ofer; Shafferman, Avigdor

2017-10-20

We recently reported the development of a novel, next-generation, live attenuated anthrax spore vaccine based on disruption of the htrA (High Temperature Requirement A) gene in the Bacillus anthracis Sterne veterinary vaccine strain. This vaccine exhibited a highly significant decrease in virulence in murine, guinea pig and rabbit animal models yet preserved the protective value of the parental Sterne strain. Here, we report the evaluation of additional mutations in the lef and cya genes, encoding for the toxin components lethal factor (LF) and edema factor (EF), to further attenuate the SterneΔhtrA strain and improve its compatibility for human use. Accordingly, we constructed seven B. anthracis Sterne-derived strains exhibiting different combinations of mutations in the htrA, cya and lef genes. The various strains were indistinguishable in growth in vitro and in their ability to synthesise the protective antigen (PA, necessary for the elicitation of protection). In the sensitive murine model, we observed a gradual increase (ΔhtrA<ΔhtrAΔcya<ΔhtrAΔlef<ΔhtrAΔlefΔcya) in attenuation - up to 10 8 -fold relative to the parental Sterne vaccine strain. Most importantly, all various SterneΔhtrA derivative strains did not differ in their ability to elicit protective immunity in guinea pigs. Immunisation of guinea pigs with a single dose (10 9 spores) or double doses (>10 7 spores) of the most attenuated triple mutant strain SterneΔhtrAlef MUT Δcya induced a robust immune response, providing complete protection against a subsequent respiratory lethal challenge. Partial protection was observed in animals vaccinated with a double dose of as few as 10 5 spores. Furthermore, protective immune status was maintained in all vaccinated guinea pigs and rabbits for at least 40 and 30weeks, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Advances in the development of next-generation anthrax vaccines.

PubMed

Friedlander, Arthur M; Little, Stephen F

2009-11-05

Anthrax, a disease of herbivores, only rarely infects humans. However, the threat of using Bacillus anthracis, the causative agent, to intentionally produce disease has been the impetus for development of next-generation vaccines. Two licensed vaccines have been available for human use for several decades. These are composed of acellular culture supernatants containing the protective antigen (PA) component of the anthrax toxins. In this review we summarize the various approaches used to develop improved vaccines. These efforts have included the use of PA with newer adjuvants and delivery systems, including bacterial and viral vectors and DNA vaccines. Attempts to broaden the protection afforded by PA-based vaccines have focused on adding other B. anthracis components, including spore and capsule antigens.

Status of cold chain in routine immunisation centres of the Expanded Programme on Immunisation in Quetta, Pakistan.

PubMed

Buledi, Rahim; Butt, Zahid Ahmad; Ahmed, Jamil; Alizai, Aamir Akram

2017-05-01

To determine the status of cold chain and knowledge and practices of health workers about cold chain maintenance in routine immunisation health centres. This cross-sectional study was conducted in Quetta, Pakistan, from May to July 2012, and comprised health facilities in the district. We interviewed the staff responsible for vaccine storage and cold chain maintenance and used a checklist to assess cold chain maintenance of routine expanded programme on immunisation vaccines. SPSS 16 was used for data analysis.. Of the 42 health facilities, staff of 13(30%) wrongly indicated that measles and Bacillus Calmette-Guérin were cold sensitive vaccines. Temperature of the ice-lined refrigerators was not maintained twice daily in 18(43%) centres. There were no voltage stabilisers and standby power generators in 31(74%) and 38(90%) centres, respectively. Vaccine arrangement was found to be inappropriate in ice-lined refrigerators of 38(90%) centres and ice packs were incorrectly used in carriers in 22(52%) centres. Vaccine stock was not charted in 39(93%) centres. Moreover, 4(10%) facilities did not have dedicated expanded programme on immunisation rooms whereas about 5(12%) and 33(79%) had no vaccinator and separate expanded programme on immunisation incharge appointed. Also, 32(76%) centres did not have a female vaccinator appointed. Although the majority of health staff had adequate knowledge, there were weaknesses in practice of maintaining the cold chain.

BCG vaccination drives accumulation and effector function of innate lymphoid cells in murine lungs.

PubMed

Steigler, Pia; Daniels, Naomi J; McCulloch, Tim R; Ryder, Brin M; Sandford, Sarah K; Kirman, Joanna R

2018-04-01

The tuberculosis (TB) vaccine bacille Calmette-Guérin (BCG) prevents disseminated childhood TB; however, it fails to protect against the more prevalent pulmonary TB. Limited understanding of the immune response to Mycobacterium tuberculosis, the causative agent of TB, has hindered development of improved vaccines. Although memory CD4 T cells are considered the main mediators of protection against TB, recent studies suggest there are other key subsets that contribute to antimycobacterial immunity. To that end, innate cells may be involved in the protective response. In this study, we investigated the primary response of innate lymphoid cells (ILCs) to BCG exposure. Using a murine model, we showed that ILCs increased in number in the lungs and lymph nodes in response to BCG vaccination. Additionally, there was significant production of the antimycobacterial cytokine IFN-γ by ILCs. As ILCs are located at mucosal sites, it was investigated whether mucosal vaccination (intranasal) stimulated an enhanced response compared to the traditional vaccination approach (intradermal or subcutaneous). Indeed, in response to intranasal vaccination, the number of ILCs, and IFN-γ production in NK cells and ILC1s in the lungs and lymph nodes, were higher than that provoked through intradermal or subcutaneous vaccination. This work provides the first evidence that BCG vaccination activates ILCs, paving the way for future research to elucidate the protective potential of ILCs against mycobacterial infection. Additionally, the finding that lung ILCs respond rigorously to mucosal vaccination may have implications for the delivery of novel TB vaccines. © 2018 Australasian Society for Immunology Inc.

Cell wall lipids from Mycobacterium bovis BCG are inflammatory when inoculated within a gel matrix: characterization of a new model of the granulomatous response to mycobacterial components.

PubMed

Rhoades, Elizabeth R; Geisel, Rachel E; Butcher, Barbara A; McDonough, Sean; Russell, David G

2005-05-01

The chronic inflammatory response to Mycobacterium generates complex granulomatous lesions that balance containment with destruction of infected tissues. To study the contributing factors from host and pathogen, we developed a model wherein defined mycobacterial components and leukocytes are delivered in a gel, eliciting a localized response that can be retrieved and analysed. We validated the model by comparing responses to the cell wall lipids from Mycobacterium bovis bacillus Calmette-Guerin (BCG) to reported activities in other models. BCG lipid-coated beads and bone marrow-derived macrophages (input macrophages) were injected intraperitoneally into BALB/c mice. Input macrophages and recruited peritoneal exudate cells took up fluorescently tagged BCG lipids, and matrix-associated macrophages and neutrophils produced tumor necrosis factor, interleukin-1alpha, and interleukin-6. Leukocyte numbers and cytokine levels were greater in BCG lipid-bearing matrices than matrices containing non-coated or phosphatidylglycerol-coated beads. Leukocytes arrived in successive waves of neutrophils, macrophages and eosinophils, followed by NK and T cells (CD4(+), CD8(+), or gammadelta) at 7 days and B cells within 12 days. BCG lipids also predisposed matrices for adherence and vascularization, enhancing cellular recruitment. We submit that the matrix model presents pertinent features of the murine granulomatous response that will prove to be an adaptable method for study of this complex response.

[Zinc-dependent metalloprotease 1 promotes apoptosis of RAW264.7 macrophages].

PubMed

Li, Peng; He, Yonglin; Zhang, Jiming; Fang, Chencheng

2015-12-01

To construct the eukaryotic expression vector of zinc-dependent metalloprotease 1 (zmp1) gene from Bacillus Calmette-Guerin (BCG) and investigate its impact on the apoptosis of RAW264.7 macrophages. Zmp1 gene was amplified from the genome of BCG by PCR. The zmp1 gene fragment was inserted into multiple cloning sites of pEGFP-N1 to construct the eukaryotic expression vector pEGFP-N1-zmp1. The constructed pEGFP-N1-zmp1 was transfected into RAW264.7 cells by Lipofectamine(TM) 2000. The expression of green fluorescent protein (GFP) was observed by fluorescence microscopy. The zmp1 mRNA was detected by quantitative real-time PCR (qR-PCR). The effect of Zmp1 protein on the apoptosis of RAW264.7 macrophages was detected by flow cytometry (FCM). With zmp1 gene amplified by PCR, we successfully constructed the recombinant vector pEGFP-N1-zmp1 as demonstrated by restriction enzyme analysis and sequencing. GFP was seen in RAW264.7 cells 24 hours after transfected with the recombinant plasmid. As qRT-PCR showed, the expression level of zmp1 mRNA was up-regulated. The early apoptotic rate increased 48 hours after transfection. The increased expression of Zmp1 in RAW264.7 cells promotes the apoptosis of RAW264.7 cells.

STING-Dependent 2'-5' Oligoadenylate Synthetase-Like Production Is Required for Intracellular Mycobacterium leprae Survival.

PubMed

de Toledo-Pinto, Thiago Gomes; Ferreira, Anna Beatriz Robottom; Ribeiro-Alves, Marcelo; Rodrigues, Luciana Silva; Batista-Silva, Leonardo Ribeiro; Silva, Bruno Jorge de Andrade; Lemes, Robertha Mariana Rodrigues; Martinez, Alejandra Nóbrega; Sandoval, Felipe Galvan; Alvarado-Arnez, Lucia Elena; Rosa, Patrícia Sammarco; Shannon, Edward Joseph; Pessolani, Maria Cristina Vidal; Pinheiro, Roberta Olmo; Antunes, Sérgio Luís Gomes; Sarno, Euzenir Nunes; Lara, Flávio Alves; Williams, Diana Lynn; Ozório Moraes, Milton

2016-07-15

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Evaluating the Validity of a Two-stage Sample in a Birth Cohort Established from Administrative Databases.

PubMed

El-Zein, Mariam; Conus, Florence; Benedetti, Andrea; Parent, Marie-Elise; Rousseau, Marie-Claude

2016-01-01

When using administrative databases for epidemiologic research, a subsample of subjects can be interviewed, eliciting information on undocumented confounders. This article presents a thorough investigation of the validity of a two-stage sample encompassing an assessment of nonparticipation and quantification of the extent of bias. Established through record linkage of administrative databases, the Québec Birth Cohort on Immunity and Health (n = 81,496) aims to study the association between Bacillus Calmette-Guérin vaccination and asthma. Among 76,623 subjects classified in four Bacillus Calmette-Guérin-asthma strata, a two-stage sampling strategy with a balanced design was used to randomly select individuals for interviews. We compared stratum-specific sociodemographic characteristics and healthcare utilization of stage 2 participants (n = 1,643) with those of eligible nonparticipants (n = 74,980) and nonrespondents (n = 3,157). We used logistic regression to determine whether participation varied across strata according to these characteristics. The effect of nonparticipation was described by the relative odds ratio (ROR = ORparticipants/ORsource population) for the association between sociodemographic characteristics and asthma. Parental age at childbirth, area of residence, family income, and healthcare utilization were comparable between groups. Participants were slightly more likely to be women and have a mother born in Québec. Participation did not vary across strata by sex, parental birthplace, or material and social deprivation. Estimates were not biased by nonparticipation; most RORs were below one and bias never exceeded 20%. Our analyses evaluate and provide a detailed demonstration of the validity of a two-stage sample for researchers assembling similar research infrastructures.

The biography of the immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies.

PubMed

Krone, Bernd; Kölmel, Klaus F; Grange, John M

2014-08-16

The historical basis and contemporary evidence for the use of immune strategies for prevention of malignancies are reviewed. Emphasis is focussed on the Febrile Infections and Melanoma (FEBIM) study on melanoma and on malignancies that seem to be related to an overexpression of human endogenous retrovirus K (HERV-K). It is claimed that, as a result of recent observational studies, measures for prevention of some malignancies such as melanoma and certain forms of leukaemia are already at hand: vaccination with Bacille Calmette-Guérin (BCG) of new-borns and vaccination with the yellow fever 17D (YFV) vaccine of adults. While the evidence of their benefit for prevention of malignancies requires substantiation, the observations that vaccinations with BCG and/or vaccinia early in life improved the outcome of patients after surgical therapy of melanoma are of practical relevance as the survival advantage conferred by prior vaccination is greater than any contemporary adjuvant therapy. The reviewed findings open a debate as to whether controlled vaccination studies should be conducted in patients and/or regions for whom/where they are needed most urgently. A study proposal is made and discussed. If protection is confirmed, the development of novel recombinant vaccines with wider ranges of protection based, most likely, on BCG, YFV or vaccinia, could be attempted.

Protection of farm goats by combinations of recombinant peptides and formalin inactivated spores from a lethal Bacillus anthracis challenge under field conditions.

PubMed

Koehler, Susanne M; Buyuk, Fatih; Celebi, Ozgur; Demiraslan, Hayati; Doganay, Mehmet; Sahin, Mitat; Moehring, Jens; Ndumnego, Okechukwu C; Otlu, Salih; van Heerden, Henriette; Beyer, Wolfgang

2017-07-12

Bacillus (B.) anthracis, the causal agent of anthrax, is effectively controlled by the Sterne live spore vaccine (34F2) in animals. However, live spore vaccines are not suitable for simultaneous vaccination and antibiotic treatment of animals being at risk of infection in an outbreak situation. Non-living vaccines could close this gap. In this study a combination of recombinant protective antigen and recombinant Bacillus collagen-like antigen (rBclA) with or without formalin inactivated spores (FIS), targeted at raising an immune response against both the toxins and the spore of B. anthracis, was tested for immunogenicity and protectiveness in goats. Two groups of goats received from local farmers of the Kars region of Turkey were immunized thrice in three weeks intervals and challenged together with non-vaccinated controls with virulent B. anthracis, four weeks after last immunization. In spite of low or none measurable toxin neutralizing antibodies and a surprisingly low immune response to the rBclA, 80% of the goats receiving the complete vaccine were protected against a lethal challenge. Moreover, the course of antibody responses indicates that a two-step vaccination schedule could be sufficient for protection. The combination of recombinant protein antigens and FIS induces a protective immune response in goats. The non-living nature of this vaccine would allow for a concomitant antibiotic treatment and vaccination procedure. Further studies should clarify how this vaccine candidate performs in a post infection scenario controlled by antibiotics.

Using a prime and pull approach, lentivector vaccines expressing Ag85A induce immunogenicity but fail to induce protection against Mycobacterium bovis bacillus Calmette–Guérin challenge in mice

PubMed Central

Britton, Gary; MacDonald, Douglas C; Brown, Jeremy S; Collins, Mary K; Goodman, Anna L

2015-01-01

Although bacillus Calmette–Guérin (BCG) is an established vaccine with excellent efficacy against disseminated Mycobacterium tuberculosis infection in young children, efficacy in adults suffering from respiratory tuberculosis (TB) is suboptimal. Prime-boost viral vectored vaccines have been shown to induce effective immune responses and lentivectors (LV) have been shown to improve mucosal immunity in the lung. A mucosal boost to induce local immunogenicity is also referred to as a ‘pull’ in a prime and pull approach, which has been found to be a promising vaccine strategy. The majority of infants worldwide receive BCG immunization through current vaccine protocols. We therefore aimed to investigate the role of a boost (or pull) immunization with an LV vaccine expressing the promising TB antigen (Ag85A). We immunized BALB/c mice subcutaneously with BCG or an LV vaccine expressing a nuclear factor-κB activator vFLIP together with Ag85A (LV vF/85A), then boosted with intranasal LV vF/85A. Prime and pull immunization with LV85A induced significantly enhanced CD8+ and CD4+ T-cell responses in the lung, but did not protect against intranasal BCG challenge. In contrast, little T-cell response in the lung was seen when the prime vaccine was BCG, and intranasal vF/85A provided no additional protection against mucosal BCG infection. Our study demonstrates that not all LV prime and pull approaches may be successful against TB in man and careful antigen and immune activator selection is therefore required. PMID:26095282

Purification and properties of the heterogeneous subunits of elongation factor EF-1 from Guerin epithelioma cells.

PubMed

Marcinkiewicz, C; Gajko, A; Gałasiński, W

1991-01-01

Elongation factor EF-1 from Guerin epithelioma was separated into two subunit forms EF-1A and EF-1B by chromatography in the presence of 25% glycerol, successively on CM-Sephadex and DEAE-Sephadex. It was shown that EF-1A is a thermolabile, single polypeptide which catalyses the binding of aminoacyl-tRNA to ribosomes, similarly as eukaryotic EF-1 alpha or prokaryotic EF-Tu. EF-1B was characterized as a complex composed of at least two polypeptides. One of them is EF-1A, the other EF-1C, which stimulates EF-1A activity and protects this elongation factor from thermal inactivation.

Tuberculosis Screening by Tuberculosis Skin Test or QuantiFERON®-TB Gold In-Tube Assay among an Immigrant Population with a High Prevalence of Tuberculosis and BCG Vaccination

PubMed Central

Painter, John A.; Graviss, Edward A.; Hai, Hoang Hoa; Nhung, Duong Thi Cam; Nga, Tran Thi Thanh; Ha, Ngan P.; Wall, Kirsten; Loan, Le Thien Huong; Parker, Matt; Manangan, Lilia; O’Brien, Rick; Maloney, Susan A.; Hoekstra, R. M.; Reves, Randall

2013-01-01

Rationale Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth. Objectives 1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR. Methods We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR. Results The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants. Conclusions During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population.  PMID:24367546

Routine Vaccination Coverage in Northern Nigeria: Results from 40 District-Level Cluster Surveys, 2014-2015.

PubMed

Gunnala, Rajni; Ogbuanu, Ikechukwu U; Adegoke, Oluwasegun J; Scobie, Heather M; Uba, Belinda V; Wannemuehler, Kathleen A; Ruiz, Alicia; Elmousaad, Hashim; Ohuabunwo, Chima J; Mustafa, Mahmud; Nguku, Patrick; Waziri, Ndadilnasiya Endie; Vertefeuille, John F

2016-01-01

Despite recent success towards controlling poliovirus transmission, Nigeria has struggled to achieve uniformly high routine vaccination coverage. A lack of reliable vaccination coverage data at the operational level makes it challenging to target program improvement. To reliably estimate vaccination coverage, we conducted district-level vaccine coverage surveys using a pre-existing infrastructure of polio technical staff in northern Nigeria. Household-level cluster surveys were conducted in 40 polio high risk districts of Nigeria during 2014-2015. Global positioning system technology and intensive supervision by a pool of qualified technical staff were used to ensure high survey quality. Vaccination status of children aged 12-23 months was documented based on vaccination card or caretaker's recall. District-level coverage estimates were calculated using survey methods. Data from 7,815 children across 40 districts were analyzed. District-level coverage with the third dose of diphtheria-pertussis-tetanus vaccine (DPT3) ranged widely from 1-63%, with all districts having DPT3 coverage below the target of 80%. Median coverage across all districts for each of eight vaccine doses (1 Bacille Calmette-Guérin dose, 3 DPT doses, 3 oral poliovirus vaccine doses, and 1 measles vaccine dose) was <50%. DPT3 coverage by survey was substantially lower (range: 28%-139%) than the 2013 administrative coverage reported among children aged <12 months. Common reported reasons for non-vaccination included lack of knowledge about vaccines and vaccination services (50%) and factors related to access to routine immunization services (15%). Survey results highlighted vaccine coverage gaps that were systematically underestimated by administrative reporting across 40 polio high risk districts in northern Nigeria. Given the limitations of administrative coverage data, our approach to conducting quality district-level coverage surveys and providing data to assess and remediate issues

Protection against bovine tuberculosis induced by oral vaccination of cattle with Mycobacterium bovis BCG is not enhanced by co-administration of mycobacterial protein vaccines.

PubMed

Wedlock, D Neil; Aldwell, Frank E; Vordermeier, H Martin; Hewinson, R Glyn; Buddle, Bryce M

2011-12-15

Mycobacterium bovis bacille Calmette-Guérin (BCG) delivered to calves by the oral route in a formulated lipid matrix has been previously shown to induce protection against bovine tuberculosis. A study was conducted in cattle to determine if a combination of a low dose of oral BCG and a protein vaccine could induce protective immunity to tuberculosis while not sensitising animals to tuberculin. Groups of calves (10 per group) were vaccinated by administering 2 × 10(7)colony forming units (CFU) of BCG orally or a combination of 2 × 10(7)CFU oral BCG and a protein vaccine comprised of M. bovis culture filtrate proteins (CFP) formulated with the adjuvants Chitin and Gel 01 and delivered by the intranasal route, or CFP formulated with Emulsigen and the TLR2 agonist Pam(3)CSK(4) and administered by the subcutaneous (s.c.) route. Two further groups were vaccinated with the CFP/Chitin/Gel 01 or CFP/Emulsigen/Pam(3)CSK(4) vaccines alone. Positive control groups were given 10(8)CFU oral BCG or 10(6)CFU s.c. BCG while a negative control group was non-vaccinated. All animals were challenged with M. bovis 15 weeks after vaccination and euthanized and necropsied at 16 weeks following challenge. Groups of cattle vaccinated with s.c. BCG, 10(8)CFU or 2 × 10(7)CFU oral BCG showed significant reductions in seven, three and four pathological or microbiological disease parameters, respectively, compared to the results for the non-vaccinated group. There was no evidence of protection in calves vaccinated with the combination of oral BCG and CFP/Emulsigen/Pam(3)CSK(4) or oral BCG and CFP/Chitin/Gel 01 or vaccinated with the protein vaccines alone. Positive responses in the comparative cervical skin test at 12 weeks after vaccination were only observed in animals vaccinated with s.c. BCG, 10(8)CFU oral BCG or a combination of 2 × 10(7)CFU oral BCG and CFP/Chitin/Gel 01. In conclusion, co-administration of a protein vaccine, administered by either systemic or mucosal routes with oral

Genetic and Physiological Studies of Bacillus anthracis Related to Development of an Improved Vaccine

DTIC Science & Technology

1986-07-01

demonstrated that plasmid pLS20 of B. subtilis ( natto ) is capa le of promoting the transfer of pBC16 from B. subtilis to a variety of Bacillus s ecies...anthracis. Hofetver, results of recent experiments demonstrate that pL320, a 34-megadalton plasmid of B. subtilis ( natto ), is capable of promoting the...plasmid in Bacillus subtilis ( natto ).20 IV. Determination of the size of pX02 by restriction analysis-....... 24 V. Transfer of pXO1 by the B

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis.

PubMed

Leung-Theung-Long, Stéphane; Coupet, Charles-Antoine; Gouanvic, Marie; Schmitt, Doris; Ray, Aurélie; Hoffmann, Chantal; Schultz, Huguette; Tyagi, Sandeep; Soni, Heena; Converse, Paul J; Arias, Lilibeth; Kleinpeter, Patricia; Sansas, Benoît; Mdluli, Khisimuzi; Vilaplana, Cristina; Cardona, Pere-Joan; Nuermberger, Eric; Marchand, Jean-Baptiste; Silvestre, Nathalie; Inchauspé, Geneviève

2018-01-01

Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host's immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections.

Presenting Influenza A M2e Antigen on Recombinant Spores of Bacillus subtilis

PubMed Central

Obuchowski, Michał; Nidzworski, Dawid

2016-01-01

Effective vaccination against influenza virus infection is a serious problem mainly due to antigenic variability of the virus. Among many of investigated antigens, the extracellular domain of the M2 protein (M2e) features high homology in all strains of influenza A viruses and antibodies against M2e and is protective in animal models; this makes it a potential candidate for generation of a universal influenza vaccine. However, due to the low immunogenicity of the M2e, formulation of a vaccine based on this antigen requires some modification to induce effective immune responses. In this work we evaluated the possible use of Bacillus subtilis spores as a carrier of the Influenza A M2e antigen in mucosal vaccination. A tandem repeat of 4 consensus sequences coding for human—avian—swine—human M2e (M2eH-A-S-H) peptide was fused to spore coat proteins and stably exposed on the spore surface, as demonstrated by the immunostaining of intact, recombinant spores. Oral immunization of mice with recombinant endospores carrying M2eH-A-S-H elicited specific antibody production without the addition of adjuvants. Bacillus subtilis endospores can serve as influenza antigen carriers. Recombinant spores constructed in this work showed low immunogenicity although were able to induce antibody production. The System of influenza antigen administration presented in this work is attractive mainly due to the omitting time-consuming and cost-intensive immunogen production and purification. Therefore modification should be made to increase the immunogenicity of the presented system. PMID:27902762

Tuberculin skin test and Quantiferon test agreement and influencing factors in tuberculosis screening of healthcare workers: a systematic review and meta-analysis.

PubMed

Lamberti, Monica; Uccello, Rossella; Monaco, Maria Grazia Lourdes; Muoio, Mariarosaria; Feola, Daniela; Sannolo, Nicola; Nienhaus, Albert; Chiodini, Paolo

2015-01-01

A systematic review and meta-analysis was conducted to evaluate the agreement between Tuberculin Skin Test (TST) and Quantiferon (QFT) in screening for tuberculosis (TB) infection among healthcare workers (HCWs) and to estimate associations between TST and QFT agreement and variables of interest, such as Bacillus Calmette-Guérin (BCG) vaccination and incidence of TB. Cross-sectional and longitudinal studies on HCWs, published in English until October 2013, comparing TST and QFT results, were selected. For each study Cohen's κ value and a 95% confidence interval were calculated. Summary measures and indexes of heterogeneity between studies were calculated. 29 studies were selected comprising a total of 11,434 HCWs. Cohen's κ for agreement between TST and QFT for 24 of them was 0.28 (95% CI 0.22 to 0.35), with the best value in high TB incidence countries and the lowest rate of BCG vaccination. Currently, there is no gold standard for TB screening and the most-used diagnostic tools show low agreement. For evidence-based health surveillance in HCWs, occupational physicians need to consider a number of factors influencing screening results, such as TB incidence, vaccination status, age and working seniority.

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

PubMed

Higgins, Julian P T; Soares-Weiser, Karla; López-López, José A; Kakourou, Artemisia; Chaplin, Katherine; Christensen, Hannah; Martin, Natasha K; Sterne, Jonathan A C; Reingold, Arthur L

2016-10-13

 To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A.  Systematic review, including assessment of risk of bias, and meta-analyses of similar studies.  Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5.  Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified.  Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences

The history of antivenoms development: Beyond Calmette and Vital Brazil.

PubMed

Squaiella-Baptistão, Carla Cristina; Sant'Anna, Osvaldo Augusto; Marcelino, José Roberto; Tambourgi, Denise V

2018-05-17

This review presents the main contributions to our knowledge regarding the development of antivenoms for therapeutic use in victims of venomous animal bites. We cover the progress of serum therapy since tetanus and diphtheria antitoxins in Germany and France until the current scenario of antivenom production worldwide. During these more than 120 years of antivenom development, many researchers contributed to establish what are nowadays the antivenoms used for therapeutic purpose. The history of antivenoms development is fascinating! This review aims to recognize all those who contributed to the establishment of new sera, new methodologies and saving lives: much more than Calmette and Vital Brazil. Copyright © 2018 Elsevier Ltd. All rights reserved.

New generation of oral mucosal vaccines targeting dendritic cells.

PubMed

Owen, Jennifer L; Sahay, Bikash; Mohamadzadeh, Mansour

2013-12-01

As most infectious organisms gain entry at mucosal surfaces, there is a great deal of interest in developing vaccines that elicit effective mucosal immune responses against pathogen challenge. Targeted vaccination is one of the most effective methods available to prevent and control infectious diseases. Mucosal vaccines can offer lower costs, better accessibility, needle free delivery, and a higher capacity for mass immunizations during pandemics. Both local mucosal immunity and robust systemic responses can be achieved through mucosal vaccination. Recent progress in understanding the molecular and cellular components of the mucosal immune system have allowed for the development of a novel mucosal vaccine platform utilizing specific dendritic cell-targeting peptides and orally administered lactobacilli to elicit efficient antigen specific immune responses against infections, including Bacillus anthracis in experimental models of disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - A systematic review of randomized trials, observational studies and case reports.

PubMed

Croce, Evelina; Hatz, Christoph; Jonker, Emile F; Visser, L G; Jaeger, Veronika K; Bühler, Silja

2017-03-01

Live vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice. To estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT). A search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches. Randomized trials, observational studies and case reports. Patients with IMID or SOT on immunosuppressive treatment and BMT patients <2years after transplantation. Live vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette-Guérin (BCG), smallpox. One author performed the data extraction using predefined data fields. It was cross-checked by two other authors. 7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV

Thermal Inactivation of Bacillus anthracis Spores Using Rapid Resistive Heating

DTIC Science & Technology

2016-03-24

thermal inactivation research. However, the research conducted to support this thesis utilizes the B.a. Sterne strain which is used in livestock vaccines...methodology conducted for this research including hard surface recovery, thermal inactivation of Bacillus anthracis spores, and the rapid resistive heating...to 500°C range but again, many of the thermal inactivation studies were conducted in the 350 to 2000°C range. Sample plots will be discussed in

Genetic and Physiological Studies of Bacillus Anthracis Related to Development of an Improved Vaccine

DTIC Science & Technology

1990-07-01

charartorization of the conjugative pl&a.dd, PLS2O, of Baci~llu sbtllis ( natto ) amd its ability to tranisfer pla&iuids v" iitrains of B. inthraci~s, B...2-r-ich atms;hwre. A smll amount of effort wa spent on further’ characterization of the Bacillus subtilis ( natto ) fertility plasmid. pLS2I, which...previously cured of pX02. All transcipients that inherited the pXO2::Tn9l7 derivatives exhibited the donor phenotype. The 64.2-kb Bacillus subtilis ( natto

Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

PubMed

Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

2015-11-01

Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in

Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months.

PubMed

Thøstesen, Lisbeth Marianne; Kjaer, Henrik Fomsgaard; Pihl, Gitte Thybo; Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjaergaard, Jesper; Jensen, Aksel Karl Georg; Aaby, Peter; Olesen, Annette Wind; Stensballe, Lone Graff; Jeppesen, Dorthe Lisbeth; Benn, Christine Stabell; Kofoed, Poul-Erik

2017-09-01

Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age. By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Vaccination of cattle with Mycobacterium bovis BCG by a combination of systemic and oral routes.

PubMed

Buddle, Bryce M; Denis, Michel; Aldwell, Frank E; Martin Vordermeier, H; Glyn Hewinson, R; Neil Wedlock, D

2008-11-01

Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine delivered to calves by the subcutaneous (s.c.) or by the oral route in a formulated lipid matrix has been previously shown to induce similar levels of protection against bovine tuberculosis. The current study was aimed at determining whether a combination of delivering BCG by s.c. and oral routes would enhance levels of protection, compared to only one route of vaccination. Forty calves were randomly divided into four groups (10/group). Calves were vaccinated with 10(6)colony forming units (CFU) of BCG Pasteur by the s.c. route or orally with 10(9)CFU BCG incorporated into a lipid formulation. One group received a combination of BCG administered by both the s.c. and oral routes and a non-vaccinated group served as a control. The two groups of calves that received s.c. BCG produced strong IFN-gamma responses in whole blood cultures stimulated with bovine purified protein derivative (PPD) 3 weeks after vaccination. Cattle vaccinated just with oral BCG in a lipid matrix produced a strong IFN-gamma response 8 weeks after vaccination, and peaking at 11 weeks after vaccination. All calves were challenged by the intratracheal route with M. bovis 15 weeks after vaccination and were euthanized and necropsied to assess protection at 17 weeks following challenge. BCG given s.c. or orally induced significant and comparable levels of protection against the virulent challenge. Vaccination of cattle by a combination of s.c./oral routes did not enhance protection beyond that achieved by s.c. or oral vaccination alone. We conclude that vaccination of cattle with BCG by a combination of routes has no beneficial additive effects, compared to a single s.c. administration of BCG or BCG given orally in a lipid formulation.

Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms.

PubMed

Zhang, Lu; Ru, Huan-Wei; Chen, Fu-Zeng; Jin, Chun-Yan; Sun, Rui-Feng; Fan, Xiao-Yong; Guo, Ming; Mai, Jun-Tao; Xu, Wen-Xi; Lin, Qing-Xia; Liu, Jun

2016-02-01

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development.

Surveillance and compensation claims for adverse events following immunization from 2011 to 2016 in the Republic of Korea.

PubMed

Kim, Min-Kyung; Lee, Yeon Kyeong; Kim, Tae Eun; Kong, Insik; Yang, Hyeon-Jong; Suh, Eun Sook

2017-07-01

In recent years, research on reported adverse events following immunization (AEFI) and claims filed for compensation has been lacking. We reviewed reported AEFIs and compensation claims in Korea from 2011 to 2016. We listed all of the AEFI registered in the Integrated Management System of Disease and Public Health and reviewed the list of claims filed and serious AEFIs reported from 2011 to 2016. An average of 278 AEFI cases was reported annually from 2011 to 2016. Of these, 31 deaths were reported. However, there was no association found between these deaths and vaccinations when evaluating vaccine lot, reviewing autopsies, and considering underlying diseases. AEFI reporting rate was as high as 20.8 cases for bacillus Calmette-Guérin (BCG) vaccine, 7.3 cases for 23-valent pneumococcal polysaccharide vaccine (PPV23), and 5.4 cases for human papillomavirus vaccine per 100,000 vaccination doses in 2016. Of the 469 total cases that claimed vaccine injury compensation from 2011 to 2016, the BCG vaccine was most commonly involved, with 235 cases (50%), followed by influenza vaccine and PPV23, with 90 and 55 cases, respectively. Of these cases, 96% of BCG-related AEFI were compensated, while only 31% and 49% of AEFI following influenza and PPV23 vaccination, respectively, were compensated. Common characteristics of uncompensated cases included the elderly subjects, receiving influenza vaccine, having underlying disease, or a very short time interval between vaccination and symptoms. We have maintained vaccine safety management system through both rapid response to serious AEFI and vaccine injury compensation in order to sustain public trust in the National Immunization Program.

THE EFFECT OF GAMMA-RAYS OF Co$sup 60$ ON SMALLPOX VACCINE CONTAMINATING MICROORGANISMS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalenina, E.F.; Abidov, A.Z.

1963-02-01

Liquid smallpox vaccine inactivated by gamma irradiation proved to be fully adequate for studying the effects of gamma irradiation on the viability of microorganism artificially added to it. The complete inactivation of Staphylococcus albus and Bacillus subtilis, which most frequently contaminate smallpox vaccine, occurs by gamma irradiation from Co/sup 60/ ranging from 900,000 to 1.5-million r doses at 47 impulses/second magnitude. (OTS)

Aerogenic Vaccination With a Burkholderia mallei Auxotroph Protects Against Aerosol-Initiated Glanders in Mice

DTIC Science & Technology

2005-03-14

Vaccine 23 (2005) 1986–1992 Aerogenic vaccination with a Burkholderia mallei auxotroph protects against aerosol-initiated glanders in mice Ricky L...October 2004 Available online 11 November 2004 Abstract Burkholderia mallei is an obligate mammalian pathogen that causes the zoonotic disease glanders ... Burkholderia mallei , the causative agent of glanders , is gram-negative bacillus. It is a highly adapted parasite of quines and cannot persist in nature

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis

PubMed Central

Coupet, Charles-Antoine; Gouanvic, Marie; Schmitt, Doris; Ray, Aurélie; Hoffmann, Chantal; Schultz, Huguette; Tyagi, Sandeep; Soni, Heena; Converse, Paul J.; Arias, Lilibeth; Kleinpeter, Patricia; Sansas, Benoît; Mdluli, Khisimuzi; Vilaplana, Cristina; Cardona, Pere-Joan; Nuermberger, Eric; Marchand, Jean-Baptiste; Silvestre, Nathalie; Inchauspé, Geneviève

2018-01-01

Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host’s immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections. PMID:29718990

Immunization studies with attenuated strains of Bacillus anthracis.

PubMed Central

Ivins, B E; Ezzell, J W; Jemski, J; Hedlund, K W; Ristroph, J D; Leppla, S H

1986-01-01

Live, attenuated strains of Bacillus anthracis lacking either the capsule plasmid pXO2, the toxin plasmid pXO1, or both were tested for their efficacy as vaccines against intravenous challenge with anthrax toxin in Fischer 344 rats and against aerosol or intramuscular challenge with virulent anthrax spores in Hartley guinea pigs. Animals immunized with toxigenic, nonencapsulated (pXO1+, pXO2-) strains survived toxin and spore challenge and demonstrated postimmunization antibody titers to the three components of anthrax toxin (protective antigen, lethal factor, and edema factor). Immunization with two nontoxigenic, encapsulated (pXO1-, pXO2+), Pasteur vaccine strains neither provided protection nor elicited titers to any of the toxin components. Therefore, to immunize successfully against anthrax toxin or spore challenge, attenuated, live strains of B. anthracis must produce the toxin components specified by the pXO1 plasmid. PMID:3084383

Immunization of children at risk of infection with human immunodeficiency virus.

PubMed Central

Moss, William J.; Clements, C. John; Halsey, Neal A.

2003-01-01

This paper reviews the English language literature on the safety, immunogenicity and effectiveness in children infected with the human immunodeficiency virus (HIV) of vaccines currently recommended by WHO for use in national immunization programmes. Immunization is generally safe and beneficial for children infected with HIV, although HIV-induced immune suppression reduces the benefit compared with that obtained in HIV-uninfected children. However, serious complications can occur following immunization of severely immunocompromised children with bacillus Calmette-Gu rin (BCG) vaccine. The risk of serious complications attributable to yellow fever vaccine in HIV-infected persons has not been determined. WHO guidelines for immunizing children with HIV infection and infants born to HIV-infected women differ only slightly from the general guidelines. BCG and yellow fever vaccines should be withheld from symptomatic HIV-infected children. Only one serious complication (fatal pneumonia) has been attributed to measles vaccine administered to a severely immunocompromised adult. Although two HIV-infected infants have developed vaccine-associated paralytic poliomyelitis, several million infected children have been vaccinated and the evidence does not suggest that there is an increased risk. The benefits of measles and poliovirus vaccines far outweigh the potential risks in HIV-infected children. The policy of administering routine vaccines to all children, regardless of possible HIV exposure, has been very effective in obtaining high immunization coverage and control of preventable diseases. Any changes in this policy would have to be carefully examined for a potential negative impact on disease control programmes in many countries. PMID:12640478

Is new always better than old?: The development of human vaccines for anthrax.

PubMed

Baillie, Leslie W

2009-12-01

Anthrax is caused by a Gram-positive aerobic spore-forming bacillus called Bacillus anthracis. Although primarily a disease of animals, it can also infect man, sometimes with fatal consequences. As a result of concerns over the illicit use of this organism, considerable effort is focused on the development of therapies capable of conferring protection against anthrax. while effective concerns over the toxicity of the current vaccines have driven the development of second-generation products. Recombinant Protective Antigen (rPA), the nontoxic cell-binding component of anthrax lethal toxin, is the principal immunogen of the vaccines currently undergoing human clinical trials. While these new vaccines are likely to show reduced side effects they will still require multiple needle based dosing and the inclusion of the adjuvant alum which will make them expensive to administer and stockpile. To address these issues, researchers are seeking to develop vaccine formulations capable of stimulating rapid protection following needle-free injection which are stable at room temperature to facilitate stockpiling and mass vaccination programs. Recent concerns over the potential use of molecular biology to engineer vaccine resistant strains has prompted investigators to identify additional vaccine targets with which to extend the spectrum of protection conferred by rPA. While the injection of research dollars has seen a dramatic expansion of the anthrax vaccine field it is sobering to remember that work to develop the current second generation vaccines began around the time of the first gulf war. Almost two decades and millions of dollars later we still do not have a replacement vaccine and even when we do some argue that the spectrum of protection that it confers will not be as broad as the vaccine it replaces. If we are to respond effectively to emerging biological threats we need to develop processes that generate protective vaccines in a meaningful time frame and yield

Routine Vaccination Coverage in Northern Nigeria: Results from 40 District-Level Cluster Surveys, 2014-2015

PubMed Central

Ogbuanu, Ikechukwu U.; Adegoke, Oluwasegun J.; Scobie, Heather M.; Uba, Belinda V.; Wannemuehler, Kathleen A.; Ruiz, Alicia; Elmousaad, Hashim; Ohuabunwo, Chima J.; Mustafa, Mahmud; Nguku, Patrick; Waziri, Ndadilnasiya Endie; Vertefeuille, John F.

2016-01-01

Background Despite recent success towards controlling poliovirus transmission, Nigeria has struggled to achieve uniformly high routine vaccination coverage. A lack of reliable vaccination coverage data at the operational level makes it challenging to target program improvement. To reliably estimate vaccination coverage, we conducted district-level vaccine coverage surveys using a pre-existing infrastructure of polio technical staff in northern Nigeria. Methods Household-level cluster surveys were conducted in 40 polio high risk districts of Nigeria during 2014–2015. Global positioning system technology and intensive supervision by a pool of qualified technical staff were used to ensure high survey quality. Vaccination status of children aged 12–23 months was documented based on vaccination card or caretaker’s recall. District-level coverage estimates were calculated using survey methods. Results Data from 7,815 children across 40 districts were analyzed. District-level coverage with the third dose of diphtheria-pertussis-tetanus vaccine (DPT3) ranged widely from 1–63%, with all districts having DPT3 coverage below the target of 80%. Median coverage across all districts for each of eight vaccine doses (1 Bacille Calmette-Guérin dose, 3 DPT doses, 3 oral poliovirus vaccine doses, and 1 measles vaccine dose) was <50%. DPT3 coverage by survey was substantially lower (range: 28%–139%) than the 2013 administrative coverage reported among children aged <12 months. Common reported reasons for non-vaccination included lack of knowledge about vaccines and vaccination services (50%) and factors related to access to routine immunization services (15%). Conclusions Survey results highlighted vaccine coverage gaps that were systematically underestimated by administrative reporting across 40 polio high risk districts in northern Nigeria. Given the limitations of administrative coverage data, our approach to conducting quality district-level coverage surveys and

Bacillus atrophaeus inactivated spores as a potential adjuvant for veterinary rabies vaccine.

PubMed

Oliveira-Nascimento, L; Caricati, A T P; Abdulack-Lopes, F; Neves, L C M; Caricati, C P; Penna, T C V; Stephano, M A

2012-05-14

Rabies is a viral encephalitis, nearly always fatal, but preventable through vaccines. Rabid animal bite is the prime transmission act, while veterinary vaccination is one of the best strategies for rabies general prevention. Aluminum compounds and saponin are the commercial adjuvants used for this vaccine nowadays. Nevertheless, aluminum compounds can provoke undesired side effects and saponin has a narrow activity range without toxicity. B. atrophaeus inactivated spores (BAIS), with or without saponin, were then used as an alternative to boost the inactivated rabies virus response. BAIS was as effective as saponin in augmenting antibody titers, but combination of both adjuvants doubled the titers raised by them individually. The combined adjuvant formulation maintained viability for 21 months when stored at 4-8°C. Overall, BAIS was demonstrated as a viable alternative to commercial adjuvants, while its combination with saponin resulted in even higher vaccine potency with good stability. Copyright © 2012 Elsevier Ltd. All rights reserved.

Comparison of the fibronectin-binding ability and antitumor efficacy of various mycobacteria.

PubMed

Hudson, M A; Ritchey, J K; Catalona, W J; Brown, E J; Ratliff, T L

1990-07-01

Although the mechanism by which Bacillus Calmette-Guerin (BCG) exerts an antitumor effect on superficial bladder tumors is not fully understood, recent evidence has implicated binding of BCG organisms to fibronectin (FN) as requisite for this antitumor efficacy. Various substrains of BCG and other mycobacteria were tested in vitro for their relative capacities to bind both matrix and soluble FN. A substrain of Mycobacterium kansasii, designated the "high-binding strain," was found to bind FN more readily (P less than 0.05) in in vitro studies, when compared to commercially available substrains of BCG (Tice, Connaught, and Armand Frappier). The binding by the three commercial strains of BCG to FN in vitro appeared to be equivalent. The high-binding strain was further demonstrated to attach more readily in vivo to the acutely injured murine bladder (P less than 0.005) than the Armand Frappier substrain. Finally, using the MB49 murine bladder tumor model, an enhanced antitumor effect (P less than 0.05) was noted in mice treated with intravesical high-binding strain, in comparison to the Armand Frappier substrain, during five weekly treatments. It appears not only that the commercial substrains of BCG bind FN in an equivalent manner but also that the relative binding capacities of the substrains correlate directly with antitumor activity. A substrain of M. kansasii appears to have been identified which may prove more clinically effective than the currently available strains of BCG.

Histopathological and immunohistochemical aspects of American cutaneous leishmaniasis before and after different treatments.

PubMed

Viana, Agostinho Gonçalves; Mayrink, Wilson; Fraga, Carlos Alberto de Carvalho; Silva, Luciana Maria; Domingos, Patrícia Luciana Batista; Bonan, Paulo Rogério Ferreti; Paula, Alfredo Maurício Batista de; Botelho, Ana Cristina de Carvalho

2013-01-01

The histopathology and immune responses of the healing process of leishmaniasis are still poorly studied. This study aimed to examine the histopathological and immunological aspects of lesions of patients with cutaneous leishmaniasis before and after different therapeutic methods. We studied 23 individuals grouped according to the treatments: Glucantime, Glucantime + Leishvacin and Glucantime + Leishvacin associated with Bacillus Calmette-Guerin. For analysis of the histopathological changes present in the dermis and epidermis, histological sections were stained with hematoxylin and eosin. The samples were immunostained before and after treatment to analyze the expression of interferon (IFN)-γ, interleukin (IL) 12, IL-10 and IL-4. Before treatment the presence of intense infiltrates of mononuclear cells was noticed and after treatment, even with a diagnosis of clinical cure, the subjects still showed a moderate inflammatory process. In the immunohistochemical analyses, we noticed a difference between the cytokines, with increased expression of cytokines IFN-γ and IL-12 compared to IL 10 and IL-4, both before and after treatment and, comparatively, the difference in this expression was more intense before treatment. However, the cytokine expression analyzed by treatment group showed no statistically significant difference. We conclude that a clinical cure does not always coincide with the histopathological one, and that before treatment there is a predominance of Th1 cytokines. In terms of treatment type, there was no difference in the progression of healing for all the three types of treatment, indicating their clinical equivalence.

Biochemical characteristics among Mycobacterium bovis BCG substrains.

PubMed

Hayashi, Daisuke; Takii, Takemasa; Mukai, Tetsu; Makino, Masahiko; Yasuda, Emi; Horita, Yasuhiro; Yamamoto, Ryuji; Fujiwara, Akiko; Kanai, Keita; Kondo, Maki; Kawarazaki, Aya; Yano, Ikuya; Yamamoto, Saburo; Onozaki, Kikuo

2010-05-01

In order to evaluate the biochemical characteristics of 14 substrains of Mycobacterium bovis bacillus Calmette Guérin (BCG) - Russia, Moreau, Japan, Sweden, Birkhaug, Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia and Pasteur - we performed eight different biochemical tests, including those for nitrate reduction, catalase, niacin accumulation, urease, Tween 80 hydrolysis, pyrazinamidase, p-amino salicylate degradation and resistance to thiophene 2-carboxylic acid hydrazide. Catalase activities of the substrains were all low. Data for nitrate reduction, niacin accumulation, Tween 80 hydrolysis, susceptibility to hydrogen peroxide and nitrate, and optimal pH for growth were all variable among these substrains. These findings suggest that the heterogeneities of biochemical characteristics are relevant to the differences in resistance of BCG substrains to environmental stress. The study also contributes to the re-evaluation of BCG substrains for use as vaccines.

Bacillus velezensis is not a later heterotypic synonym of Bacillus amyloliquefaciens; Bacillus methylotrophicus, Bacillus amyloliquefaciens subsp plantarum and ‘Bacillus oryzicola’ are later heterotypic synonyms of Bacillus

USDA-ARS?s Scientific Manuscript database

The rhizosphere isolated bacteria belonging to the Bacillus amyloliquefaciens subsp. plantarum and Bacillus methylotrophicus clades are an important group of strains that are used as plant growth promoters and antagonists of plant pathogens. These properties have made these strains the focus of comm...

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis.

PubMed

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A; Lozza, Laura; Saikali, Philippe; Sander, Leif E; Vogelzang, Alexis; Kaufmann, Stefan H E; Kupz, Andreas

2016-11-22

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (T RM ) cells have been implicated in protective immune responses against viral infections, but the role of T RM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and T RM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4 + T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8 + T cells displayed prototypical T RM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. BCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models; however, the

Optimizing HIV-1-specific CD8+ T-cell induction by recombinant BCG in prime-boost regimens with heterologous viral vectors.

PubMed

Hopkins, Richard; Bridgeman, Anne; Bourne, Charles; Mbewe-Mvula, Alice; Sadoff, Jerald C; Both, Gerald W; Joseph, Joan; Fulkerson, John; Hanke, Tomáš

2011-12-01

The desire to induce HIV-1-specific responses soon after birth to prevent breast milk transmission of HIV-1 led us to propose a vaccine regimen which primes HIV-1-specific T cells using a recombinant Mycobacterium bovis bacillus Calmette-Guérin (rBCG) vaccine. Because attenuated live bacterial vaccines are typically not sufficiently immunogenic as stand-alone vaccines, rBCG-primed T cells will likely require boost immunization(s). Here, we compared modified Danish (AERAS-401) and Pasteur lysine auxotroph (222) strains of BCG expressing the immunogen HIVA for their potency to prime HIV-1-specific responses in adult BALB/c mice and examined four heterologous boosting HIVA vaccines for their immunogenic synergy. We found that both BCG.HIVA(401) and BCG.HIVA(222) primed HIV-1-specific CD8(+) T-cell-mediated responses. The strongest boosts were delivered by human adenovirus-vectored HAdV5.HIVA and sheep atadenovirus-vectored OAdV7.HIVA vaccines, followed by poxvirus MVA.HIVA; the weakest was plasmid pTH.HIVA DNA. The prime-boost regimens induced T cells capable of efficient in vivo killing of sensitized target cells. We also observed that the BCG.HIVA(401) and BCG.HIVA(222) vaccines have broadly similar immunologic properties, but display a number of differences mainly detected through distinct profiles of soluble intercellular signaling molecules produced by immune splenocytes in response to both HIV-1- and BCG-specific stimuli. These results encourage further development of the rBCG prime-boost regimen. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tuberculosis among dislocated North Koreans entering Republic of Korea since 1999.

PubMed

Choi, Chang Min; June, Jung Hee; Kang, Cheol In; Park, Jung Tak; Oh, Soo Yon; Lee, Jin Beom; Lee, Chang Hoon; Yim, Jae Joon; Kim, Hee Jin

2007-12-01

The collapse of North Korea's public health system has increased the development of tuberculosis (TB) in its populace. This study investigated the prevalence of active and latent TB infection (LTBI) in such people who have settled in the Republic of Korea since 1999. From 1999 to August 2006, 7,722 dislocated North Koreans entered the Republic of Korea and all were screened immediately for active TB. Demographic and clinical characteristics were reviewed from the official records of the Settlement Support Office for Dislocated North Koreans, based in the Ministry of Unification. Of 7,722 participants, 87 (1.13%) were diagnosed with active TB from 1999 to August 2006. Of these, 78 (90%) had pulmonary TB. Checking for the presence of a Bacille Calmette-Guerin (BCG) scar and tuberculin skin test has been performed in all dislocated North Koreans since November 2005. Of 1,112 participants, BCG vaccination scars were found in 67.4%. The tuberculin-positive rate using two tuberculin unit doses of the purified protein derivative RT23 (> or =10mm in diameter) was 81.5%. The prevalence of active TB and LTBI in dislocated North Koreans was high. Because this group bears a disproportionate burden of TB, we need to initiate a specific control programme and to plan for the impact of this disease in the Republic of Korea.

Expression of interferon-gamma and tumour necrosis factor-alpha messenger RNA does not correlate with protection in guinea pigs challenged with virulent Mycobacterium tuberculosis by the respiratory route.

PubMed

Jeevan, Amminikutty; Bonilla, Diana Lucia; McMurray, David Neil

2009-09-01

Cytokine messenger RNA (mRNA) expression was investigated in the spleen and lung digest cells of bacillus Calmette-Guérin (BCG)-vaccinated and non-vaccinated guinea pigs following low-dose, pulmonary exposure to virulent Mycobacterium tuberculosis. After purified protein derivative (PPD) stimulation, the levels of lung cell interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and spleen cell interleukin-12 (IL-12) p40 mRNAs were significantly increased in the non-vaccinated M. tuberculosis-infected guinea pigs compared to the BCG-vaccinated guinea pigs. In contrast, the expression of anti-inflammatory transforming growth factor-beta and IL-10 mRNAs was significantly enhanced in the spleens of BCG-vaccinated animals. Despite the presence of protective cytokine mRNA expression, the non-vaccinated guinea pigs had significantly higher lung and spleen bacterial burdens. In contrast, BCG-vaccinated guinea pigs controlled the bacterial multiplication in their lungs and spleens, indicating that both protective as well as anti-inflammatory cytokine responses are associated with a reduction in bacteria. In addition, lung digest cells from non-vaccinated guinea pigs contained a significantly higher percentage of neutrophils, CD3(+) and CD8(+) T cells, while the percentage of macrophages was increased in the BCG-vaccinated animals. Total and purified lung digest T cells co-cultured with lung macrophages (LMøs) proliferated poorly after PPD stimulation in both non-vaccinated and BCG-vaccinated animals while robust proliferation to PPD was observed when T cells were co-cultured with peritoneal macrophages (PMøs). Macrophages within the lung compartment appear to regulate the response of T cells irrespective of the vaccination status in guinea pigs. Taken together, our results suggest that type I cytokine mRNA expression is not associated with vaccine-induced protection in the low-dose guinea pig model of tuberculosis.

Surveillance of adverse events following vaccination in the French armed forces, 2011-2012.

PubMed

Mayet, A; Duron, S; Meynard, J-B; Koeck, J-L; Deparis, X; Migliani, R

2015-06-01

French military personnel are subject to a compulsory vaccination schedule. The aim of this study was to present the results of surveillance of vaccine adverse events (VAEs) reported from 2011 to 2012 in the French armed forces. VAEs were surveyed among all French armed forces from 2011 to 2012 by the epidemiological departments of the military health service. For each case, a notification form providing patient and clinical information was provided. Case definitions were derived from the French drug safety guidelines. Three types of VAE were considered: non-serious, serious and unexpected. Incidence rates were calculated by relating VAEs to the number of vaccine doses delivered. In total, 161 VAE cases were reported. The overall VAE reporting rate was 24.6 VAEs per 100,000 doses, and the serious VAE rate was 1.3 per 100,000 doses (nine cases). The serious VAEs included two cases of Guillain-Barré syndrome, one case of optic neuritis, one case of a meningeal-like syndrome, one case of rheumatoid purpura, one case of acute asthma and three cases of fainting. The highest rates of VAE were observed with the Bacille Calmette-Guérin vaccine (BCG) (482.3 per 100,000 doses), inactivated diphtheria-tetanus-poliovirus with acellular pertussis vaccine (dTap-IPV) (106.1 per 100,000 doses) and meningococcal quadrivalent glycoconjugate vaccine (MenACWY-CRM) (39.3 per 100,000 doses). The global rates of VAE observed in 2011 and 2012 confirm the increase that has been observed since 2009 in the French armed forces, which could reflect improved practitioner awareness about VAEs and the use of certain vaccines added to the vaccination schedule recently (dTap-IPV in 2008 and MenACWY-CRM in 2010). VAEs appear to be relatively rare, particularly serious VAEs, which indicates acceptable tolerance of vaccines. Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study

PubMed Central

2011-01-01

Background The development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country - Zambia - relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guérin (BCG) vaccination coverage. Methods We conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30-year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy. Results Relative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of $3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of $5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost

Innate Cellular Immunity in Newly Diagnosed Pulmonary Tuberculosis Patients and During Chemotherapy.

PubMed

Edem, Victory Fabian; Arinola, Ganiyu Olatunbosun

2015-01-01

Leukocyte migration (LM) and intracellular killing aspects of the innate immune response play important roles in protection against and containment and cure of Mycobacterium tuberculosis infection, and thus may be exploited as immunotherapeutic targets to improve the management and treatment outcomes of patients with tuberculosis (TB). The aim of this study was to assess LM and mediators of intracellular killing in patients with TB at the time of diagnosis and during anti-TB chemotherapy and compare them with apparently healthy controls. We recruited 24 patients who were newly diagnosed with pulmonary TB and 20 apparently healthy individuals. Blood was drawn from patients with TB at the time of diagnosis, and after 2, 4, and 6 months of anti-TB chemotherapy and control. In vitro percentage LM (%LM) upon stimulation with Bacillus Calmette-Guérin vaccine, percentage nitroblue tetrazolium (%NBT) reduction, plasma concentrations of hydrogen peroxide (H2O2), and nitric oxide (NO) were assessed in both groups. Percentage NBT was significantly reduced in patients with TB at 2 months of anti-TB chemotherapy compared with patients at diagnosis and in healthy controls, whereas %LM was significantly increased in patients at 4 months of anti-TB chemotherapy compared with patients at diagnosis and controls. Mean plasma H2O2 and NO were significantly reduced in patients at diagnosis and throughout the period of anti-TB chemotherapy compared with the control group. Significant decreases were demonstrated in mean plasma H2O2 and NO in patients at 2 and 4 months of anti-TB chemotherapy, respectively, compared with patients at diagnosis. There was significant positive correlation between %NBT with plasma H2O2 and NO, but %LM was negatively correlated with plasma H2O2 in this group. The intracellular killing aspect of innate cellular immunity is deficient in patients with TB, especially 2 to 4 months after commencement of treatment. Therefore, measures (eg, arginine supplementation

A COMPARATIVE STUDY OF THE BIOLOGICAL CHARACTERS AND PATHOGENESIS OF BACILLUS X (STERNBERG), BACILLUS ICTEROIDES (SANARELLI), AND THE HOG-CHOLERA BACILLUS (SALMON AND SMITH)

PubMed Central

Reed, Walter; Carroll, James

1900-01-01

1. Bacillus X (Sternberg) belongs to the colon group. 2. Bacillus icteroides (Sanarelli) is a member of the hog-cholera group. 3. The various channels of infection, the duration of the disease and the gross and microscopical lesions in mice, guinea-pigs and rabbits are the same for Bacillus icteroides and the hog-cholera bacillus. 4. The clinical symptoms and the lesions observed in dogs inoculated intravenously with Bacillus icteroides, are reproduced in these animals by infection with the hog-cholera bacillus. 5. Bacillus icteroides when fed to the domestic pig causes fatal infection, accompanied by diphtheritic, necrotic and ulcerative lesions in the digestive tract, such as are seen in hogs when infected with the hog-cholera bacillus. 6. This disease may be acquired by exposing swine in pens already infected with Bacillus icteroides, or by feeding them with the viscera of infected pigs. 7. Guinea-pigs may be immunized with sterilized cultures ofBacillus icteroides from a fatal dose of the hog-cholera bacillus and vice versa. 8. Rabbits may be rendered immune by gradually increasing doses of a living culture of Bacillus icteroides of weak virulence from a fatal dose of a virulent culture of the hog-cholera bacillus 9. The sera of animals immunized with Bacillus icteroides and with the hog-cholera bacillus, respectively, show a marked reciprocal agglutinative reaction. 10. While the blood of yellow fever practically does not exercise an agglutinative reaction upon Bacillus icteroides, the blood of hog-cholera agglutinates this bacillus in a much more marked degree, thus pointing, we think, to the closer etiological relationship of this bacillus to hog-cholera than to yellow fever. PMID:19866945

Association between tuberculosis and atopy: role of the CD14-159C/T polymorphism.

PubMed

Baççioğlu Kavut, A; Kalpaklioğlu, F; Birben, E; Ayaslioğlu, E

2012-01-01

The development of allergic hypersensitivity depends on both genetic and environmental factors. Different amounts of microbial products could affect patients with atopy and different genotypes. We aimed to evaluate the role of varying degrees of exposure to infection by Mycobacterium tuberculosis (tuberculosis) in atopic patients and analyze the association with genetic factors. We performed CD14-159C/T genotyping in atopic patients (n=118) and healthy individuals (n=62) and recorded the following variables: rural lifestyle, exposure to persons with tuberculosis, bacille Calmette-Guerin (BCG) vaccination, tuberculin skin test (TST), skin prick test, and phenotypes of atopy. Blood samples were analyzed for soluble-CD14 (sCD14), interferon (IFN) y, total immunoglobulin (Ig) E, and eosinophil levels. A score was used to identify the likelihood of exposure to tuberculosis. Almost all the study participants had had a BCG vaccination, and half had a positive TST result. No differences were observed between atopic patients with high/low tuberculosis scores and CD14 genotypes in terms of atopic phenotypes, allergen sensitization, and levels of total IgE, sCD14, and IFN-y. However, the frequency of asthma was higher in atopic patients with a high tuberculosis score and was not associated with CD14 genotypes. Eosinophil counts in blood were higher in atopic patients with a high tuberculosis score and CC+CT genotypes. These results suggest that the C allele of the CD14-159C/T polymorphism has a marked effect on eosinophil levels in atopic patients with increased exposure to tuberculosis. In addition, the degree of exposure to tuberculosis in atopic patients may modify the development of asthma.

Characterization of exochelins of the Mycobacterium bovis type strain and BCG substrains.

PubMed

Gobin, J; Wong, D K; Gibson, B W; Horwitz, M A

1999-04-01

Pathogenic mycobacteria must acquire iron in the host in order to multiply and cause disease. To do so, they release abundant quantities of siderophores called exochelins, which have the capacity to scavenge iron from host iron-binding proteins and deliver it to the mycobacteria. In this study, we have characterized the exochelins of Mycobacterium bovis, the causative agent of bovine and occasionally of human tuberculosis, and the highly attenuated descendant of M. bovis, bacillus Calmette-Guérin (BCG), widely used as a vaccine against human tuberculosis. The M. bovis type strain, five substrains of M. bovis BCG (Copenhagen, Glaxo, Japanese, Pasteur, and Tice), and two strains of virulent Mycobacterium tuberculosis all produce the same set of exochelins, although the relative amounts of individual exochelins may differ. Among these mycobacteria, the total amount of exochelins produced is greatest in M. tuberculosis, intermediate in M. bovis, and smallest in M. bovis BCG.

Validation of a pXO2-A PCR Assay To Explore Diversity among Italian Isolates of Bacillus anthracis Strains Closely Related to the Live, Attenuated Carbosap Vaccine

PubMed Central

Muscillo, M.; La Rosa, G.; Sali, M.; De Carolis, E.; Adone, R.; Ciuchini, F.; Fasanella, A.

2005-01-01

Several circulating Bacillus anthracis strains isolated in Italy and belonging to the A1.a cluster, genotype 3 (A1.a-3) are genotypically indistinguishable from Carbosap, a live attenuated vaccine strain, containing both pXO1 and pXO2 plasmids. The genotype was assessed by using eight-locus multilocus variable-number tandem repeat analysis. We describe here the use of a ninth locus able to explore variability among strains that have the same genotype. It is important to be able to genotype the wild isolate of B. anthracis strains from outbreaks of anthrax in areas where Carbosap vaccination of cattle and sheep is common practice. A total of 27 representative field strains isolated in Italy and four vaccinal strains, namely, Carbosap, Sterne, Pasteur I, and Pasteur II, were characterized by a ninth marker, called pXO2-A. Twenty-three field strains were genotype 3 and therefore identical to Carbosap. The marker was in the pXO2 plasmid and is based on the polymorphism of the already-known VX2-3 locus. Detection was obtained by PCR with fluorescence-labeled forward primers in order to produce appropriate fragments for capillary electrophoresis with an ABI 310 genetic analyzer. Genetic relationships showed heterogeneity in all of the examined samples. Interestingly, with respect to genotype 3, samples grouped into eight different subtypes, A to H, and the subtype G, had only two samples indistinguishable from Carbosap. The results of the present study confirm the validity of a hierarchical progressive protocol for discrimination among closely related isolates. PMID:16145138

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

PubMed Central

Dumas, Eric K.; Gross, Timothy; Larabee, Jason; Pate, Lance; Cuthbertson, Hannah; Charlton, Sue; Hallis, Bassam; Engler, Renata J. M.; Collins, Limone C.; Spooner, Christina E.; Chen, Hua; Ballard, Jimmy; James, Judith A.

2017-01-01

ABSTRACT Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n = 33) versus anthrax vaccine adsorbed (AVA; n = 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 ± 58.6) of EF antibodies than AVA (4.2% and 7.8 ± 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines. PMID:28877928

Developing whole mycobacteria cell vaccines for tuberculosis: Workshop proceedings, Max Planck Institute for Infection Biology, Berlin, Germany, July 9, 2014.

PubMed

2015-06-12

On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease. Copyright © 2015. Published by Elsevier Ltd.. All rights reserved.

Oral vaccination of brushtail possums with BCG: Investigation into factors that may influence vaccine efficacy and determination of duration of protection.

PubMed

Buddle, B M; Aldwell, F E; Keen, D L; Parlane, N A; Hamel, K L; de Lisle, G W

2006-10-01

To determine factors that may influence the efficacy of an oral pelleted vaccine containing Mycobacterium bovis bacille Calmette-Guérin (BCG) to induce protection of brushtail possums against tuberculosis. To determine the duration of protective immunity following oral administration of BCG. In Study 1, a group of possums (n=7) was immunised by feeding 10 pellets containing dead Pasteur BCG, followed 15 weeks later with a single pellet of live Pasteur BCG. At that time, four other groups of possums (n=7 per group) were given a single pellet of live Pasteur BCG orally, a single pellet of live Danish BCG orally, 10 pellets of live Pasteur BCG orally, or a subcutaneous injection of live Pasteur BCG. For the oral pelleted vaccines, BCG was formulated into a lipid matrix, and each pellet contained approximately 107 colony forming units (cfu) of BCG, while the vaccine injected subcutaneously contained 106 cfu of BCG. A sixth, non-vaccinated, group (n=7) served as a control. All possums were challenged by the aerosol route with a low dose of virulent M. bovis 7 weeks after vaccination, and killed 7-8 weeks after challenge. Protection against challenge with M. bovis was assessed from pathological and bacteriological findings. In Study 2, lipid-formulated live Danish BCG was administered orally to three groups of possums (10-11 per group), and these possums were challenged with virulent M. bovis 8, 29 or 54 weeks later. The possums were killed 7 weeks after challenge, to assess protection in comparison to a non-vaccinated group. The results from Study 1 showed that vaccine efficacy was not adversely affected by feeding dead BCG prior to live BCG. Feeding 10 vaccine pellets induced a level of protection similar to feeding a single pellet. Protection was similar when feeding possums a single pellet containing the Pasteur or Danish strains of BCG. All vaccinated groups had significantly reduced pathological changes or bacterial counts when compared to the non-vaccinated group

Treatment of non muscle invasive bladder tumor related to the problem of bacillus Calmette-Guerin availability. Consensus of a Spanish expert's panel. Spanish Association of Urology.

PubMed

Fernández-Gómez, J M; Carballido-Rodríguez, J; Cozar-Olmo, J M; Palou-Redorta, J; Solsona-Narbón, E; Unda-Urzaiz, J M

2013-01-01

Since June 2012, the has been a worldwide lack of available of the Connaught strain. In December 2012, a group of experts met in the Spanish Association of Urology to analyze this situation and propose alternatives. To present the work performed by said committee and the resulting recommendations. An update has been made of the principal existing evidence in the treatment of middle and high risk tumors. Special mention has been made regarding the those related with the use of BCG and their possible alternative due to the different availability of BCG. In tumors with high risk of progression, immediate cystectomy should be considered when BCG is not available, with dose reduction or alternating with chemotherapy as methods to economize on the use of BCG when availability is reduced. In tumors having middle risk of progression, chemotherapy can be used, although when it is associated to a high risk of relapse, BCG would be indicated if available with the mentioned savings guidelines. BCG requires maintenance to maintain its effectiveness, it being necessary to optimize the application of endovesical chemotherapy and to use systems that increase its penetration into the bladder wall (EMDA) if they are available. Due to the scarcity of BCG, it has been necessary to agree on a series of recommendations that have been published on the web page of the Spanish Association of Urology. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

Potentiation of anthrax vaccines using protective antigen-expressing viral replicon vectors.

PubMed

Wang, Hai-Chao; An, Huai-Jie; Yu, Yun-Zhou; Xu, Qing

2015-02-01

DNA vaccines require improvement for human use because they are generally weak stimulators of the immune system in humans. The efficacy of DNA vaccines can be improved using a viral replicon as vector to administer antigen of pathogen. In this study, we comprehensively evaluated the conventional non-viral DNA, viral replicon DNA or viral replicon particles (VRP) vaccines encoding different forms of anthrax protective antigen (PA) for specific immunity and protective potency against anthrax. Our current results clearly suggested that these viral replicon DNA or VRP vaccines derived from Semliki Forest virus (SFV) induced stronger PA-specific immune responses than the conventional non-viral DNA vaccines when encoding the same antigen forms, which resulted in potent protection against challenge with the Bacillus anthracis strain A16R. Additionally, the naked PA-expressing SFV replicon DNA or VRP vaccines without the need for high doses or demanding particular delivery regimens elicited robust immune responses and afforded completely protective potencies, which indicated the potential of the SFV replicon as vector of anthrax vaccines for use in clinical application. Therefore, our results suggest that these PA-expressing SFV replicon DNA or VRP vaccines may be suitable as candidate vaccines against anthrax. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of Mycobacterium tuberculosis Early Secreted Antigenic Target 6 Recombinant Protein as a Diagnostic Marker in Skin Test.

PubMed

Moradi, Jale; Mosavari, Nader; Ebrahimi, Mahmoud; Arefpajohi, Reza; Tebianian, Majid

2015-02-01

Tuberculosis (TB) is the leading infectious disease in the developing world. Delayed-type hypersensitivity skin test diagnoses TB using tuberculin purified protein derivative (PPD), but this test is incapable of distinguishing Mycobacterium tuberculosis (MTB) infection from bacillus Calmette-Guérin (BCG) vaccination or an infection caused by nontuberculous mycobacteria (NTM). This study was performed to evaluate the use of recombinant early secretory antigenic target 6 (rESAT-6), a secretory protein found only in MTB, Mycobacterium bovis, and few other mycobacterial species, as a skin marker for MTB in guinea pigs. We prepared recombinant MTB ESAT-6 and evaluated its use as a specific antigen for MTB in guinea pigs. Our results show that the purified MTB rESAT-6 antigen is capable of inducing a positive reaction only in guinea pigs sensitized to MTB. No such reaction was observed in the animals sensitized to M. bovis, BCG vaccination, or NTM (Mycobacterium avium). Our study results confirm that the ESAT-6 antigen is more specific to MTB infection than PPD and could be used in more specific skin tests for detection of MTB in large animals and in humans.

Trial watch

PubMed Central

Vacchelli, Erika; Galluzzi, Lorenzo; Eggermont, Alexander; Fridman, Wolf Hervé; Galon, Jerome; Sautès-Fridman, Catherine; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido

2012-01-01

Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy. PMID:23162757

Rabbit and Nonhuman Primate Models of Toxin-Targeting Human Anthrax Vaccines

PubMed Central

Phipps, Andrew J.; Premanandan, Christopher; Barnewall, Roy E.; Lairmore, Michael D.

2004-01-01

The intentional use of Bacillus anthracis, the etiological agent of anthrax, as a bioterrorist weapon in late 2001 made our society acutely aware of the importance of developing, testing, and stockpiling adequate countermeasures against biological attacks. Biodefense vaccines are an important component of our arsenal to be used during a biological attack. However, most of the agents considered significant threats either have been eradicated or rarely infect humans alive today. As such, vaccine efficacy cannot be determined in human clinical trials but must be extrapolated from experimental animal models. This article reviews the efficacy and immunogenicity of human anthrax vaccines in well-defined animal models and the progress toward developing a rugged immunologic correlate of protection. The ongoing evaluation of human anthrax vaccines will be dependent on animal efficacy data in the absence of human efficacy data for licensure by the U.S. Food and Drug Administration. PMID:15590776

Bacillus subtilis spore with surface display of paramyosin from Clonorchis sinensis potentializes a promising oral vaccine candidate.

PubMed

Sun, Hengchang; Lin, Zhipeng; Zhao, Lu; Chen, Tingjin; Shang, Mei; Jiang, Hongye; Tang, Zeli; Zhou, Xinyi; Shi, Mengchen; Zhou, Lina; Ren, Pengli; Qu, Honglin; Lin, Jinsi; Li, Xuerong; Xu, Jin; Huang, Yan; Yu, Xinbing

2018-03-07

Clonorchiasis caused by Clonorchis sinensis has become increasingly prevalent in recent years. Effective prevention strategies are urgently needed to control this food-borne infectious disease. Previous studies indicated that paramyosin of C. sinensis (CsPmy) is a potential vaccine candidate. We constructed a recombinant plasmid of PEB03-CotC-CsPmy, transformed it into Bacillus subtilis WB600 strain (B.s-CotC-CsPmy), and confirmed CsPmy expression on the spore surface by SDS-PAGE, Western blotting and immunofluorescence assay. The immune response and protective efficacy of the recombinant spore were investigated in BALB/c mice after intragastrical or intraperitoneal immunization. Additionally, biochemical enzyme activities in sera, the intestinal histopathology and gut microflora of spore-treated mice were investigated. CsPmy was successfully expressed on the spore surface and the fusion protein on the spore surface with thermostability. Specific IgG in sera and intestinal mucus were increased after intraperitoneal and intragastrical immunization. The sIgA level in intestinal mucus, feces and bile of B.s-CotC-CsPmy orally treated mice were also significantly raised. Furthermore, numerous IgA-secreting cells were detected in intestinal mucosa of intragastrically immunized mice. No inflammatory injury was observed in the intestinal tissues and there was no significant difference in levels of enzyme-indicated liver function among the groups. Additionally, the diversity and abundance of gut microbiota were not changed after oral immunization. Intragastric and intraperitoneal immunization of B.s-CotC-CsPmy spores in mice resulted in egg reduction rates of 48.3 and 51.2% after challenge infection, respectively. Liver fibrosis degree in B.s-CotC-CsPmy spores treated groups was also significantly reduced. CsPmy expressed on the spore surface maintained its immunogenicity. Both intragastrical and intraperitoneal immunization with B.s-CotC-CsPmy spores induced systemic and

On the impact of masking and blocking hypotheses for measuring the efficacy of new tuberculosis vaccines.

PubMed

Arregui, Sergio; Sanz, Joaquín; Marinova, Dessislava; Martín, Carlos; Moreno, Yamir

2016-01-01

Over the past 60 years, the Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used worldwide to prevent tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, offering a wide range of protection in adults against pulmonary TB. One of the most accepted hypotheses to explain these inconsistencies points to the existence of a pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium tuberculosis. Specifically, two different mechanisms have been hypothesized to explain this phenomenon: the masking and the blocking effects. According to masking hypothesis, previous sensitization confers some level of protection against TB that masks vaccine's effects. In turn, the blocking hypothesis postulates that previous immune response prevents vaccine taking of a new TB vaccine. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. We apply our methodology to the data reported by BCG-REVAC clinical trials, which were specifically designed for studying BCG efficacy variability. Our results yield estimates that are consistent with high levels of blocking (41% in Manaus -95% CI [14-68]- and 96% in Salvador -95% CI [52-100]-). Moreover, we also show that masking does not play any relevant role in modifying vaccine's efficacy either alone or in addition to blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-tuberculosis vaccines, which are susceptible of being affected by similar effects, especially if applied on individuals previously exposed to mycobacterial antigens.

Immunization of Mice with Formalin-Inactivated Spores from Avirulent Bacillus cereus Strains Provides Significant Protection from Challenge with Bacillus anthracis Ames

PubMed Central

Vergis, James M.; Cote, Christopher K.; Bozue, Joel; Alem, Farhang; Ventura, Christy L.; Welkos, Susan L.

2013-01-01

Bacillus anthracis spores are the infectious form of the organism for humans and animals. However, the approved human vaccine in the United States is derived from a vegetative culture filtrate of a toxigenic, nonencapsulated B. anthracis strain that primarily contains protective antigen (PA). Immunization of mice with purified spore proteins and formalin-inactivated spores (FIS) from a nonencapsulated, nontoxigenic B. anthracis strain confers protection against B. anthracis challenge when PA is also administered. To investigate the capacity of the spore particle to act as a vaccine without PA, we immunized mice subcutaneously with FIS from nontoxigenic, nonencapsulated B. cereus strain G9241 pBCXO1−/pBC210− (dcG9241), dcG9241 ΔbclA, or 569-UM20 or with exosporium isolated from dcG9241. FIS vaccination provided significant protection of mice from intraperitoneal or intranasal challenge with spores of the virulent B. anthracis Ames or Ames ΔbclA strain. Immunization with dcG9241 ΔbclA FIS, which are devoid of the immunodominant spore protein BclA, provided greater protection from challenge with either Ames strain than did immunization with FIS from BclA-producing strains. In addition, we used prechallenge immune antisera to probe a panel of recombinant B. anthracis Sterne spore proteins to identify novel immunogenic vaccine candidates. The antisera were variably reactive with BclA and with 10 other proteins, four of which were previously tested as vaccine candidates. Overall our data show that immunization with FIS from nontoxigenic, nonencapsulated B. cereus strains provides moderate to high levels of protection of mice from B. anthracis Ames challenge and that neither PA nor BclA is required for this protection. PMID:23114705

Use of the mice passive protection test to evaluate the humoral response in goats vaccinated with Sterne 34F2 live spore vaccine.

PubMed

Phaswana, P H; Ndumnego, O C; Koehler, S M; Beyer, W; Crafford, J E; van Heerden, H

2017-09-07

The Sterne live spore vaccine (34F2) is the most widely used veterinary vaccine against anthrax in animals. Antibody responses to several antigens of Bacillus anthracis have been described with a large focus on those against protective antigen (PA). The focus of this study was to evaluate the protective humoral immune response induced by the live spore anthrax vaccine in goats. Boer goats vaccinated twice (week 0 and week 12) with the Sterne live spore vaccine and naive goats were used to monitor the anti-PA and toxin neutralizing antibodies at week 4 and week 17 (after the second vaccine dose) post vaccination. A/J mice were passively immunized with different dilutions of sera from immune and naive goats and then challenged with spores of B. anthracis strain 34F2 to determine the protective capacity of the goat sera. The goat anti-PA ELISA titres indicated significant sero-conversion at week 17 after the second doses of vaccine (p = 0.009). Mice receiving undiluted sera from goats given two doses of vaccine (twice immunized) showed the highest protection (86%) with only 20% of mice receiving 1:1000 diluted sera surviving lethal challenge. The in vitro toxin neutralization assay (TNA) titres correlated to protection of passively immunized A/J mice against lethal infection with the vaccine strain Sterne 34F2 spores using immune goat sera up to a 1:10 dilution (r s  ≥ 0.522, p = 0.046). This study suggests that the passive mouse protection model could be potentially used to evaluate the protective immune response in livestock animals vaccinated with the current live vaccine and new vaccines.

Histopathological and immunohistochemical aspects of American cutaneous leishmaniasis before and after different treatments*

PubMed Central

Viana, Agostinho Gonçalves; Mayrink, Wilson; Fraga, Carlos Alberto de Carvalho; Silva, Luciana Maria; Domingos, Patrícia Luciana Batista; Bonan, Paulo Rogério Ferreti; de Paula, Alfredo Maurício Batista; Botelho, Ana Cristina de Carvalho

2013-01-01

BACKGROUND The histopathology and immune responses of the healing process of leishmaniasis are still poorly studied. OBJECTIVES This study aimed to examine the histopathological and immunological aspects of lesions of patients with cutaneous leishmaniasis before and after different therapeutic methods. METHODS We studied 23 individuals grouped according to the treatments: Glucantime, Glucantime + Leishvacin and Glucantime + Leishvacin associated with Bacillus Calmette-Guerin. For analysis of the histopathological changes present in the dermis and epidermis, histological sections were stained with hematoxylin and eosin. The samples were immunostained before and after treatment to analyze the expression of interferon (IFN)-γ, interleukin (IL) 12, IL-10 and IL-4. RESULTS Before treatment the presence of intense infiltrates of mononuclear cells was noticed and after treatment, even with a diagnosis of clinical cure, the subjects still showed a moderate inflammatory process. In the immunohistochemical analyses, we noticed a difference between the cytokines, with increased expression of cytokines IFN-γ and IL-12 compared to IL 10 and IL-4, both before and after treatment and, comparatively, the difference in this expression was more intense before treatment. However, the cytokine expression analyzed by treatment group showed no statistically significant difference. CONCLUSION We conclude that a clinical cure does not always coincide with the histopathological one, and that before treatment there is a predominance of Th1 cytokines. In terms of treatment type, there was no difference in the progression of healing for all the three types of treatment, indicating their clinical equivalence. PMID:23539001

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

PubMed

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; da Silva Nunes, Iseu; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.

Human herpes virus type 6 can cause skin lesions at the BCG inoculation site similar to Kawasaki Disease.

PubMed

Kakisaka, Yosuke; Ohara, Tomoichiro; Katayama, Saori; Suzuki, Tasuku; Sasai, Shu; Hino-Fukuyo, Naomi; Kure, Shigeo

2012-12-01

Kawasaki Disease (KD) is acute, febrile, multisystem vasculitis of early childhood, the detailed mechanism of which is still unclear. Skin symptoms occur in KD, such as edema of the hands and feet with subsequent desquamation and redness at the inoculation site of bacillus Calmette-Guerin (BCG). The change at the BCG inoculation site has been considered as a specific feature of KD, although its mechanism is not fully understood. We present an 11-month-old boy who developed fever with redness of the BCG site due to infection with human herpes virus type 6 (HHV6). At the age of 3 months, the patient received BCG. His fever remitted 7 days after the onset of skin redness, with sequential desquamation at the BCG site and extremities, which is not a common feature of HHV6 infection that typically lasts for 3 days. The final diagnosis was exanthema subitum. Characteristically, the HHV6 infection in our patient appeared to be associated with the invigoration of the T cell system, as represented by the elevated serum levels of soluble interleukin-2 receptor (3,490 U/ml vs. normal range 145-519 U/ml). This patient clearly showed redness and crusting at the BCG inoculation site, suggesting that HHV6 infection might cause skin changes similar to those of KD via an unknown mechanism. In addition, we suggest that the activation of the T cell system may account for the skin lesions in KD, characterized by redness and subsequent crusting of the BCG inoculation site and desquamation of the extremities.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Hu, E-mail: austhudong@126.com; Medical Inspection Center, Anhui University of Science and Technology, Huainan; Jing, Wu, E-mail: wujing8008@126.com

In recent years, increasing studies have found that pathogenic Mycobacterium tuberculosis (Mtb) inhibits autophagy, which mediates the anti-mycobacterial response, but the mechanism is not clear. We previously reported that secretory acid phosphatase (SapM) of Mtb can negatively regulate autophagy flux. Recently, another virulence factor of Mtb, early secretory antigenic target 6 (ESAT6), has been found to be involved in inhibiting autophagy, but the mechanism remains unclear. In this study, we show that ESAT6 hampers autophagy flux to boost bacillus Calmette-Guerin (BCG) proliferation and reveals a mechanism by which ESAT6 blocks autophagosome-lysosome fusion in a mammalian target of rapamycin (MTOR)-dependent manner.more » In both Raw264.7 cells and primary macrophages derived from the murine abdominal cavity (ACM), ESAT6 repressed autophagy flux by interfering with the autophagosome-lysosome fusion, which resulted in an increased load of BCG. Impaired degradation of LC3Ⅱ and SQSTM1 by ESAT6 was related to the upregulated activity of MTOR. Contrarily, inhibiting MTOR with Torin1 removed the ESAT6-induced autophagy block and lysosome dysfunction. Furthermore, in both Raw264.7 and ACM cells, MTOR inhibition significantly suppressed the survival of BCG. In conclusion, our study highlights how ESAT6 blocks autophagy and promotes BCG survival in a way that activates MTOR. - Highlights: • A mechanism for disruping autophagy flux induced by ESAT6. • ESAT6-inhibited autophagy is MTOR-dependent. • ESAT6-boosted BCG is MTOR-dependent.« less

Alexandre Yersin (1863-1943): discoverer of the plague bacillus, explorer and agronomist.

PubMed

Hawgood, Barbara J

2008-08-01

Alexandre Yersin was born in French Switzerland and later took French nationality. While a medical student he worked in Paris with Emile Roux to discover the exotoxin produced by the diphtheria bacillus. Two years after graduation, he left Paris for French Indochina where he was the first European to explore and map the central highlands of Vietnam. As a member of the French Colonial Health Service he was sent to Hong Kong in 1894 to investigate the outbreak of bubonic plague. He isolated from buboes the causative bacillus that later was named Yersinia pestis in his honour. In Vietnam, Yersin established a Pasteur Institute at the coastal village of Nha Trang where he lived for the rest of his life. He developed vaccines and antisera for both men and animals and, as an agronomist, he introduced the Brazilian rubber tree and Peruvian cinchona tree (for quinine) into the country. In Vietnam, as in France, the name of Yersin continues to be venerated.

Study of mural painting isolates, leading to the transfer of 'Bacillus maroccanus' and 'Bacillus carotarum' to Bacillus simplex, emended description of Bacillus simplex, re-examination of the strains previously attributed to 'Bacillus macroides' and description of Bacillus muralis sp. nov.

PubMed

Heyrman, Jeroen; Logan, Niall A; Rodríguez-Díaz, Marina; Scheldeman, Patsy; Lebbe, Liesbeth; Swings, Jean; Heyndrickx, Marc; De Vos, Paul

2005-01-01

A group of 24 strains was isolated from deteriorated mural paintings situated in Spain (necropolis of Carmona) and Germany (church of Greene-Kreiensen). (GTG)5-PCR genomic fingerprinting was performed on these strains to assess their genomic variability and the strains were delineated into four groups. Representatives were studied by 16S rRNA gene sequencing and were found to be closely related to Bacillus simplex and the species 'Bacillus macroides' (strain NCIMB 8796) and 'Bacillus maroccanus' (names not validly published) according to a fasta search. The close similarity between B. simplex, 'B. macroides' NCIMB 8796, 'B. maroccanus' and the mural painting isolates was confirmed by additional (GTG)5-PCR, ARDRA, FAME and SDS-PAGE analyses. Furthermore, these techniques revealed that strains of 'Bacillus carotarum', another name that has not been validly published, also showed high similarity to this group of organisms. On the other hand, it was shown that the strains labelled 'B. macroides' in different collections do not all belong to the same species. Strain NCIMB 8796 can be allocated to B. simplex, while strain DSM 54 (=ATCC 12905) shares the highest 16S rRNA gene sequence similarity with Bacillus sphaericus and Bacillus fusiformis (both around 98.6 %). On the basis of further DNA-DNA hybridization data and the study of phenotypic characteristics, one group of five mural painting strains was attributed to a novel species in the genus Bacillus, for which the name Bacillus muralis sp. nov. is proposed. Finally, the remaining mural painting strains, one (LMG 18508=NCIMB 8796) of two strains belonging to 'B. macroides' and strains belonging to 'B. maroccanus' and 'B. carotarum' are allocated to the species B. simplex and an emended description of B. simplex is given.

Socioeconomic inequalities are still a barrier to full child vaccine coverage in the Brazilian Amazon: a cross-sectional study in Assis Brasil, Acre, Brazil.

PubMed

Branco, Fernando Luiz Cunha Castelo; Pereira, Thasciany Moraes; Delfino, Breno Matos; Braña, Athos Muniz; Oliart-Guzmán, Humberto; Mantovani, Saulo Augusto Silva; Martins, Antonio Camargo; Oliveira, Cristieli Sérgio de Menezes; Ramalho, Alanderson Alves; Codeço, Claudia Torres; da Silva-Nunes, Mônica

2014-11-27

Vaccines are very important to reduce morbidity and mortality by preventable infectious diseases, especially during childhood. Optimal coverage is not always achieved, for several reasons. Here we assessed vaccine coverage for the first 12 months of age in children between 12 and 59 months old, residing in the urban area of a small Amazonian city, and factors associated with incomplete vaccination. A census was performed in the urban area of Assis Brasil, in the Brazilian Amazon, in January 2010, with mothers of 282 children aged 12 to 59 months old, using structured interviews and data from vaccination cards. Mixed logistic regression was used to determine factors associated with incomplete vaccination schemes. Only 82.6% of all children had a completed the basic vaccine scheme for the first year of life. Vaccine coverage ranged from 52.7% coverage (oral rotavirus vaccine) to 99.7% coverage (for Bacille Calmette-Guérin). The major deficiencies occurred in doses administered after the first six months of life. Incomplete vaccination was associated with not having enough income to buy a house (aOR = 2.12, 95% CI 1.06-4.21), low maternal schooling (aOR = 2.60, 95% CI 1.28 - 5.29) , and time of residence of the child in the urban area of the city (aOR = 0.73, 95% CI 0.55 - 0.95). This study showed that vaccine coverage in the first twelve months of life in Assis Brasil is similar to other areas in the Amazon and it is below the coverage postulated by the Brazilian Ministry of Health. Low vaccine coverage was associated with socioeconomic inequities that still prevail in the Brazilian Amazon. Short and long-term strategies must be taken to update child vaccines and increase vaccine coverage in the Amazon.

Socioeconomic inequalities and vaccination coverage: results of an immunisation coverage survey in 27 Brazilian capitals, 2007-2008.

PubMed

Barata, Rita Barradas; Ribeiro, Manoel Carlos Sampaio de Almeida; de Moraes, José Cássio; Flannery, Brendan

2012-10-01

Since 1988, Brazil's Unified Health System has sought to provide universal and equal access to immunisations. Inequalities in immunisation may be examined by contrasting vaccination coverage among children in the highest versus the lowest socioeconomic strata. The authors examined coverage with routine infant immunisations from a survey of Brazilian children according to socioeconomic stratum of residence census tract. The authors conducted a household cluster survey in census tracts systematically selected from five socioeconomic strata, according to average household income and head of household education, in 26 Brazilian capitals and the federal district. The authors calculated coverage with recommended vaccinations among children until 18 months of age, according to socioeconomic quintile of residence census tract, and examined factors associated with incomplete vaccination. Among 17,295 children with immunisation cards, 14,538 (82.6%) had received all recommended vaccinations by 18 months of age. Among children residing in census tracts in the highest socioeconomic stratum, 77.2% were completely immunised by 18 months of age versus 81.2%-86.2% of children residing in the four census tract quintiles with lower socioeconomic indicators (p<0.01). Census tracts in the highest socioeconomic quintile had significantly lower coverage for bacille Calmette-Guérin, oral polio and hepatitis B vaccines than those with lower socioeconomic indicators. In multivariable analysis, higher birth order and residing in the highest socioeconomic quintile were associated with incomplete vaccination. After adjusting for interaction between socioeconomic strata of residence census tract and household wealth index, only birth order remained significant. Evidence from Brazilian capitals shows success in achieving high immunisation coverage among poorer children. Strategies are needed to reach children in wealthier areas.

[PERSPECTIVES OF DEVELOPMENT OF LIVE RECOMBINANT ANTHRAX VACCINES BASED ON OPPORTUNISTIC AND APATHOGENIC MICROORGANISMS].

PubMed

Popova, P Yu; Mikshis, N I

2016-01-01

Live genetic engineering anthrax vaccines on the platform of avirulent and probiotic micro-organisms are a safe and adequate alternative to preparations based on attenuated Bacillus anthracis strains. Mucosal application results in a direct contact of the vaccine preparations with mucous membranes in those organs arid tissues of the macro-organisms, that are exposed to the pathogen in the first place, resulting in a development of local and systemic immune response. Live recombinant anthrax vaccines could be used both separately as well as in a prime-boost immunization scheme. The review focuses on immunogenic and protective properties of experimental live genetic engineering prearations, created based on members of geni of Salmonella, Lactobacillus and adenoviruses.

Protective activity and immunogenicity of two recombinant anthrax vaccines for veterinary use.

PubMed

Fasanella, A; Tonello, F; Garofolo, G; Muraro, L; Carattoli, A; Adone, R; Montecucco, C

2008-10-23

In this study, the efficacy of two experimental vaccines against Bacillus anthracis toxinaemia was evaluated in the rabbit model. A recombinant Protective Antigen (rPA) mutant and a trivalent vaccine (TV) composed by the rPA, a inactive mutant of Lethal Factor (mLF-Y728A; E735A) and a inactive mutant of Edema Factor (mEF-K346R), both emulsified with mineral oils, were evaluated for their immunogenicity and protective activity in New Zealand white rabbits. Rabbits vaccinated subcutaneously with rPA and TV rapidly produced high level of anti-PA, anti-LF and anti-EF antibodies, which were still present 6 months later. In the efficacy test, these vaccines protected 100% of rabbits challenged with B. anthracis virulent strain 0843 one week after the vaccination. Moreover, all animals vaccinated twice with rPA and TV, resisted B. anthracis infection 6 months later. Our data indicate that rPA and TV could be good vaccine candidates for inducing protection against B. anthracis infection in target animal host. They could successfully be used in an emergency with simultaneous long-acting antibiotics to halt incubating infections or during an anthrax epidemic.

Increased long-term immunity to Bacillus anthracis protective antigen in mice immunized with a CIA06B-adjuvanted anthrax vaccine.

PubMed

Wui, Seo Ri; Han, Ji Eun; Kim, Yeon Hee; Rhie, Gi-eun; Lee, Na Gyong

2013-04-01

Anthrax is an acute infectious disease caused by Bacillus anthracis. We previously reported that the adjuvant CIA06B, which consists of TLR4 agonist CIA05 and aluminum hydroxide (alum), enhanced the immune response to anthrax protective antigen (PA) in mice. This study was carried out to determine whether CIA06B can enhance long-term immune responses to PA in mice. BALB/c mice were immunized intramuscularly three times at 2-week intervals with recombinant PA alone or PA combined with alum or CIA06B. At 8 and 24 weeks post-immunization, the immunological responses including serum anti-PA IgG antibody titer, toxin-neutralizing antibody titer, splenic cytokine secretion and the frequency of PA-specific memory B cells were assessed. Compared with mice injected with PA alone or PA plus alum, mice injected with PA plus CIA06B had higher titers of serum anti-PA IgG antibodies, and higher frequencies of PA-specific memory B cells and interferon-γ secreting cells. Furthermore, anti-PA antibodies induced by CIA06B were more effective in neutralizing anthrax toxin. These results demonstrated that CIA06B is capable of providing long-term immunity when used as an adjuvant in a PA-based anthrax vaccine.

Generation and Characterization of Human Monoclonal Antibodies Targeting Anthrax Protective Antigen following Vaccination with a Recombinant Protective Antigen Vaccine.

PubMed

Chi, Xiangyang; Li, Jianmin; Liu, Weicen; Wang, Xiaolin; Yin, Kexin; Liu, Ju; Zai, Xiaodong; Li, Liangliang; Song, Xiaohong; Zhang, Jun; Zhang, Xiaopeng; Yin, Ying; Fu, Ling; Xu, Junjie; Yu, Changming; Chen, Wei

2015-05-01

The anthrax protective antigen (PA) is the central component of the three-part anthrax toxin, and it is the primary immunogenic component in the approved AVA anthrax vaccine and the "next-generation" recombinant PA (rPA) anthrax vaccines. Animal models have indicated that PA-specific antibodies (AB) are sufficient to protect against infection with Bacillus anthracis. In this study, we investigated the PA domain specificity, affinity, mechanisms of neutralization, and synergistic effects of PA-specific antibodies from a single donor following vaccination with the rPA vaccine. Antibody-secreting cells were isolated 7 days after the donor received a boost vaccination, and 34 fully human monoclonal antibodies (hMAb) were identified. Clones 8H6, 4A3, and 22F1 were able to neutralize lethal toxin (LeTx) both in vitro and in vivo. Clone 8H6 neutralized LeTx by preventing furin cleavage of PA in a dose-dependent manner. Clone 4A3 enhanced degradation of nicked PA, thereby interfering with PA oligomerization. The mechanism of 22F1 is still unclear. A fourth clone, 2A6, that was protective only in vitro was found to be neutralizing in vivo in combination with a toxin-enhancing antibody, 8A7, which binds to domain 3 of PA and PA oligomers. These results provide novel insights into the antibody response elicited by the rPA vaccine and may be useful for PA-based vaccine and immunotherapeutic cocktail design. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Maternal education is associated with vaccination status of infants less than 6 months in Eastern Uganda: a cohort study.

PubMed

Nankabirwa, Victoria; Tylleskär, Thorkild; Tumwine, James K; Sommerfelt, Halvor

2010-12-15

Despite provision of free childhood vaccinations, less than half of all Ugandan infants are fully vaccinated. This study compares women with some secondary schooling to those with only primary schooling with regard to their infants' vaccination status. A community-based prospective cohort study conducted between January 2006 and May 2008 in which 696 pregnant women were followed up to 24 weeks post partum. Information was collected on the mothers' education and vaccination status of the infants. At 24 weeks, the following vaccinations had been received: bacille Calmette-Guérin (BCG): 92%; polio-1: 91%; Diphteria-Pertussis-Tetanus-Hepatitis B-Haemophilus Influenza b (DPT-HB-Hib) 3 and polio-3: 63%. About 51% of the infants were fully vaccinated (i.e., had received all the scheduled vaccinations: BCG, polio 0, polio 1, DPT-HB-Hib1, polio 2, DPT-HB-Hib 2, polio 3 and DPT-HB-Hib 3). Only 46% of the infants whose mothers' had 5-7 years of primary education had been fully vaccinated compared to 65% of the infants whose mothers' had some secondary education. Infants whose mothers had some secondary education were less likely to miss the DPT-HB-Hib-2 vaccine (RR: 0.5, 95% CI: 0.3, 0.8), Polio-2 (RR: 0.4, 95%CI: 0.3, 0.7), polio-3 (RR: 0.5, 95%CI: 0.4, 0.7) and DPT-HB-Hib-3 (RR: 0.5, 95%CI: 0.4, 0.7). Other factors showing some association with a reduced risk of missed vaccinations were delivery at a health facility (RR = 0.8; 95%CI: 0.7, 1.0) and use of a mosquito net (RR: 0.8; 95%CI: 0.7, 1.0). Infants whose mothers had a secondary education were at least 50% less likely to miss scheduled vaccinations compared to those whose mothers only had primary education. Strategies for childhood vaccinations should specifically target women with low formal education.

Microbial Disease Spectrum Linked to a Novel IL-12Rβ1 N-Terminal Signal Peptide Stop-Gain Homozygous Mutation with Paradoxical Receptor Cell-Surface Expression

PubMed Central

Louvain de Souza, Thais; de Souza Campos Fernandes, Regina C.; Azevedo da Silva, Juliana; Gomes Alves Júnior, Vladimir; Gomes Coelho, Adelia; Souza Faria, Afonso C.; Moreira Salomão Simão, Nabia M.; Souto Filho, João T.; Deswarte, Caroline; Boisson-Dupuis, Stéphanie; Torgerson, Dara; Casanova, Jean-Laurent; Bustamante, Jacinta; Medina-Acosta, Enrique

2017-01-01

Patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) exhibit variable vulnerability to infections by mycobacteria and other intramacrophagic bacteria (e.g., Salmonella and Klebsiella) and fungi (e.g., Histoplasma, Candida, Paracoccidioides, Coccidioides, and Cryptococcus). The hallmark of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or the lack of response to it. Mutations in the interleukin (IL)-12 receptor subunit beta 1 (IL12RB1) gene accounts for 38% of cases of MSMD. Most IL12RB1 pathogenic allele mutations, including ten known stop-gain variants, cause IL-12Rβ1 complete deficiency (immunodeficiency-30, IMD30) by knocking out receptor cell-surface expression. IL12RB1 loss-of-function genotypes impair both IL-12 and IL-23 responses. Here, we assess the health effects of a rare, novel IL12RB1 stop-gain homozygous genotype with paradoxical IL-12Rβ1 cell-surface expression. We appraise four MSMD children from three unrelated Brazilian kindreds by clinical consultation, medical records, and genetic and immunologic studies. The clinical spectrum narrowed down to Bacillus Calmette-Guerin (BCG) vaccine-related suppurative adenitis in all patients with one death, and recrudescence in two, histoplasmosis, and recurrence in one patient, extraintestinal salmonellosis in one child, and cutaneous vasculitis in another. In three patients, we established the homozygous Trp7Ter predicted loss-of-function inherited genotype and inferred it from the heterozygote parents of the fourth case. The Trp7Ter mutation maps to the predicted IL-12Rβ1 N-terminal signal peptide sequence. BCG- or phytohemagglutinin-blasts from the three patients have reduced cell-surface expression of IL-12Rβ1 with impaired production of IFN-γ and IL-17A. Screening of 227 unrelated healthy subjects from the same geographic region revealed one heterozygous genotype (allele frequency 0.0022) vs. one in over 841,883 public genome/exomes. We also show that the

Global Health in Conflict Understanding Opposition to Vitamin A Supplementation in India

PubMed Central

Wallace, Sarah K.

2012-01-01

Vitamin A supplementation is a public health intervention that clinical trials have suggested can significantly improve child survival in the developing world. Yet, prominent scientists in India have questioned its scientific validity, opposed its implementation, and accused its advocates of corruption and greed. It is ironic that these opponents were among the pioneers of populationwide vitamin A supplementation for ocular health. Historically, complex interests have shaped vitamin A supplementation resistance in India. Local social and nutritional revolutions and shifting international paradigms of global health have played a role. Other resistance movements in Indian history, such as those in response to campaigns for bacillus Calmette-Guérin and novel vaccines, have been structured around similar themes. Public health resistance is shaped by the cultural and political context in which it develops. Armed with knowledge of the history of a region and patterns of past resistance, public health practitioners can better understand how to negotiate global health conflicts. PMID:22594752

Global health in conflict. Understanding opposition to vitamin A supplementation in India.

PubMed

Wallace, Sarah K

2012-07-01

Vitamin A supplementation is a public health intervention that clinical trials have suggested can significantly improve child survival in the developing world. Yet, prominent scientists in India have questioned its scientific validity, opposed its implementation, and accused its advocates of corruption and greed. It is ironic that these opponents were among the pioneers of populationwide vitamin A supplementation for ocular health. Historically, complex interests have shaped vitamin A supplementation resistance in India. Local social and nutritional revolutions and shifting international paradigms of global health have played a role. Other resistance movements in Indian history, such as those in response to campaigns for bacillus Calmette-Guérin and novel vaccines, have been structured around similar themes. Public health resistance is shaped by the cultural and political context in which it develops. Armed with knowledge of the history of a region and patterns of past resistance, public health practitioners can better understand how to negotiate global health conflicts.

Bacteriophage T4 as a Nanoparticle Platform to Display and Deliver Pathogen Antigens: Construction of an Effective Anthrax Vaccine.

PubMed

Tao, Pan; Li, Qin; Shivachandra, Sathish B; Rao, Venigalla B

2017-01-01

Protein-based subunit vaccines represent a safer alternative to the whole pathogen in vaccine development. However, limitations of physiological instability and low immunogenicity of such vaccines demand an efficient delivery system to stimulate robust immune responses. The bacteriophage T4 capsid-based antigen delivery system can robustly elicit both humoral and cellular immune responses without any adjuvant. Therefore, it offers a strong promise as a novel antigen delivery system. Currently Bacillus anthracis, the causative agent of anthrax, is a serious biothreat agent and no FDA-approved anthrax vaccine is available for mass vaccination. Here, we describe a potential anthrax vaccine using a T4 capsid platform to display and deliver the 83 kDa protective antigen, PA, a key component of the anthrax toxin. This T4 vaccine platform might serve as a universal antigen delivery system that can be adapted to develop vaccines against any infectious disease.

An application of forward-backward difference approximation method on the optimal control problem in the transmission of tuberculosis model

NASA Astrophysics Data System (ADS)

Rahmah, Z.; Subartini, B.; Djauhari, E.; Anggriani, N.; Supriatna, A. K.

2017-03-01

Tuberculosis (TB) is a disease that is infected by the bacteria Mycobacterium tuberculosis. The World Health Organization (WHO) recommends to implement the Baccilus Calmete Guerin (BCG) vaccine in toddler aged two to three months to be protected from the infection. This research explores the numerical simulation of forward-backward difference approximation method on the model of TB transmission considering this vaccination program. The model considers five compartments of sub-populations, i.e. susceptible, vaccinated, exposed, infected, and recovered human sub-populations. We consider here the vaccination as a control variable. The results of the simulation showed that vaccination can indeed reduce the number of infected human population.

Recent progress in the development of anthrax vaccines.

PubMed

Kaur, Manpreet; Bhatnagar, Rakesh

2011-12-01

Bacillus anthracis is the etiological agent of anthrax. Although anthrax is primarily an epizootic disease; humans are at risk for contracting anthrax. The potential use of B. anthracis spores as biowarfare agent has led to immense attention. Prolonged vaccination schedule of current anthrax vaccine and variable protection conferred; often leading to failure of therapy. This highlights the need for alternative anthrax countermeasures. A number of approaches are being investigated to substitute or supplement the existing anthrax vaccines. These relied on expression of Protective antigen (PA), the key protective immunogen; in bacterial or plant systems; or utilization of attenuated strains of B. anthracis for immunization. Few studies have established potential of domain IV of PA for immunization. Other targets including the spore, capsule, S-layer and anthrax toxin components have been investigated for imparting protective immunity. It has been shown that co-immunization of PA with domain I of lethal factor that binds PA resulted in higher antibody responses. Of the epitope based vaccines, the loop neutralizing determinant, in particular; elicited robust neutralizing antibody response and conferred 97% protection upon challenge. DNA vaccination resulted in varying degree of protection and seems a promising approach. Additionally, the applicability of monoclonal and therapeutic antibodies in the treatment of anthrax has also been demonstrated. The recent progress in the direction of anthrax prophylaxis has been evaluated in this review.

Efficacy of a capsule conjugate vaccine against inhalational anthrax in rabbits and monkeys.

PubMed

Chabot, Donald J; Joyce, Joseph; Caulfield, Michael; Cook, James; Hepler, Robert; Wang, Su; Vietri, Nicholas J; Ruthel, Gordon; Shoop, Wesley; Pitt, Louise; Leffel, Elizabeth; Ribot, Wilson; Friedlander, Arthur M

2012-01-20

Bacillus anthracis, the causative agent of anthrax, is recognized as one of the most serious bioterrorism threats. The current human vaccines are based on the protective antigen component of the anthrax toxins. Concern about possible vaccine resistant strains and reliance on a single antigen has prompted the search for additional immunogens. Bacterial capsules, as surface-expressed virulence factors, are well-established components of several licensed vaccines. In a previous study we showed that an anthrax vaccine consisting of the B. anthracis poly-γ-D-glutamic acid capsule covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B protected mice against parenteral B. anthracis challenge. Here we tested this vaccine in rabbits and monkeys against an aerosol spore challenge. The vaccine induced anti-capsule antibody responses in both species, measured by ELISA and a macrophage opsono-adherence assay. While rabbits were not protected against a high aerosol challenge dose, significant protection was observed in monkeys receiving the capsule conjugate vaccine. The results confirm that the capsule is a protective immunogen against anthrax, being the first non-toxin antigen shown to be efficacious in monkeys and suggest that addition of capsule may broaden and enhance the protection afforded by protective antigen-based vaccines. Published by Elsevier Ltd.

Immunogenicity and efficacy of an anthrax/plague DNA fusion vaccine in a mouse model.

PubMed

Albrecht, Mark T; Eyles, Jim E; Baillie, Les W; Keane-Myers, Andrea M

2012-08-01

The efficacy of multi-agent DNA vaccines consisting of a truncated gene encoding Bacillus anthracis lethal factor (LFn) fused to either Yersinia pestis V antigen (V) or Y . pestis F1 was evaluated. A/J mice were immunized by gene gun and developed predominantly IgG1 responses that were fully protective against a lethal aerosolized B. anthracis spore challenge but required the presence of an additional DNA vaccine expressing anthrax protective antigen to boost survival against aerosolized Y. pestis. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Immunization with a Recombinant, Pseudomonas fluorescens-Expressed, Mutant Form of Bacillus anthracis-Derived Protective Antigen Protects Rabbits from Anthrax Infection.

PubMed

Reed, Matthew D; Wilder, Julie A; Mega, William M; Hutt, Julie A; Kuehl, Philip J; Valderas, Michelle W; Chew, Lawrence L; Liang, Bertrand C; Squires, Charles H

2015-01-01

Protective antigen (PA), one of the components of the anthrax toxin, is the major component of human anthrax vaccine (Biothrax). Human anthrax vaccines approved in the United States and Europe consist of an alum-adsorbed or precipitated (respectively) supernatant material derived from cultures of toxigenic, non-encapsulated strains of Bacillus anthracis. Approved vaccination schedules in humans with either of these vaccines requires several booster shots and occasionally causes adverse injection site reactions. Mutant derivatives of the protective antigen that will not form the anthrax toxins have been described. We have cloned and expressed both mutant (PA SNKE167-ΔFF-315-E308D) and native PA molecules recombinantly and purified them. In this study, both the mutant and native PA molecules, formulated with alum (Alhydrogel), elicited high titers of anthrax toxin neutralizing anti-PA antibodies in New Zealand White rabbits. Both mutant and native PA vaccine preparations protected rabbits from lethal, aerosolized, B. anthracis spore challenge subsequent to two immunizations at doses of less than 1 μg.

Multivalent Chromosomal Expression of the Clostridium botulinum Serotype A Neurotoxin Heavy-Chain Antigen and the Bacillus anthracis Protective Antigen in Lactobacillus acidophilus.

PubMed

O'Flaherty, Sarah; Klaenhammer, Todd R

2016-10-15

Clostridium botulinum and Bacillus anthracis produce potent toxins that cause severe disease in humans. New and improved vaccines are needed for both of these pathogens. For mucosal vaccine delivery using lactic acid bacteria, chromosomal expression of antigens is preferred over plasmid-based expression systems, as chromosomal expression circumvents plasmid instability and the need for antibiotic pressure. In this study, we constructed three strains of Lactobacillus acidophilus NCFM expressing from the chromosome (i) the nontoxic host receptor-binding domain of the heavy chain of Clostridium botulinum serotype A neurotoxin (BoNT/A-Hc), (ii) the anthrax protective antigen (PA), and (iii) both the BoNT/A-Hc and the PA. The BoNT/A-Hc vaccine cassette was engineered to contain the signal peptide from the S-layer protein A from L. acidophilus and a dendritic-cell-targeting peptide. A chromosomal region downstream of lba0889 carrying a highly expressed enolase gene was selected for insertion of the vaccine cassettes. Western blot analysis confirmed the heterologous expression of the two antigens from plasmid and chromosome locations. Stability assays demonstrated loss of the vaccine cassettes from expression plasmids without antibiotic maintenance. RNA sequencing showed high expression of each antigen and that insertion of the vaccine cassettes had little to no effect on the transcription of other genes in the chromosome. This study demonstrated that chromosomal integrative recombinant strains are promising vaccine delivery vehicles when targeted into high-expression chromosomal regions. Levels of expression match high-copy-number plasmids and eliminate the requirement for antibiotic selective maintenance of recombinant plasmids. Clostridium botulinum and Bacillus anthracis produce potent neurotoxins that pose a biochemical warfare concern; therefore, effective vaccines against these bacteria are required. Chromosomal expression of antigens is preferred over plasmid

Multivalent Chromosomal Expression of the Clostridium botulinum Serotype A Neurotoxin Heavy-Chain Antigen and the Bacillus anthracis Protective Antigen in Lactobacillus acidophilus

PubMed Central

Klaenhammer, Todd R.

2016-01-01

ABSTRACT Clostridium botulinum and Bacillus anthracis produce potent toxins that cause severe disease in humans. New and improved vaccines are needed for both of these pathogens. For mucosal vaccine delivery using lactic acid bacteria, chromosomal expression of antigens is preferred over plasmid-based expression systems, as chromosomal expression circumvents plasmid instability and the need for antibiotic pressure. In this study, we constructed three strains of Lactobacillus acidophilus NCFM expressing from the chromosome (i) the nontoxic host receptor-binding domain of the heavy chain of Clostridium botulinum serotype A neurotoxin (BoNT/A-Hc), (ii) the anthrax protective antigen (PA), and (iii) both the BoNT/A-Hc and the PA. The BoNT/A-Hc vaccine cassette was engineered to contain the signal peptide from the S-layer protein A from L. acidophilus and a dendritic-cell-targeting peptide. A chromosomal region downstream of lba0889 carrying a highly expressed enolase gene was selected for insertion of the vaccine cassettes. Western blot analysis confirmed the heterologous expression of the two antigens from plasmid and chromosome locations. Stability assays demonstrated loss of the vaccine cassettes from expression plasmids without antibiotic maintenance. RNA sequencing showed high expression of each antigen and that insertion of the vaccine cassettes had little to no effect on the transcription of other genes in the chromosome. This study demonstrated that chromosomal integrative recombinant strains are promising vaccine delivery vehicles when targeted into high-expression chromosomal regions. Levels of expression match high-copy-number plasmids and eliminate the requirement for antibiotic selective maintenance of recombinant plasmids. IMPORTANCE Clostridium botulinum and Bacillus anthracis produce potent neurotoxins that pose a biochemical warfare concern; therefore, effective vaccines against these bacteria are required. Chromosomal expression of antigens is

Anthrax, Toxins and Vaccines: A 125-Year Journey Targeting Bacillus anthracis

DTIC Science & Technology

2009-01-01

response. More promising, perhaps, is the use of probiotics generally regarded as safe, such as Lactobacillus spp. expressing PA fused to a peptide that...antigens from probiotic lactic acid bacteria. Expert Rev. Vaccines 7(2), 163-174 (2008). 184 Chen J, Anderson JB, DeWeese-Scott C et al. MMDB: Entrez’s

Socioeconomic inequalities and vaccination coverage: results of an immunisation coverage survey in 27 Brazilian capitals, 2007–2008

PubMed Central

Sampaio de Almeida Ribeiro, Manoel Carlos; de Moraes, José Cássio; Flannery, Brendan

2012-01-01

Background Since 1988, Brazil's Unified Health System has sought to provide universal and equal access to immunisations. Inequalities in immunisation may be examined by contrasting vaccination coverage among children in the highest versus the lowest socioeconomic strata. The authors examined coverage with routine infant immunisations from a survey of Brazilian children according to socioeconomic stratum of residence census tract. Methods The authors conducted a household cluster survey in census tracts systematically selected from five socioeconomic strata, according to average household income and head of household education, in 26 Brazilian capitals and the federal district. The authors calculated coverage with recommended vaccinations among children until 18 months of age, according to socioeconomic quintile of residence census tract, and examined factors associated with incomplete vaccination. Results Among 17 295 children with immunisation cards, 14 538 (82.6%) had received all recommended vaccinations by 18 months of age. Among children residing in census tracts in the highest socioeconomic stratum, 77.2% were completely immunised by 18 months of age versus 81.2%–86.2% of children residing in the four census tract quintiles with lower socioeconomic indicators (p<0.01). Census tracts in the highest socioeconomic quintile had significantly lower coverage for bacille Calmette-Guérin, oral polio and hepatitis B vaccines than those with lower socioeconomic indicators. In multivariable analysis, higher birth order and residing in the highest socioeconomic quintile were associated with incomplete vaccination. After adjusting for interaction between socioeconomic strata of residence census tract and household wealth index, only birth order remained significant. Conclusions Evidence from Brazilian capitals shows success in achieving high immunisation coverage among poorer children. Strategies are needed to reach children in wealthier areas. PMID:22268129

Vaccination of rhesus macaques with the anthrax vaccine adsorbed vaccine produces a serum antibody response that effectively neutralizes receptor-bound protective antigen in vitro.

PubMed

Clement, Kristin H; Rudge, Thomas L; Mayfield, Heather J; Carlton, Lena A; Hester, Arelis; Niemuth, Nancy A; Sabourin, Carol L; Brys, April M; Quinn, Conrad P

2010-11-01

Anthrax toxin (ATx) is composed of the binary exotoxins lethal toxin (LTx) and edema toxin (ETx). They have separate effector proteins (edema factor and lethal factor) but have the same binding protein, protective antigen (PA). PA is the primary immunogen in the current licensed vaccine anthrax vaccine adsorbed (AVA [BioThrax]). AVA confers protective immunity by stimulating production of ATx-neutralizing antibodies, which could block the intoxication process at several steps (binding of PA to the target cell surface, furin cleavage, toxin complex formation, and binding/translocation of ATx into the cell). To evaluate ATx neutralization by anti-AVA antibodies, we developed two low-temperature LTx neutralization activity (TNA) assays that distinguish antibody blocking before and after binding of PA to target cells (noncomplexed [NC] and receptor-bound [RB] TNA assays). These assays were used to investigate anti-PA antibody responses in AVA-vaccinated rhesus macaques (Macaca mulatta) that survived an aerosol challenge with Bacillus anthracis Ames spores. Results showed that macaque anti-AVA sera neutralized LTx in vitro, even when PA was prebound to cells. Neutralization titers in surviving versus nonsurviving animals and between prechallenge and postchallenge activities were highly correlated. These data demonstrate that AVA stimulates a myriad of antibodies that recognize multiple neutralizing epitopes and confirm that change, loss, or occlusion of epitopes after PA is processed from PA83 to PA63 at the cell surface does not significantly affect in vitro neutralizing efficacy. Furthermore, these data support the idea that the full-length PA83 monomer is an appropriate immunogen for inclusion in next-generation anthrax vaccines.

Recombinant protective antigen 102 (rPA102): profile of a second-generation anthrax vaccine.

PubMed

Keitel, Wendy A

2006-08-01

Recent terrorist attacks involving the use of Bacillus anthracis spores have stimulated interest in the development of new vaccines for anthrax prevention. Studies of the pathogenesis of anthrax and of the immune responses following infection and immunization underscore the pivotal role that antibodies to the protective antigen play in protection. The most promising vaccine candidates contain purified recombinant protective antigen. Clinical trials of one of these, recombinant protective antigen (rPA)102, are underway. Initial results suggest that rPA102 is well tolerated and immunogenic. Additional trials are necessary to identify optimal formulations and immunization regimens for pre- and postexposure prophylaxis. Future licensure of these and other candidate vaccines will depend on their safety and immunogenicity profiles in humans, and their ability to confer protection in animal models of inhalational anthrax.

Differentiation of Bacillus Anthracis and Other Bacillus Species by Use of Lectins

DTIC Science & Technology

1983-07-18

TITL9 fAnd Subtfitle) S.TypeO REPORT gi PZRCC rvt 4 DIFFERENTIATION OF BACIL-LUSg’ ANTHRAtgACIS D OTHER BACILLUS , SPECIES BY-USE OYLECTINS" Inter[im...Ricinus communis. Some strains of Bacillus cer-eus var. m-ycoides (B. Mycoides) were strongly reactive with the lectin from Helbi pomtia and weakly reacti...ve with the Glycine max lectin. The differential iCnteractions between Bacillus species and lectins af forded a means of distinguishing B. anthracis

"The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" - Meeting report.

PubMed

Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi; Shea, Jaqueline; Ramakrishnan, Lalita; Behar, Samuel; Ernst, Joel D; Porcelli, Steven A; Maeurer, Markus; Kornfeld, Hardy

2017-06-14

Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7-8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on "The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb-specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission. Copyright © 2017.

Structural and metabolic characterization of RNAs from rats with experimental Guerin tumor - I. Nucleotide composition of RNAs from the liver and tumor tissues of rats.

PubMed

Ratkiewicz, A; Galasinski, W

1976-01-01

The characteristics of the ribonucleic acids of Guerin tumor was the subject of this work. The effect of tumor development on the structure of the ribonucleic acids in the liver of tumor bearing rats was studied. Some differences of nucleotide compositions in RNAs isolated from subcellular fractions of liver of control and tumor bearing rats and of cancer tissue were observed. The nucleotide compositions of cancer nuclear RNA is distinctly different from liver RNA. The changes in primary structure of liver RNAs due by development of tumor in rats may be result of metabolic peculiarities of these RNAs.

Disappointment and adherence among parents of newborns allocated to the control group: a qualitative study of a randomized clinical trial.

PubMed

Meinich Petersen, Sandra; Zoffmann, Vibeke; Kjærgaard, Jesper; Graff Stensballe, Lone; Graff Steensballe, Lone; Greisen, Gorm

2014-04-15

When a child participates in a clinical trial, informed consent has to be given by the parents. Parental motives for participation are complex, but the hope of getting a new and better treatment for the child is important. We wondered how parents react when their child is allocated to the control group of a randomized controlled trial, and how it will affect their future engagement in the trial. We included parents of newborns randomized to the control arm in the Danish Calmette study at Rigshospitalet in Copenhagen. The Calmette study is a randomized clinical trial investigating the non-specific effects of early BCG-vaccine to healthy neonates. Randomization is performed immediately after birth and parents are not blinded to the allocation. We set up a semi-structured focus group with six parents from four families. Afterwards we telephone-interviewed another 19 mothers to achieve saturation. Thematic analysis was used to identify themes across the data sets. The parents reported good understanding of the randomization process. Their most common reaction to allocation was disappointment, though relief was also seen. A model of reactions to being allocated to the control group was developed based on the participants' different positions along two continuities from 'Our participation in trial is not important' to 'Our participation in trial is important', and 'Vaccine not important to us' to 'Vaccine important to us'. Four very disappointed families had thought of getting the vaccine elsewhere, and one had actually had their child vaccinated. All parents involved in the focus group and the telephone interviews wanted to participate in the follow-ups planned for the Calmette study. This study identified an almost universal experience of disappointment among parents of newborns who were randomized to the control group, but also a broad expression of understanding and accepting the idea of randomization. The trial staff might use the model of reactions in understanding

Early-shared Mycobacterium bovis bacillus Calmette-Guérin sub-strains induce Th1 cytokine production in vivo.

PubMed

Taniguchi, Keiichi; Miyatake, Yuuji; Hayashi, Daisuke; Takami, Atsuro; Itoh, Saotomo; Yamamoto, Saburo; Hida, Shigeaki; Onozaki, Kikuo; Takii, Takemasa

2015-11-01

Interleukin-12 is one of the cytokines that induce acquired immunity by progressing the differentiation of T cells. When antigens are presented by APCs, including macrophages and DCs, T cells are activated and produce the Th1 cytokines IL-2 and IFN-γ. We have previously reported greater IL-12 production from macrophages infected with early-shared BCG sub-strains (ex. BCG-Japan, -Sweden) than from those infected with late-shared BCG (ex. BCG-Pasteur and -Connaught) . In this study, we investigated the Th1 cytokine-inducing activity of splenocytes co-cultured with BCG-infected DCs. Early-shared BCG-infected DCs produced IL-12 and TNF-α⋅ Furthermore, when they were co-cultured with purified protein derivative-stimulated DCs, the splenocytes of mice immunized with BCG-Tokyo/Japan produced more Th1 cytokine than did those of mice immunized with BCG-Connaught. In conclusion, early-shared BCG sub-strains more strongly induce Th1 cytokine production in vivo. This study provides basic information to inform the selection of candidates for primary vaccination. © 2015 The Societies and Wiley Publishing Asia Pty Ltd.

Phages Preying on Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis: Past, Present and Future

PubMed Central

Gillis, Annika; Mahillon, Jacques

2014-01-01

Many bacteriophages (phages) have been widely studied due to their major role in virulence evolution of bacterial pathogens. However, less attention has been paid to phages preying on bacteria from the Bacillus cereus group and their contribution to the bacterial genetic pool has been disregarded. Therefore, this review brings together the main information for the B. cereus group phages, from their discovery to their modern biotechnological applications. A special focus is given to phages infecting Bacillus anthracis, B. cereus and Bacillus thuringiensis. These phages belong to the Myoviridae, Siphoviridae, Podoviridae and Tectiviridae families. For the sake of clarity, several phage categories have been made according to significant characteristics such as lifestyles and lysogenic states. The main categories comprise the transducing phages, phages with a chromosomal or plasmidial prophage state, γ-like phages and jumbo-phages. The current genomic characterization of some of these phages is also addressed throughout this work and some promising applications are discussed here. PMID:25010767

Bacillus infantis sp. nov. and Bacillus idriensis sp. nov., isolated from a patient with neonatal sepsis.

PubMed

Ko, Kwan Soo; Oh, Won Sup; Lee, Mi Young; Lee, Jang Ho; Lee, Hyuck; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon

2006-11-01

Two Gram-positive bacilli, designated as strains SMC 4352-1T and SMC 4352-2T, were isolated sequentially from the blood of a newborn child with sepsis. They could not be identified by using conventional clinical microbiological methods. 16S rRNA gene sequencing and phylogenetic analysis revealed that both strains belonged to the genus Bacillus but clearly diverged from known Bacillus species. Strain SMC 4352-1T and strain SMC 4352-2T were found to be closely related to Bacillus firmus NCIMB 9366T (98.2% sequence similarity) and Bacillus cibi JG-30T (97.1% sequence similarity), respectively. They also displayed low DNA-DNA reassociation values (less than 40%) with respect to the most closely related Bacillus species. On the basis of their polyphasic characteristics, strain SMC 4352-1T and strain SMC 4352-2T represent two novel species of the genus Bacillus, for which the names Bacillus infantis sp. nov. (type strain SMC 4352-1T=KCCM 90025T=JCM 13438T) and Bacillus idriensis sp. nov. (type strain SMC 4352-2T=KCCM 90024T=JCM 13437T) are proposed.

Comparative sequence analyses on the 16S rRNA (rDNA) of Bacillus acidocaldarius, Bacillus acidoterrestris, and Bacillus cycloheptanicus and proposal for creation of a new genus, Alicyclobacillus gen. nov

NASA Technical Reports Server (NTRS)

Wisotzkey, J. D.; Jurtshuk, P. Jr; Fox, G. E.; Deinhard, G.; Poralla, K.

1992-01-01

Comparative 16S rRNA (rDNA) sequence analyses performed on the thermophilic Bacillus species Bacillus acidocaldarius, Bacillus acidoterrestris, and Bacillus cycloheptanicus revealed that these organisms are sufficiently different from the traditional Bacillus species to warrant reclassification in a new genus, Alicyclobacillus gen. nov. An analysis of 16S rRNA sequences established that these three thermoacidophiles cluster in a group that differs markedly from both the obligately thermophilic organisms Bacillus stearothermophilus and the facultatively thermophilic organism Bacillus coagulans, as well as many other common mesophilic and thermophilic Bacillus species. The thermoacidophilic Bacillus species B. acidocaldarius, B. acidoterrestris, and B. cycloheptanicus also are unique in that they possess omega-alicylic fatty acid as the major natural membranous lipid component, which is a rare phenotype that has not been found in any other Bacillus species characterized to date. This phenotype, along with the 16S rRNA sequence data, suggests that these thermoacidophiles are biochemically and genetically unique and supports the proposal that they should be reclassified in the new genus Alicyclobacillus.

Expression of an endotoxin-free S-layer/allergen fusion protein in gram-positive Bacillus subtilis 1012 for the potential application as vaccines for immunotherapy of atopic allergy

PubMed Central

2011-01-01

Background Genetic fusion of the major birch pollen allergen (Bet v1) to bacterial surface-(S)-layer proteins resulted in recombinant proteins exhibiting reduced allergenicity as well as immunomodulatory capacity. Thus, S-layer/allergen fusion proteins were considered as suitable carriers for new immunotherapeutical vaccines for treatment of Type I hypersensitivity. Up to now, endotoxin contamination of the fusion protein which occurred after isolation from the gram-negative expression host E. coli had to be removed by an expensive and time consuming procedure. In the present study, in order to achieve expression of pyrogen-free, recombinant S-layer/allergen fusion protein and to study the secretion of a protein capable to self-assemble, the S-layer/allergen fusion protein rSbpA/Bet v1 was produced in the gram-positive organism Bacillus subtilis 1012. Results The chimaeric gene encoding the S-layer protein SbpA of Lysinibacillus sphaericus CCM 2177 as well as Bet v1 was cloned and expressed in B. subtilis 1012. For that purpose, the E. coli-B. subtilis shuttle vectors pHT01 for expression in the B. subtilis cytoplasm and pHT43 for secretion of the recombinant fusion protein into the culture medium were used. As shown by western blot analysis, immediately after induction of expression, B. subtilis 1012 was able to secret rSbpA/Bet v1 mediated by the signal peptide amyQ of Bacillus amyloliquefaciens. Electron microscopical investigation of the culture medium revealed that the secreted fusion protein was able to form self-assembly products in suspension but did not recrystallize on the surface of the B. subtilis cells. The specific binding mechanism between the N-terminus of the S-layer protein and a secondary cell wall polymer (SCWP), located in the peptidoglycan-containing sacculi of Ly. sphaericus CCM 2177, could be used for isolation and purification of the secreted fusion protein from the culture medium. Immune reactivity of rSbpA/Bet v1 could be demonstrated in

Dihydrolipoamide dehydrogenase-Lpd (Rv0462)-specific T cell recall responses are higher in healthy household contacts of TB: a novel immunodominant antigen from M. tuberculosis.

PubMed

Devasundaram, Santhi; Raja, Alamelu

2017-07-01

The partial effectiveness against pulmonary tuberculosis (PTB), displayed by the existing tuberculosis (TB) vaccine, bacillus Calmette-Guérin (BCG), highlights the need for novel vaccines to replace or improve BCG. In TB immunology, antigen-specific cellular immune response is frequently considered indispensable. Latency-associated antigens are intriguing as targets for TB vaccine development. The mycobacterial protein, dihydrolipoamide dehydrogenase (Lpd; Rv0462), the third enzyme of the pyruvate dehydrogenase (PDH) complex, facilitates Mycobacterium tuberculosis to resist host reactive nitrogen intermediates. Multicolor flow cytometry analysis of whole-blood cultures showed higher Lpd-specific Th1 recall response (IFN-γ, TNF-α, and IL-2; P = 0.0006) and memory CD4 + and CD8 + T cells (CCR7 + CD45RA - and CCR7 - CD45RA - ) in healthy household contacts (HHC) of TB ( P < 0.0001), which is comparable with or higher than the standard antigens, ESAT-6 and CFP-10. The frequency of Lpd-specific multifunctional T cells was higher in HHC compared with PTB patients. However, there is no significant statistical correlation. Regulatory T cell (T reg ) analysis of HHCs and active TB patients demonstrated very low Lpd-specific CD4 + T regs relative to ESAT-6 and CFP-10. Our study demonstrates that the Lpd antigen induces a strong cellular immune response in healthy mycobacteria-infected individuals. In consideration of this population having demonstrated immunologic protection against active TB disease development, our data are encouraging about the possible use of Lpd as a target for further TB subunit vaccine development. © Society for Leukocyte Biology.

Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer.

PubMed

Sanguedolce, Francesca; Cormio, Antonella; Massenio, Paolo; Pedicillo, Maria C; Cagiano, Simona; Fortunato, Francesca; Calò, Beppe; Di Fino, Giuseppe; Carrieri, Giuseppe; Bufo, Pantaleo; Cormio, Luigi

2018-04-01

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue. We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG). HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS. Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

Biomarkers in patients treated with BCG: an update.

PubMed

Klap, Julia; Schmid, Marianne; Loughlin, Kevin R

2014-08-01

Bacillus Calmette-Guerin (BCG) instillations are the recommended treatment for non-muscle invasive bladder cancer but high recurrence and progression rates remain after treatment. Despite patients risk stratification, BCG effectiveness remains unpredictable. A close, invasive and expensive follow up is mandatory. To improve or even replace this heavy surveillance in this high risk population, validated biomarkers were developed. To identify the useful tools for the urologist in monitoring bladder cancer patients, we reviewed the literature focusing on plasma and urinary biomarkers of BCG-therapy outcome. Articles dated from 1988 to 2013 including specific keywords (urinary bladder neoplasm, biological markers, intravesical administration, recurrence) were examined and relevant papers were selected. Before treatment initiation, genetic polymorphisms of multiple agents (cytokines, matrix-metalloproteinases) were found to become very useful to tailor therapy and monitoring. Those biomarkers belong to personalized medicine which is a topic of great interest today, but still need to be validated in cohorts from different ethnicities. During instillations, cytokines (IL-2, IL-8, IL-6/IL-10) were reported to be reliable to determine treatment response and efficacy. Further studies are needed to confirm results and standardize thresholds. After treatment, UroVysion, the FDA-approved fluorescence in situ hybridization (FISH), appeared to be the most robust marker of all the clinical parameters reviewed; but is not yet validated for BCG-treated patients. No recommendations for everyday practice can be established today, but a combination of several markers and clinicopathological characteristics may be the future. As bladder cancer diagnosis and management are evolving, practicing urologists should be aware of and utilize bladder cancer markers in clinical practice.

Systemic Immunotherapy of Non–Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor

PubMed Central

Vandeveer, Amanda J.; Fallon, Jonathan K.; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W.

2016-01-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non–muscle invasive, nonmetastatic human urothelial carcinoma. While the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non–muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1 and avelumab administration induced significant (P<0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non–muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. PMID:26921031

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer

PubMed Central

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; Nunes, Iseu da Silva; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC. PMID:26191134

Topical and systemic immunoreaction triggered by intravesical chemotherapy in an N-butyl-N-(4-hydroxybutyl) nitorosamine induced bladder cancer mouse model

PubMed Central

Nakai, Yasushi; Tanaka, Nobumichi; Fujimoto, Kiyohide

2017-01-01

Intravesical bacillus Calmette-Guerin (BCG) treatment is the most common therapy to prevent progression and recurrence of non-muscle invasive bladder cancer (NMIBC). Although the immunoreaction elicited by BCG treatment is well documented, those induced by intravesical treatment with chemotherapeutic agents are much less known. We investigated the immunological profiles caused by mitomycin C, gemcitabine, adriamycin and docetaxel in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced orthotopic bladder cancer mouse model. Ninety mice bearing orthotopic bladder cancer induced by BBN were randomly divided into six groups and treated with chemotherapeutic agents once a week for four weeks. After last treatment, bladder and serum samples were analyzed for cell surface and immunological markers (CD4, CD8, CD56, CD204, Foxp3, and PD-L1) using immunohistochemistry staining. Serum and urine cytokine levels were evaluated by ELISA. All chemotherapeutic agents presented anti-tumor properties similar to those of BCG. These included changes in immune cells that resulted in fewer M2 macrophages and regulatory T cells around tumors. This result was compatible with those in human samples. Intravesical chemotherapy also induced systemic changes in cytokines, especially urinary interleukin (IL)-17A and granulocyte colony stimulating factor (G-CSF), as well as in the distribution of blood neutrophils, lymphocytes, and monocytes. Our findings suggest that intravesical treatment with mitomycin C and adriamycin suppresses protumoral immunity while enhancing anti-tumor immunity, possibly through the action of specific cytokines. A better understanding of the immunoreaction induced by chemotherapeutic agents can lead to improved outcomes and fewer side effects in intravesical chemotherapy against NMIBC. PMID:28406993

Development of vaccines for bio-warfare agents.

PubMed

Rosenthal, S R; Clifford, J C M

2002-01-01

There is a recognized need for the development of new vaccines (as well as other biologicals and drugs) to counteract the effects of a potential bio-terrorist or bio-warfare event in the U.S. domestic population and military forces. Regulation of products to protect against potential bio-warfare agents poses unique challenges since the usual measures of efficacy that require exposure to natural disease may not currently be possible, for epidemiological and ethical reasons. To help to address this issue, the FDA has published and requested comments on a proposed animal rule intended to address certain efficacy issues for new agents for use against lethal or permanently disabling toxic substances. Recent product development activity has focused on Bacillus anthracis (anthrax) and variola major (smallpox), agents that are regarded as highest priority in posing a risk to national security. FDA resources exist to assist vaccine developers with regard to the novel challenges posed in the dinical development of these products.

Towards a human oral vaccine for anthrax: the utility of a Salmonella Typhi Ty21a-based prime-boost immunization strategy.

PubMed

Baillie, Leslie W J; Rodriguez, Ana L; Moore, Stephen; Atkins, Helen S; Feng, Chiguang; Nataro, James P; Pasetti, Marcela F

2008-11-11

We previously demonstrated the ability of an orally administered attenuated Salmonella enterica serovar Typhimurium strain expressing the protective antigen (PA) of Bacillus anthracis to confer protection against lethal anthrax aerosol spore challenge [Stokes MG, Titball RW, Neeson BN, et al. Oral administration of a Salmonella enterica-based vaccine expressing Bacillus anthracis protective antigen confers protection against aerosolized B. anthracis. Infect Immun 2007;75(April (4)):1827-34]. To extend the utility of this approach to humans we constructed variants of S. enterica serovar Typhi Ty21a, an attenuated typhoid vaccine strain licensed for human use, which expressed and exported PA via two distinct plasmid-based transport systems: the Escherichia coli HlyA haemolysin and the S. Typhi ClyA export apparatus. Murine immunogenicity studies confirmed the ability of these constructs, especially Ty21a expressing the ClyA-PA fusion protein, to stimulate strong PA-specific immune responses following intranasal immunization. These responses were further enhanced by a subsequent boost with either parenterally delivered recombinant PA or the licensed US human alum-adsorbed anthrax vaccine (AVA). Anthrax toxin neutralizing antibody responses using this prime-boost regimen were rapid, vigorous and broad in nature. The results of this study demonstrate the feasibility of employing a mucosal prime with a licensed Salmonella Typhi vaccine strain followed by a parenteral protein boost to stimulate rapid protective immunity against anthrax.

The Mobile Solutions for Immunization (M-SIMU) Trial: A Protocol for a Cluster Randomized Controlled Trial That Assesses the Impact of Mobile Phone Delivered Reminders and Travel Subsidies to Improve Childhood Immunization Coverage Rates and Timeliness in Western Kenya.

PubMed

Gibson, Dustin G; Kagucia, E Wangeci; Ochieng, Benard; Hariharan, Nisha; Obor, David; Moulton, Lawrence H; Winch, Peter J; Levine, Orin S; Odhiambo, Frank; O'Brien, Katherine L; Feikin, Daniel R

2016-05-17

Text message (short message service, SMS) reminders and incentives are two demand-side interventions that have been shown to improve health care-seeking behaviors by targeting participant characteristics such as forgetfulness, lack of knowledge, and transport costs. Applying these interventions to routine pediatric immunizations may improve vaccination coverage and timeliness. The Mobile Solutions for Immunization (M-SIMU) trial aims to determine if text message reminders, either with or without mobile phone-based incentives, sent to infant's parents can improve immunization coverage and timeliness of routine pediatric vaccines in rural western Kenya. This is a four-arm, cluster, randomized controlled trial. Villages are randomized to one of four study arms prior to enrollment of participants. The study arms are: (1) no intervention (a general health-related text message will be texted to this group at the time of enrollment), (2) text message reminders only, (3) text message reminders and a 75 Kenyan Shilling (KES) incentive, or (4) text message reminders and a KES200 incentive. Participants assigned to study arms 2-4 will receive two text message reminders; sent 3 days before and one day before the scheduled immunization visit at 6, 10, and 14 weeks for polio and pentavalent (containing diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenza type b antigens) type b antigens) vaccines, and at 9 months for measles vaccine. Participants in incentive arms will, in addition to text message reminders as above, receive mobile phone-based incentives after each timely vaccination, where timely is defined as vaccination within 2 weeks of the scheduled date for each of the four routine expanded program immunization (EPI) vaccination visits. Mother-infant pairs will be followed to 12 months of age where the primary outcome, a fully immunized child, will be ascertained. A fully immunized child is defined as a child receiving vaccines for bacille Calmette-Guerin