scholarly journals Failure of the Mycobacterium bovis BCG Vaccine: Some Species of Environmental Mycobacteria Block Multiplication of BCG and Induction of Protective Immunity to Tuberculosis

2002 ◽  
Vol 70 (2) ◽  
pp. 672-678 ◽  
Author(s):  
Lise Brandt ◽  
Joana Feino Cunha ◽  
Anja Weinreich Olsen ◽  
Ben Chilima ◽  
Penny Hirsch ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Bovis ◽  
Protective Immunity ◽  
Low Frequency ◽  
Prior Exposure ◽  
Bcg Vaccine ◽  
Subunit Vaccines ◽  
Bcg Vaccination ◽  
Environmental Mycobacteria ◽  
Different Populations

ABSTRACT The efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine against pulmonary tuberculosis (TB) varies enormously in different populations. The prevailing hypothesis attributes this variation to interactions between the vaccine and mycobacteria common in the environment, but the precise mechanism has so far not been clarified. Our study demonstrates that prior exposure to live environmental mycobacteria can result in a broad immune response that is recalled rapidly after BCG vaccination and controls the multiplication of the vaccine. In these sensitized mice, BCG elicits only a transient immune response with a low frequency of mycobacterium-specific cells and no protective immunity against TB. In contrast, the efficacy of TB subunit vaccines was unaffected by prior exposure to environmental mycobacteria. Six different isolates from soil and sputum samples from Karonga district in Northern Malawi (a region in which BCG vaccination has no effect against pulmonary TB) were investigated in the mouse model, and two strains of the Mycobacterium avium complex were found to block BCG activity completely.

scholarly journals Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques

2015 ◽  
Vol 22 (9) ◽  
pp. 992-1003 ◽  
Author(s):  
A. D. White ◽  
C. Sarfas ◽  
K. West ◽  
L. S. Sibley ◽  
A. S. Wareham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bcg Vaccine ◽  
Effector Memory ◽  
Dependent Manner ◽  
Aerosol Delivery ◽  
Memory Phenotype ◽  
Bcg Vaccination

ABSTRACTNine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, theMycobacterium bovisBCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

scholarly journals Clinical and Immune Impact of Mycobacterium bovis BCG Vaccination Scarring

2002 ◽  
Vol 70 (11) ◽  
pp. 6188-6195 ◽  
Author(s):  
Janine Jason ◽  
Lennox K. Archibald ◽  
Okey C. Nwanyanwu ◽  
Peter N. Kazembe ◽  
Julie A. Chatt ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Clinical Symptoms ◽  
Surrogate Marker ◽  
Bcg Vaccine ◽  
World Health ◽  
Interleukin 4 ◽  
Bcg Vaccination ◽  
Cytokine Pattern

ABSTRACT The World Health Organization recommends Mycobacterium bovis BCG vaccination in areas of high tuberculosis prevalence. BCG's clinical and immune effects, not necessarily Mycobacterium tuberculosis specific, are unclear. BCG vaccine scarring often is used as a surrogate marker of vaccination or of effective vaccination. We evaluated BCG scarring status in relation to clinical findings and outcome in 700 hospitalized Malawians, of whom 32 had M. tuberculosis bloodstream infections (BSI) (10 of whom had cellular immune studies done) and of whom 48 were infants <6 months old and therefore recently vaccinated (19 of whom had immune studies). In the patients ≥6 months old, scarring was not related to the presence of pulmonary symptoms (35 versus 30%), chronic cough or fever, mortality, or M. tuberculosis BSI. In M. tuberculosis BSI patients, scarring was unrelated to mortality, vital signs, or clinical symptoms but those with scarring had higher proportions of memory and activated T cells and more type 2-skewed cytokine profiles. Infants with either BCG scarring (n = 10) or BCG lesional inflammation (n = 5) had no symptoms of sepsis, but 18 of 33 infants without BCG vaccination lesions did. Those with BCG lesions had localized infections more often than did those without BCG lesions. These infants also had lower median percentages of lymphocytes spontaneously making interleukin-4 (IL-4) or tumor necrosis factor alpha (TNF-α) and lower ratios of T cells spontaneously making IL-4 to T cells making IL-6. Thus, we found that, in older patients, BCG vaccine scarring was not associated with M. tuberculosis-specific or nonspecific clinical protection. Those with M. tuberculosis BSI and scarring had immune findings suggesting previous M. tuberculosis antigen exposure and induction of a type 2 cytokine pattern with acute reexposure. It is unlikely that this type 2 pattern would be protective against mycobacteria, which require a type 1 response for effective containment. In infants <6 months old, recent BCG vaccination was associated with a non-M. tuberculosis-specific, anti-inflammatory cytokine profile. That the vaccinated infants had a greater frequency of localized infections and lesser frequency of sepsis symptoms suggests that this postvaccination cytokine pattern may provide some non-M. tuberculosis-specific clinical benefits.

scholarly journals Using Data from Macaques To Predict Gamma Interferon Responses after Mycobacterium bovis BCG Vaccination in Humans: a Proof-of-Concept Study of Immunostimulation/Immunodynamic Modeling Methods

2017 ◽  
Vol 24 (3) ◽  
Author(s):  
Sophie J. Rhodes ◽  
Charlotte Sarfas ◽  
Gwenan M. Knight ◽  
Andrew White ◽  
Ansar A. Pathan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Gamma Interferon ◽  
Proof Of Concept ◽  
Concept Study ◽  
Bcg Vaccination ◽  
Modeling Methods ◽  
Cynomolgus Macaques ◽  
Ifn Γ

ABSTRACT Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. We used novel immunostimulation/immunodynamic modeling methods in a proof-of-concept study to determine which macaque subpopulations best predicted immune responses in different human subpopulations. Data on gamma interferon (IFN-γ)-secreting CD4+ T cells over time after recent Mycobacterium bovis BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were baseline BCG vaccination status, time since BCG vaccination, gender, and the monocyte/lymphocyte cell count ratio. The macaque population covariate was the colony of origin. A two-compartment mathematical model describing the dynamics of the IFN-γ T cell response after BCG vaccination was calibrated to these data using nonlinear mixed-effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and the BCG immune response in each species was assessed. The macaque subpopulations that best predicted immune responses in different human subpopulations were identified using Bayesian information criteria. We found that the macaque colony and the human baseline BCG status were significantly (P < 0.05) associated with the BCG-induced immune response. For humans who were BCG naïve at baseline, Indonesian cynomolgus macaques and Indian rhesus macaques best predicted the immune response. For humans who had already been BCG vaccinated at baseline, Mauritian cynomolgus macaques best predicted the immune response. This work suggests that the immune responses of different human populations may be best modeled by different macaque colonies, and it demonstrates the potential utility of immunostimulation/immunodynamic modeling to accelerate TB vaccine development.

scholarly journals IFN-α Boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine Promoted Th1 Type Cellular Response and Protection against M. tuberculosis Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
C. E. Rivas-Santiago ◽  
G. G. Guerrero
Keyword(s):  
Immune Response ◽  
Mycobacterium Bovis ◽  
Cellular Immune Response ◽  
Cellular Response ◽  
Bacterial Load ◽  
Bcg Vaccine ◽  
Type I ◽  
Bacillus Calmette Guerin ◽  
Type I Ifns ◽  
Cellular Immune

The role of type I IFNs in the pathogenesis and control of mycobacterial infection is still controversial. It has been reported that type I IFNs exacerbated M. tuberculosis infection through hampering Th1 type cellular immune response. However, under certain conditions they can act as natural immune adjuvants for commercial vaccines. At this point, we have reported recently that successive IFN-alpha boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccinated mice protected adult mice from intradermal M. lepraemurium infection and a difference in iNOS was observed. In the present work, we have found that intramuscular IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine, either in vitro (human cell line or macrophages derived from PBMC) or in vivo (aerosol mouse model of MTb infection), promoted mostly the development of specific anti-antimycobacterial Th1 type cytokines (IFN-γ; IL-12, TNF-alpha, and IL-17; IL1β) while bacterial load reduction (0.9 logs versus PBS or BCG vaccine) was observed. These findings indicate that, under the experimental settings reported here, interferon alpha can drive or affect the TH cellular immune response in favour of BCG-inducing immunity against M. tuberculosis infection.

scholarly journals Pulmonary Mycobacterium bovis BCG Vaccination Confers Dose-Dependent Superior Protection Compared to That of Subcutaneous Vaccination

2014 ◽  
Vol 21 (4) ◽  
pp. 594-597 ◽  
Author(s):  
Nacho Aguilo ◽  
Ana Maria Toledo ◽  
Eva Maria Lopez-Roman ◽  
Esther Perez-Herran ◽  
Eamonn Gormley ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pulmonary Tuberculosis ◽  
Mycobacterium Bovis ◽  
Dose Range ◽  
Bcg Vaccine ◽  
Content Type ◽  
Mycobacterium Bovis Bcg ◽  
Bcg Vaccination ◽  
Dose Dependent

ABSTRACTWorldwide, theMycobacterium bovisBCG vaccine is one of the most widely used vaccines. However, it appears to be ineffective in preventing pulmonary tuberculosis. Here, we show that pulmonary BCG vaccination of mice with a broad dose range provides superior protection againstMycobacterium tuberculosischallenge compared to that of subcutaneous vaccination.

scholarly journals Induction of Functional Specific Antibodies, IgG-Secreting Plasmablasts and Memory B Cells Following BCG Vaccination

2022 ◽  
Vol 12 ◽  
Author(s):  
Julia Bitencourt ◽  
Marco Polo Peralta-Álvarez ◽  
Morven Wilkie ◽  
Ashley Jacobs ◽  
Daniel Wright ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Response ◽  
Bcg Vaccine ◽  
Human Populations ◽  
Vaccine Candidates ◽  
Specific Antibodies ◽  
Bcg Vaccination ◽  
Macrophage Phagocytosis

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro, which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

scholarly journals Induction of specific antibodies, IgG-secreting plasmablasts and memory B cells following BCG vaccination

2021 ◽  
Author(s):  
Julia Bitencourt ◽  
Morven Wilkie ◽  
Marco Polo Peralta Alvarez ◽  
Ashley Jacobs ◽  
Daniel Wright ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
B Cell ◽  
Cell Response ◽  
Bcg Vaccine ◽  
Human Populations ◽  
Potential Contribution ◽  
Vaccine Candidates ◽  
Specific Antibodies ◽  
Bcg Vaccination

AbstractMany tuberculosis (TB) vaccine candidates are designed as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does protect may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterised, little is known about the B cell and antibody response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titres in serum versus plasma with modestly higher titres in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a potential contribution of the antibody response to BCG vaccine-mediated control of mycobacterial growth in vitro. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

scholarly journals Cellular immune response of Curraleiro Pé-duro and Nellore calves following Mycobacterium bovis-BCG vaccination

2013 ◽  
Vol 33 (12) ◽  
pp. 1403-1408
Author(s):  
Mayara Fernanda Maggioli ◽  
Joyce Rodrigues Lobo ◽  
Maria Clorinda Soares Fioravanti ◽  
André Kipnis ◽  
Ana Paula Junqueira-Kipnis
Keyword(s):  
Immune Response ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Mycobacterium Bovis ◽  
Blood Levels ◽  
Cd4 Cells ◽  
Test Reaction ◽  
Positive Role ◽  
Bcg Vaccination ◽  
Ifn Γ

The present study aimed to assess the CD4, CD8 and γδ blood levels for Curraleiro Pé-duro, as well as the specific IFN-γ response after BCG vaccination using flow cytometry. The specific immune response against BCG was also evaluated by tuberculin skin test, performed before and 45 days after the vaccination. For comparison purposes, the same parameters were investigated on Nellore calves, an exotic bovine with resistance previously demonstrated. Naturally, Curraleiro Pé-duro animals had greater levels of CD4, CD8 and γδ lymphocytes (p<0.05). In response to vaccine, Curraleiro Pé-duro showed greater ability to respond specifically to BCG, generating resistance profile (Th1), evidenced by greater number of antigen specific CD4+ cells producing IFN-γ (p<0.05) and also higher tuberculin skin test reaction (p<0.05). Additionally, vaccinated Curraleiro Pé-duro calves had higher CD4 cells numbers than both Nellore control (p<0.05) and vaccinated groups (p<0.05). Curraleiro Pé-duro calves' higher basal lymphocytes blood level and stronger response in both IFN-γ and tuberculin skin test parameters probably play a positive role on protection/resistance to Mycobacterium bovis.

scholarly journals The Protective Effect of the Mycobacterium bovis BCG Vaccine Is Increased by Coadministration with the Mycobacterium tuberculosis 72-Kilodalton Fusion Polyprotein Mtb72F in M. tuberculosis-Infected Guinea Pigs

2004 ◽  
Vol 72 (11) ◽  
pp. 6622-6632 ◽  
Author(s):  
Lise Brandt ◽  
Yasir A. W. Skeiky ◽  
Mark R. Alderson ◽  
Yves Lobet ◽  
Wilfried Dalemans ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Guinea Pig ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Airway Remodeling ◽  
Bacterial Load ◽  
Bcg Vaccine ◽  
Protective Capacity ◽  
Bcg Vaccination ◽  
Lung Consolidation

ABSTRACT A tuberculosis vaccine candidate consisting of a 72-kDa polyprotein or fusion protein based upon the Mtb32 and Mtb39 antigens of Mycobacterium tuberculosis and designated Mtb72F was tested for its protective capacity as a potential adjunct to the Mycobacterium bovis BCG vaccine in the mouse and guinea pig models of this disease. Formulation of recombinant Mtb72F (rMtb72F) in an AS02A adjuvant enhanced the Th1 response to BCG in mice but did not further reduce the bacterial load in the lungs after aerosol challenge infection. In the more stringent guinea pig disease model, rMtb72F delivered by coadministration with BCG vaccination significantly improved the survival of these animals compared to BCG alone, with some animals still alive and healthy in their appearance at >100 weeks post-aerosol challenge. A similar trend was observed with guinea pigs in which BCG vaccination was boosted by DNA vaccination, although this increase was not statistically significant due to excellent protection conferred by BCG alone. Histological examination of the lungs of test animals indicated that while BCG controls eventually died from overwhelming lung consolidation, the majority of guinea pigs receiving BCG mixed with rMtb72F or boosted twice with Mtb72F DNA had mostly clear lungs with minimal granulomatous lesions. Lesions were still prominent in guinea pigs receiving BCG and the Mtb72F DNA boost, but there was considerable evidence of lesion healing and airway remodeling and reestablishment. These data support the hypothesis that the coadministration or boosting of BCG vaccination with Mtb72F may limit the lung consolidation seen with BCG alone and may promote lesion resolution and healing. Collectively, these data suggest that enhancing BCG is a valid vaccination strategy for tuberculosis that is worthy of clinical evaluation.

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