Influence of Advanced Age on Mycobacterium bovis BCG Vaccination in Guinea Pigs Aerogenically Infected with Mycobacterium tuberculosis

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only tuberculosis (TB) vaccine currently available, but its efficacy against adult pulmonary TB remains controversial. BCG induces specific immune responses to mycobacterial antigens and may elicit protective immunity against TB. TB remains a major public health problem, especially among the elderly, yet the efficacy of BCG in the elderly is unknown. We investigated the ability of BCG vaccination to prevent TB in young (6-week-old), middle-aged (18-month-old), and old (60-month-old) guinea pigs. BCG-Tokyo vaccination reduced the growth of Mycobacterium tuberculosis H37Rv in all three groups. By use of an enzyme-linked immunospot (ELISPOT) assay, antigen-specific gamma interferon (IFN-γ)-producing cells were detected in the 60-month-old guinea pigs after a booster vaccination with BCG-Tokyo. Our findings suggest that BCG-Tokyo has a protective effect against tuberculosis infection regardless of age.

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Immune Responses Following BCG Immunization of Infants in Uganda and United Kingdom Are Similar for Purified Protein Derivative but Differ for Secretory Proteins of Mycobacterium tuberculosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.637114 ◽

2021 ◽

Vol 12 ◽

Author(s):

Patrice A. Mawa ◽

Mateusz Hasso-Agopsowicz ◽

Lawrence Lubyayi ◽

Grace Nabakooza ◽

Marjorie Nakibuule ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

United Kingdom ◽

Immune Responses ◽

Secretory Proteins ◽

Birth Cohorts ◽

Bcg Vaccination ◽

Ifn Γ ◽

The Uk ◽

Mycobacterial Antigens ◽

Stimulation Of

Introduction: The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK.Materials and Methods: Blood samples were obtained from BCG-immunized infants of mothers with (n = 110) and without (n = 121) latent Mycobacterium tuberculosis infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (n = 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6/CFP10 to assess exposure to or infection with M. tuberculosis or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants.Results: The IFN-γ response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6/CFP10 produced significantly higher IFN-γ, TNF, IL-12p40, IL-1α, IL-1β, IL-1Ra, IP-10, MIP-1α, MIP-1β, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6/CFP10 produced significantly higher amounts of IL-8 (p = 0.0001), IL-10 (p = 0.0022), and IL-13 (p = 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52.Conclusions: Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.

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Mycobacterium tuberculosis Culture Filtrate Proteins plus CpG Oligodeoxynucleotides Confer Protection to Mycobacterium bovis BCG-Primed Mice by Inhibiting Interleukin-4 Secretion

Infection and Immunity ◽

10.1128/iai.00580-09 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5311-5321 ◽

Cited By ~ 16

Author(s):

Denise Morais da Fonseca ◽

Celio Lopes Silva ◽

Pryscilla Fanini Wowk ◽

Marina Oliveira e Paula ◽

Simone Gusmão Ramos ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mycobacterium Bovis ◽

Culture Filtrate ◽

Vaccine Development ◽

Interleukin 4 ◽

Interleukin 17 ◽

Bcg Vaccination ◽

Cpg Oligodeoxynucleotides ◽

Culture Filtrate Proteins ◽

Ifn Γ

ABSTRACT Culture filtrate proteins (CFP) are potential targets for tuberculosis vaccine development. We previously showed that despite the high level of gamma interferon (IFN-γ) production elicited by homologous immunization with CFP plus CpG oligodeoxynucleotides (CFP/CpG), we did not observe protection when these mice were challenged with Mycobacterium tuberculosis. In order to use the IFN-γ-inducing ability of CFP antigens, in this study we evaluated a prime-boost heterologous immunization based on CFP/CpG to boost Mycobacterium bovis BCG vaccination in order to find an immunization schedule that could induce protection. Heterologous BCG-CFP/CpG immunization provided significant protection against experimental tuberculosis, and this protection was sustained during the late phase of infection and was even better than that conferred by a single BCG immunization. The protection was associated with high levels of antigen-specific IFN-γ and interleukin-17 (IL-17) and low IL-4 production. The deleterious role of IL-4 was confirmed when IL-4 knockout mice vaccinated with CFP/CpG showed consistent protection similar to that elicited by BCG-CFP/CpG heterologous immunization. These findings show that a single dose of CFP/CpG can represent a new strategy to boost the protection conferred by BCG vaccination. Moreover, different immunological parameters, such as IFN-γ and IL-17 and tightly regulated IL-4 secretion, seem to contribute to the efficacy of this tuberculosis vaccine.

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Differential Expression of Gamma Interferon mRNA Induced by Attenuated and Virulent Mycobacterium tuberculosis in Guinea Pig Cells after Mycobacterium bovis BCG Vaccination

Infection and Immunity ◽

10.1128/iai.71.1.354-364.2003 ◽

2003 ◽

Vol 71 (1) ◽

pp. 354-364 ◽

Cited By ~ 26

Author(s):

Amminikutty Jeevan ◽

Teizo Yoshimura ◽

Kyeong Eun Lee ◽

David N. McMurray

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Lymph Node ◽

Amino Acid ◽

Guinea Pig ◽

Mrna Expression ◽

Mycobacterium Bovis ◽

Bcg Vaccination ◽

Lymph Node Cells ◽

Ifn Γ

ABSTRACT To determine whether Mycobacterium bovis BCG vaccination would alter gamma interferon (IFN-γ) mRNA expression in guinea pig cells exposed to Mycobacterium tuberculosis, we cloned a cDNA encoding guinea pig IFN-γ from a spleen cell cDNA library. The cDNA is composed of 1,110 bp, with an open reading frame encoding a 166-amino-acid protein which shows 56 and 41% amino acid sequence homology to human and mouse IFN-γ, respectively. Spleen or lymph node cells from naïve and BCG-vaccinated guinea pigs were stimulated with purified protein derivative (PPD) or M. tuberculosis H37Ra or H37Rv, and the total RNA was subjected to Northern blot analysis with a 32P-labeled probe derived from the cDNA clone. Compared to the IFN-γ mRNA expression in cells of naïve animals, that in spleen and lymph node cells exposed to various stimuli was enhanced after BCG vaccination. However, there was a significant reduction in IFN-γ mRNA levels when cells were stimulated with a multiplicity of infection of greater than 1 virulent M. tuberculosis bacterium per 10 cells. The enhanced IFN-γ mRNA response in BCG-vaccinated animals was associated with an increase in the proportions of CD4+ T cells in the spleens, as determined by fluorescence-activated cell sorter analysis. Furthermore, the nonadherent population in the spleens enriched either by panning with anti-guinea pig immunoglobulin G-coated plates or by purification on nylon wool columns produced more IFN-γ mRNA than whole spleen cells following stimulation with concanavalin A or PPD. This indicates that T cells are principally responsible for the upregulation of IFN-γ mRNA expression following BCG vaccination. The mechanism by which virulent mycobacteria suppress IFN-γ mRNA accumulation is currently under investigation.

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Influence of Mycobacterium bovis BCG Vaccination on Cellular Immune Response of Guinea Pigs Challenged with Mycobacterium tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00019-08 ◽

2008 ◽

Vol 15 (8) ◽

pp. 1248-1258 ◽

Cited By ~ 36

Author(s):

Diane Ordway ◽

Marcela Henao-Tamayo ◽

Crystal Shanley ◽

Erin E. Smith ◽

Gopinath Palanisamy ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Mycobacterium Bovis ◽

Guinea Pigs ◽

Lung Damage ◽

Cell Populations ◽

Lung Pathology ◽

Bcg Vaccination ◽

Macrophage Populations ◽

Cellular Immune

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG) currently remains the only licensed vaccine for the prevention of tuberculosis. In this study, we used a newly described flow cytometric technique to monitor changes in cell populations accumulating in the lungs and lymph nodes of naïve and vaccinated guinea pigs challenged by low-dose aerosol infection with virulent Mycobacterium tuberculosis. As anticipated, vaccinated guinea pigs controlled the growth of the challenge infection more efficiently than controls did. This early phase of bacterial control in immune animals was associated with increased accumulation of CD4 and CD8 T cells, including cells expressing the activation marker CD45, as well as macrophages expressing class II major histocompatibility complex molecules. As the infection continued, the numbers of T cells in the lungs of vaccinated animals waned, whereas the numbers of these cells expressing CD45 increased. Whereas BCG vaccination reduced the influx of heterophils (neutrophils) into the lungs, an early B-cell influx was observed in these vaccinated animals. Overall, vaccine protection was associated with reduced pathology and lung damage in the vaccinated animals. These data provide the first direct evidence that BCG vaccination accelerates the influx of protective T-cell and macrophage populations into the infected lungs, diminishes the accumulation of nonprotective cell populations, and reduces the severity of lung pathology.

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Mycobacterium bovis BCG vaccination modulates TNF-α production after pulmonary challenge with virulent Mycobacterium tuberculosis in guinea pigs

Tuberculosis ◽

10.1016/j.tube.2006.07.002 ◽

2007 ◽

Vol 87 (2) ◽

pp. 155-165 ◽

Cited By ~ 13

Author(s):

Toshiko Yamamoto ◽

Todd M. Lasco ◽

Kazuyuki Uchida ◽

Yoshitaka Goto ◽

Amminikutty Jeevan ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mycobacterium Bovis ◽

Guinea Pigs ◽

Mycobacterium Bovis Bcg ◽

Bcg Vaccination ◽

Tnf Α

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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

Infection and Immunity ◽

10.1128/iai.72.11.6622-6632.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6622-6632 ◽

Cited By ~ 111

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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Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination with Mycobacterium bovis BCG and Infection with Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.00704-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 4837-4846 ◽

Cited By ~ 18

Author(s):

Ajay Grover ◽

Jennifer Taylor ◽

JoLynn Troudt ◽

Andrew Keyser ◽

Kimberly Arnett ◽

...

Keyword(s):

T Cells ◽

Mrna Expression ◽

Mycobacterium Bovis ◽

T Cell Activation ◽

Guinea Pigs ◽

Cell Activation ◽

Activated T Cells ◽

Bcg Vaccination ◽

Tnf Α ◽

Ifn Γ

ABSTRACT The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, since Mycobacterium bovis BCG vaccination effectively prolongs survival after low-dose aerosol infection with virulent M. tuberculosis. To better understand how BCG extends time to death after pulmonary infection with M. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+ CD62Llow and CD8+ CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+ CD62Llow T cells at day 40, although the numbers of CD8+ CD62Llow T cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.

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Exploring spatial variation in BCG vaccination among children 0–35 months in Ethiopia: spatial analysis of Ethiopian Demographic and Health Survey 2016

BMJ Open ◽

10.1136/bmjopen-2020-043565 ◽

2021 ◽

Vol 11 (4) ◽

pp. e043565

Author(s):

Chilot Desta Agegnehu ◽

Adugnaw Zeleke Alem

Keyword(s):

Spatial Variation ◽

Health Survey ◽

Addis Ababa ◽

Public Health Problem ◽

Demographic And Health Survey ◽

Scan Statistics ◽

Major Public Health Problem ◽

Hotspot Analysis ◽

Bcg Vaccination ◽

South West

ObjectiveTuberculosis is a major public health problem and is the second leading cause of death worldwide. BCG vaccination is a life-saving and important part of standard tuberculosis control measures, particularly in Ethiopia where tuberculosis is endemic. The End Tuberculosis Strategy targets of 2020 have not been achieved. Exploring spatial variations in BCG vaccination among children is vital to designing and monitoring effective intervention programmes. Therefore, this study aimed to explore the spatial variation in BCG vaccination among children in Ethiopia.DesignCross-sectional study design.SettingEthiopia.ParticipantsChildren aged 0–35 months.Primary outcomeBCG vaccination coverage.MethodsData from the 2016 Ethiopian Demographic and Health Survey were used and a total of 4453 children aged 0–35 months were included. Spatial autocorrelation analysis, cluster and outlier analysis, hotspot analysis, spatial interpolation, and spatial scan statistics were carried out to identify geographical risk areas for BCG vaccine utilisation. ArcGIS V.10.6 and SaTScan V.9.6 statistical software were employed to explore spatial pattern and significant hotspot areas for BCG vaccination among children.ResultsBCG vaccination was spatially clustered in Ethiopia at the regional level (Global Moran’s I=0.516, p<0.001). A total of 51 most likely clusters of low BCG vaccination were identified in the Somali and Afar regions (log-likelihood ratio=136.58, p<0.001). Significant secondary clusters were also identified in North West Gambela, South Amhara, South West Addis Ababa, North East Southern Nations, Nationalities, and People’s Region, and South West Oromia.ConclusionA low probability of receiving BCG vaccination was found among children in the Somali and Afar regions. Therefore, these areas should be given attention when designing effective immunisation strategies to improve BCG vaccination among children in order to reduce the burden of tuberculosis in Ethiopia.

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Protection Elicited by Two Glutamine Auxotrophs of Mycobacterium tuberculosis and In Vivo Growth Phenotypes of the Four Unique Glutamine Synthetase Mutants in a Murine Model

Infection and Immunity ◽

10.1128/iai.00531-06 ◽

2006 ◽

Vol 74 (11) ◽

pp. 6491-6495 ◽

Cited By ~ 22

Author(s):

Sunhee Lee ◽

Bo-Young Jeon ◽

Svetoslav Bardarov ◽

Mei Chen ◽

Sheldon L. Morris ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Glutamine Synthetase ◽

Mycobacterium Bovis ◽

Murine Model ◽

Triple Mutant ◽

Auxotrophic Mutants ◽

Bcg Vaccination ◽

In Vivo Growth ◽

Subcutaneous Immunization

ABSTRACT We generated four individual glutamine synthetase (GS) mutants (ΔglnA1, ΔglnA2, ΔglnA3, and ΔglnA4) and one triple mutant (ΔglnA1EA2) of Mycobacterium tuberculosis to investigate the roles of GS enzymes. Subcutaneous immunization with the ΔglnA1EA2 and ΔglnA1 glutamine auxotrophic mutants conferred protection on C57BL/6 mice against an aerosol challenge with virulent M. tuberculosis, which was comparable to that provided by Mycobacterium bovis BCG vaccination.

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