Vaccination with BCGΔBCG1419c protects against pulmonary and extrapulmonary TB and is safer than BCG

AbstractA single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur. BCGΔBCG1419c was more attenuated than BCG in murine macrophages, athymic, BALB/c, and C57BL/6 mice. In guinea pigs, BCGΔBCG1419c was at least as attenuated as BCG and induced similar dermal reactivity to that of BCG. Vaccination of guinea pigs with BCGΔBCG1419c resulted in increased anti-PPD IgG compared with those receiving BCG. Guinea pigs vaccinated with BCGΔBCG1419c showed a significant reduction of M. tuberculosis replication in lungs and spleens compared with BCG, as well as a significant reduction of pulmonary and extrapulmonary tuberculosis (TB) pathology measured using pathology scores recorded at necropsy. Evaluation of cytokines produced in lungs of infected guinea pigs showed that BCGΔBCG1419c significantly reduced TNF-α and IL-17 compared with BCG-vaccinated animals, with no changes in IL-10. This work demonstrates a significantly improved protection against pulmonary and extrapulmonary TB provided by BCGΔBCG1419c in susceptible guinea pigs together with an increased safety compared with BCG in several models. These results support the continued development of BCGΔBCG1419c as an effective vaccine for TB.

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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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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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MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies

npj Vaccines ◽

10.1038/s41541-020-00262-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Andrew D. White ◽

Laura Sibley ◽

Charlotte Sarfas ◽

Alexandra Morrison ◽

Jennie Gullick ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Rhesus Macaques ◽

Peptide Pool ◽

Intradermal Vaccination ◽

Aerosol Exposure ◽

Tnf Α ◽

Ifn Γ ◽

Pulmonary Granulomas

AbstractA single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.

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Sucrose and Facilitated Tucking for Pain Among Neonates Receiving Vaccination, in Puducherry

International Journal of Pharmaceutical and Clinical Research ◽

10.25258/ijpcr.v9i3.8329 ◽

2017 ◽

Vol 9 (3) ◽

Author(s):

Sujatha S. ◽

Rebecca Samson ◽

Christopher Amalraj ◽

Sundaresan Sundaresan

Keyword(s):

Sucrose Solution ◽

Study Groups ◽

Primary Outcome Measure ◽

Intradermal Injection ◽

Control Group ◽

Intradermal Vaccination ◽

Term Neonates ◽

Bcg Vaccination ◽

Pharmacologic Agents ◽

Study Intervention

Neglected pain in neonates leads to various ill effects and it can be prevented by using simple and safe non-pharmacological pain relieving measures. Pharmacologic agents are not recommended in neonates for acute pain due toinvasive procedures however, administration of 24% oralsucrose solutionis found to be effective. The objective of this study was to assess the efficacy of 24%oral sucrose in combination with Facilitated tucking during BCG Vaccination through intradermalroute in term neonates which is not done elsewhere. Fifty five healthy term neonates who fulfilled the inclusion criteria such as gestational age above 37 weeks, within 24 hoursof birth age, and neonates delivered only through spontaneous vaginal delivery were included in the study. The study intervention consists of administration of 2 ml of oral 24% sucrose 2 minutes before BCG Vaccination through intradermal route and Facilitated tuckingat the time of vaccination. The primary outcome measure of cumulative NIPS score at 0, 3,5 minuteswas not significant in both the study groups. Whereas there was significant reduction in the level of pain and mean cry time in the neonates of sucrose group. Heart rateand oxygen saturation after intradermal injection also showed significant (p less than 0.001) differenceamong the neonates, who received 24% of oral sucroseand Facilitated tucking than for neonates of control group. Thus oral (24%)sucrose solution given 2 minutes before injection was effective in reducing level of neonatal pain following Intradermal Vaccination. It is a simple, safe and fast acting analgesic and should be considered for minor invasive procedures in term neonates which last for 5-7minutes.

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Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) modulates M1 macrophage polarization through TLR4/MAPK/NF-κB signaling pathways on murine macrophages

European Journal of Inflammation ◽

10.1177/20587392211000898 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110008

Author(s):

Se Hyang Hong ◽

Jin Mo Ku ◽

Ye Seul Lim ◽

Hyo In Kim ◽

Yong Cheol Shin ◽

...

Keyword(s):

Digestive Enzymes ◽

Macrophage Polarization ◽

Water Extract ◽

Cervus Nippon ◽

No Production ◽

M1 Macrophages ◽

Murine Macrophages ◽

M1 Macrophage ◽

Tnf Α ◽

Cytokine Levels

The objective of this study was to investigate the effects of Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) on the promotion of M1 macrophage polarization in murine macrophages. Macrophages polarize either to one phenotype after stimulation with LPS or IFN-γ or to an alternatively activated phenotype that is induced by IL-4 or IL-13. Cell viability of RAW264.7 cells was determined by WST-1 assay. NO production was measured by Griess assay. IL-6, IL-12, TNF-α, and iNOS mRNA levels were measured by RT-PCR. IL-6, IL-12, and IL-10 cytokine levels were determined by ELISA. TLR4/MAPK/NF-κB signaling in RAW264.7 cells was evaluated by western blotting. The level of NF-κB was determined by immunoblotting. CE induced the differentiation of M1 macrophages. CE promoted M1 macrophages to elevate NO production and cytokine levels. CE-stimulated M1 macrophages had enhanced IL-6, IL-12, and TNF-α. CE promoted M1 macrophages to activate TLR4/MAPK/NF-κB phosphorylation. M2 markers were downregulated, while M1 markers were upregulated in murine macrophages by CE. Consequently, CE has immunomodulatory activity and can be used to promote M1 macrophage polarization through the TLR4/MAPK/NF-κB signaling pathways.

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Evidence for Endogenous C1q Modulates TNF-α Receptor Synthesis and Autocrine Binding of TNF-α Associated with Lipid A Activation of Murine Macrophages for Nitric Oxide Production

Cellular Immunology ◽

10.1006/cimm.1996.0131 ◽

1996 ◽

Vol 170 (1) ◽

pp. 34-40 ◽

Cited By ~ 2

Author(s):

Hong Jiang ◽

John A. Rummage ◽

Charles A. Stewart ◽

Mary J. Herriott ◽

Irina Kolosova ◽

...

Keyword(s):

Nitric Oxide ◽

Lipid A ◽

Nitric Oxide Production ◽

Murine Macrophages ◽

Oxide Production ◽

Tnf Α

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Time trend and clinical pattern of extrapulmonary tuberculosis in Serbia, 1993-2007

Vojnosanitetski pregled ◽

10.2298/vsp1203227p ◽

2012 ◽

Vol 69 (3) ◽

pp. 227-230 ◽

Cited By ~ 3

Author(s):

Dragica Pesut ◽

Milica Bulajic ◽

Aleksandar Lesic

Keyword(s):

Incidence Rate ◽

Census Data ◽

Economic Transition ◽

Transition Period ◽

Extrapulmonary Tuberculosis ◽

High Coverage ◽

Female Ratio ◽

Bcg Vaccination ◽

Tb Treatment ◽

Directly Observed Treatment

Background/Aim. Increased incidence of extrapulmonary tuberculosis (XPTB) is reported worldwide. Serbia is a country in socio-economic transition period with lowmiddle HIV prevalence and intermediate-to-low tuberculosis (TB) incidence rate, 100% directly observed treatment (DOT) coverage, and mandatory BCG vaccination at birth. The aim of the study was to examine the incidence trend and clinical features of XPTB in Serbia during a 15-year period. Methods. This retrospective observational study included XPTB cases diagnosed in the period between 1st January 1993 and 31st Decembre 2007, according to the reports of the National Referral Institute of Lung Diseases and Tuberculosis in Belgrade and Central Tuberculosis Register. Population estimates with extrapolations were based on 1991 and 2002 census data. Results. While the overall TB incidence rate showed a slight, not significant decreasing trend (p = 0.535), a significant increase was found for XPTB (y = 1.7996 + 0.089x; R2 = 0.4141; p = 0.01). A total of 2,858 XPTB cases (newly diagnosed and 10% relapses) gave an average age specific incidence rate of 2.51/100,000 population (95% confidence interval, SD = 0.6182) with 8.9% annual increase. The male-to-female ratio was 0.54. Lymph nodes were most frequently affected site (48.5%) followed by genitourinary (20.5%), pleural (12%), and osseo-arthicular (10.3%) TB. Treatment outcome was successful in 88.29% of patients (cured and completed), 3.64% died, 5.18% interrupted, 0.57% displaced, and 2.3% unknown. Conclusion. Increasing trend of XPTB incidence rate may be a result of increased morbidity due to still present risk factors, possible higher detection rate in Serbia and better notification. A high coverage of newborns with BCG vaccination at birth might contribute to a decreased number and rare XPTB cases in children.

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Prognostic Value ofTc99m-Pertechnetate Thyroid Scintigraphy in Radioiodine Therapy in a Cohort of Chinese Graves’ Disease Patients: A Pilot Clinical Study

BioMed Research International ◽

10.1155/2015/974689 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Haifeng Hou ◽

Shu Hu ◽

Rong Fan ◽

Wen Sun ◽

Xiaofei Zhang ◽

...

Keyword(s):

Single Dose ◽

Prognostic Value ◽

Low Dose ◽

Radioiodine Therapy ◽

Treatment Success ◽

Serum Levels ◽

Graves Disease ◽

Thyroid Scintigraphy ◽

Thyroid Mass ◽

Pilot Clinical Study

Objectives. This study is to assess the prognostic value ofTc99m-pertechnetate thyroid scintigraphy for predicting the outcomes of fixed low dose of radioiodine therapy (RIT) in a cohort of Chinese Graves’ disease (GD) patients.Materials and Methods. This is a retrospective study of GD patients who received RIT with a single dose of radioiodine (5 mCi). All the patients receivedTc99m-pertechnetate thyroid scintigraphy prior to RIT. Thyroid mass,Tc99m-pertechnetate uptake, gender, age at diagnosis, duration of the disease, ophthalmopathy, and serum levels of FT4, FT3, TT4, and TT3 prior to RIT were analyzed as potential interference factors for outcomes of RIT.Results. One hundred and eighteen GD patients who completed RIT were followed up for 12 months. The outcomes (euthyroidism, hypothyroidism, and hyperthyroidism) were found to be significantly associated with thyroid mass andTc99m-pertechnetate uptake. Patients with thyroid mass ≤ 40.1 g orTc99m-pertechnetate uptake ≤ 15.2% had higher treatment success.Conclusions. A fixed low dose of 5 mCi radioiodine seems to be practical and effective for the treatment of Chinese GD patients with thyroid mass ≤ 40.1 g andTc99m-pertechnetate uptake ≤ 15.2%. This study demonstratesTc99m-pertechnetate thyroid scintigraphy is an important prognostic factor for predicting the outcomes of RIT.

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Evaluation of a Novel Therapeutic Approach to Treating Severe Pneumococcal Infection Using a Mouse Model

Clinical and Vaccine Immunology ◽

10.1128/cvi.00120-09 ◽

2009 ◽

Vol 16 (6) ◽

pp. 806-810 ◽

Cited By ~ 7

Author(s):

Nikkol Melnick ◽

Gowrisankar Rajam ◽

George M. Carlone ◽

Jacquelyn S. Sampson ◽

Edwin W. Ades

Keyword(s):

Single Dose ◽

Combination Therapy ◽

Polymorphonuclear Leukocytes ◽

Low Dose ◽

Control Level ◽

Pneumococcal Infection ◽

Amino Acid Peptide ◽

Opsonophagocytic Killing

ABSTRACT P4, a 28-amino-acid peptide, is a eukaryotic cellular activator that enhances specific in vitro opsonophagocytic killing of multiple bacterial pathogens. In a previous study, we successfully recreated this phenomenon in mice in vivo by using a two-dose regimen of P4 and pathogen-specific antibodies, which significantly reduced moribundity in mice. For the present study, we hypothesized that the inclusion of a low-dose antibiotic would make it possible to treat the infected mice with a single dose containing a mixture of P4 and a pathogen-specific antibody. A single dose consisting of P4, intravenous immunoglobulin (IVIG), and ceftriaxone effectively reduced moribundity compared to that of untreated controls (n = 10) by 75% (P < 0.05) and rescued all (10 of 10) infected animals (P < 0.05). If rescued animals were reinfected with Streptococcus pneumoniae and treated with a single dose containing P4, IVIG, and ceftriaxone, they could be rerescued. This observation of the repeated successful use of P4 combination therapy demonstrates a low risk of tolerance development. Additionally, we examined the polymorphonuclear leukocytes (PMN) derived from infected mice and observed that P4 enhanced in vitro opsonophagocytic killing (by >80% over the control level; P < 0.05). This finding supports our hypothesis that PMN are activated by P4 during opsonophagocytosis and the recovery of mice from pneumococcal infection. P4 peptide-based combination therapy may offer an alternative and rapid immunotherapy to treat fulminant pneumococcal infection.

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