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The SARS-Cov-2 virus that generates Covid-19 has generated an unprecedented medical crisis leading to more than 100,000 deaths worldwide in less than four months since its identification. The spreading pattern of the virus in the world countries is asymmetrical, with many factors that influence its pattern. Previous research have shown that BCG vaccination with can induce nonspecific protective effects against not only bacterial but also viral infections. This article aims to carry out a correlation analysis between the variables that define BCG vaccination policies and those that define the spread and deaths caused by Covid-19 and to study the spread pattern. In almost 55 days from the outbreak of the epidemic, a clear differentiation can be observed among the clusters of countries defined according to the BCG vaccination policy concerning disease rates and mortality, which leads us to the conclusion that the BCG vaccine generated non-specific immune protection.

Summary: Bacillus Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines worldwide. In addition to protection against tuberculosis, BCG confers a degree of non-specific protection against other infections by enhancing secondary immune responses to heterologous pathogens, termed “trained immunity.” To better understand BCG-induced immune reprogramming, we perform single-cell transcriptomic measurements before and after BCG vaccination using secondary immune stimulation with bacterial lipopolysaccharide (LPS). We find that BCG reduces systemic inflammation and identify 75 genes with altered LPS responses, including inflammatory mediators such as CCL3 and CCL4 that have a heightened response. Co-expression analysis reveals that gene modules containing these cytokines lose coordination after BCG. Other modules exhibit increased coordination, including several humanin nuclear isoforms that we confirm induce trained immunity in vitro. Our results link in vivo BCG administration to single-cell transcriptomic changes, validated in human genetics experiments, and highlight genes that are putatively responsible for non-specific protective effects of BCG.

Local immunological responses at the site of infections, such as at the lymph nodes and lungs, do play a role in containing infection caused by Mycobacterium bovis (M. bovis). This bovine tuberculosis (bTB) study was conducted to evaluate cellular and cytokine responses in the lymph nodes and lungs of BCG-vaccinated and non-vaccinated calves that were naturally infected with M. bovis. Immunohistochemical assays were used for examination of the responses of macrophages, T cells, cytokines and chemical mediators of 40 (22 vaccinated and 18 non-vaccinated) Holstein-Friesian-zebu crossbred calves that were naturally exposed for 1 year to a known bTB positive cattle herd. The incidence rates of bTB visible lesion were 68.2% (15/22) and 89% (16/18) in vaccinated and non-vaccinated calves, respectively. The local responses of CD4+ and CD8+ T cells, and those of IFN-γ and TNF-α within the lesions, were stronger (P < 0.05) in BCG-vaccinated calves than in non-vaccinated calves. However, there was no statistically significant difference between the two groups (P > 0.05) in the response of CD68+ cells. Thus, the findings of this study indicated stronger responses of a set of immunological cells and markers at the local granulomas of BCG-vaccinated calves than in non-vaccinated calves. Furthermore, BCG vaccination may also play a role in reducing the severity of the gross pathology at the primary site of infection.

Aim: Toll-like receptor 1 (TLR1), TLR2, TLR6 and TLR10 form the TLR2 subfamily. In our previous controlled studies in 132 subjects with osteitis after newborn Bacillus Calmette-Guérin (BCG) vaccination, TLR1, TLR2 and TLR6 variations were associated with the risk of BCG osteitis. Now, we evaluated the role of ten single nucleotide polymorphisms (SNP) of the TLR10 gene in this cohort.Methods: Five synonymous TLR10 SNPs (rs10004195, rs10856837, rs10856838, rs1109695 and rs11466652), and five missense TLR10 SNPs (rs11096955, rs11096957, rs11466649, rs11466653 and rs11466658) were determined by polymerase chain reaction (PCR)-based sequencing in 132 former BCG osteitis patients.Results: TLR10 rs10004195 polymorphism was associated with the risk of BCG osteitis, compared to Finnish population controls. The variant genotype (AT/AA) was present in 13.6% of cases versus 26.2% of controls (p = 0.024). Correspondingly, the minor allele frequency (MAF) was lower (0.075) in cases than in controls (0.152; p = 0.009). There were no significant differences in the genotypes of the other nine studied TLR10 SNPs or in the corresponding MAFs between cases and controls.Conclusion: Among ten studied TLR10 gene polymorphisms, the variation only in the TLR10 rs10004195 was associated with the BCG osteitis risk after newborn BCG vaccination. [ABSTRACT FROM AUTHOR]

Aim: A review published in 2015 showed that 331 Bacillus Calmette‐Guérin (BCG) osteitis cases were globally reported in 1976‐2012. The 222 Finnish cases from 1960 to 1988 formed two‐thirds of all cases. The present narrative review summarises epidemiological, clinical and immunological findings obtained from this Finnish cohort in relation to data from other countries. Methods: Six reports including 93 BCG osteitis cases, which were not included in the 2015 review, were identified from PubMed. Results: In all, 424 BCG osteitis cases have been published. Population‐based data were available only from Finland and Taiwan. The BCG osteitis incidence in Finnish infants was 6.4/100 000/year in 1960‐1988 compared to 3.4/100 000/year in Taiwanese infants in 1998‐2012. The incidence in Finland increased to 36.9/100 000 in 1971‐1977, and the vaccinations were temporarily discontinued. Over half of lesions were in lower limbs and nearly all were solitary in both cohorts. The outcomes after surgery and chemotherapy were good. Immunology of BCG osteitis was studied only in the Finnish cohort. There were deviations from population data in polymorphisms of genes regulating Toll‐like receptors 1, 2 and 6, mannose‐binding lectin and interleukin‐17A. Conclusion: BCG osteitis after vaccination is rare. Preliminary findings in innate immunity raise a question of genetic background. [ABSTRACT FROM AUTHOR]

Immune responses are tightly regulated yet highly variable between individuals. To investigate human population variation of trained immunity, we immunized healthy individuals with Bacillus Calmette-Guérin (BCG). This live-attenuated vaccine induces not only an adaptive immune response against tuberculosis but also triggers innate immune activation and memory that are indicative of trained immunity. We established personal immune profiles and chromatin accessibility maps over a 90-day time course of BCG vaccination in 323 individuals. Our analysis uncovered genetic and epigenetic predictors of baseline immunity and immune response. BCG vaccination enhanced the innate immune response specifically in individuals with a dormant immune state at baseline, rather than providing a general boost of innate immunity. This study advances our understanding of BCG's heterologous immune-stimulatory effects and trained immunity in humans. Furthermore, it highlights the value of epigenetic cell states for connecting immune function with genotype and the environment. [Display omitted] • Clinical study with 323 healthy individuals over a 90-day time course of BCG vaccination • Time-resolved personal immune profiles, chromatin accessibility maps, and genotypes • Baseline immunity, seasonality, genotype, and chromatin predict trained immunity responses • Trained immunity is specific to individuals with a dormant innate immune state at baseline The response to vaccination and immune stimuli varies widely between individuals. To dissect population variation in immune function, Moorlag, Folkman, ter Horst, Krausgruber, et al. perform multi-omics analysis before and after BCG vaccination. They find that trained immunity induction is most effective in individuals with a dormant immune state at baseline. [ABSTRACT FROM AUTHOR]

To assess the difference of Mantoux test result of under-five children who bad had BCG vaccination and those who bad not, a cross sectional study was conducted in the out patient child clinic of Dr. Pirngadi Hospital, Medan. This study was conducted from February 6, 1990 until March 3, 1990 comprising 328 under-five children (164 who bad received BCG vaccination and 164 who bad not). We found positive Mantoux tests in 86.0% of under-five children who bad BCG vaccination and 9.2% of under-five children who not bad (P

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide. The recombinant BCG strain expressing the genetically detoxified A subunit of the thermolabile toxin from Escherichia coli (LTAK63) adjuvant (rBCG-LTAK63) has previously been shown to confer superior protection and immunogenicity compared to BCG in a murine TB infection model. To further investigate the immunological mechanisms induced by rBCG-LTAK63, we evaluated the immune responses induced by rBCG-LTAK63, BCG, and Mycobacterium tuberculosis (Mtb) H37Rv strains in experimental infections of primary human M1 and M2 macrophages at the transcriptomic and cytokine secretion levels. The rBCG-LTAK63-infected M1 macrophages more profoundly upregulated interferon-inducible genes such as IFIT3, OAS3, and antimicrobial gene CXCL9 compared to BCG, and induced higher levels of inflammatory cytokines such as IL-12(p70), TNF-β, and IL-15. The rBCG-LTAK63-infected M2 macrophages more extensively upregulated transcripts of inflammation-related genes, TAP1, GBP1, SLAMF7, TNIP1, and IL6, and induced higher levels of cytokines related to inflammation and tissue repair, MCP-3 and EGF, as compared to BCG. Thus, our data revealed an important signature of immune responses induced in human macrophages by rBCG-LTAK63 associated with increased inflammation, activation, and tissue repair, which may be correlated with a protective immune response against TB.

Long-term immunoreactivity to mycobacterial antigens in Bovis Calmette-Guérin (BCG)-vaccinated population is not well investigated. Herein, 361 volunteer healthy donors (HDs) with neonatal BCG vaccination from Shanghai region (China) were enrolled. They were subdivided into ESAT-6/CFP10- (E6C10-) and ESAT-6/CFP10+ (E6C10+) groups based on gamma-interferon release assays (IGRAs). Three mycobacterial antigens, including Rv0934, Rv3006, and Rv3841, were subjected to the determination of immunoreactivity by ELISPOT assay. The immunoreactivities to three mycobacterial antigens were firstly compared among TB patients (N=39), E6C10+ HDs (N=78, 21.61% of HDs) and E6C10- HDs (N=283, 78.39% of HDs). It was revealed that Rv3006 was dominant upon M.tb infection, while Rv3841 was likely to be more responsive upon latent TB infection. In E6C10- population, the immunoreactivity to Rv3841 maintained along with aging, whereas those to Rv3006 and Rv0934 attenuated in E6C10- HDs older than 45 years old. Our study implies the shift of dominant antigens at different infection statuses, providing the clues for the selection of mycobacterial antigens in vaccine development and precision revaccination in the future.

This paper describes a case of papulonecrotic tuberculid after Bacille Calmette-Guerin (BCG) vaccination. A 6-month-old boy was seen in our emergency room with a fever and erythematous papular. He received BCG vaccination at the age of 5 months and there were no systemic problems after the vaccination. There were no abnormal physical findings except for skin lesions and fever. Histopathologically, the lesion was associated with pyogenic granulomatous inflammation and fibrosis, with multiple instances of vascularization and infiltration of various inflammatory cells. Acid-fast stain, culture,and polymerase chain reaction for tuberculous bacillus DNA of the papulonecrotic skin lesions were negative. He was diagnosed papulonecrotic tuberculid caused by BCG vaccination. The fever lasted 10 days, and all lesions healed spontaneously in 2 months. Papulonecrotic tuberculid is a vasculitis caused by an allergic reaction to an internal focus of Mycobacterium tuberculosis or its metabolites. The appearance of an unexplained skin rash may cause parental anxiety, nevertheless the disease may require no treatment unless the patient is immunocompromised. It is necessary to improve awareness regarding the disease as a side effect of BCG vaccination.

Patients with primary immunodeficiency disease (PID) are not only vulnerable to mycobacterial disease, but are also more likely to develop adverse events following BCG vaccination. These events can range from regional disease (BCGitis) to disseminated disease (BCGosis). Chronic granulomatous disease (CGD), which is characterized by impaired leukocyte phagocytic function, is one of the many inherited PIDs that increase the body’s susceptibility to recurrent bacterial and fungal infections. Here, we report a 6-year-old boy with no significant past medical history who presented with progressive lymphadenopathy six years after BCG vaccination. He was later diagnosed with CGD on further evaluation.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has kept the whole world in tenterhooks due to its severe life‐threatening infectious disease, COVID‐19. The virus is distinct from its cousins, SARS‐CoV and MERS‐CoV in terms of severity of the infection. The obligated killing properties of the SARS‐CoV‐2 virus is mediated by its unique structure. Efforts for developing vaccines for COVID‐19 are ongoing, but it is unlikely to be available in the immediate future. Due to the absence of precise treatment, the investigators are discovering other effective, protective, and healing choices. However, the lower than a predictable number of SARS‐CoV‐2 cases in countries with fragile health systems is mystifying. Recently, there has been a buzz about the protective effect of Bacille Calmette‐Guérin (BCG) vaccine in COVID‐19 through long‐term boosting of trained immunity. Based on epidemiological correlations, we link up that BCG vaccination adopted by different countries might influence the SARS‐CoV‐2 transmission patterns and/or COVID‐19 associated mortality through the vaccine's capacity to confer heterologous protection. A number of clinical studies are underway to investigate this possibility but even if they prove effective‐many questions will remain. Moreover, responsible stewardship of the BCG vaccine in the context of the COVID‐19 epidemic is directly needed. [ABSTRACT FROM AUTHOR]

Even though Indonesia has achieved elimination status, leprosy is still an important health problem in Indonesia because of its debilitating nature. East Java is one of the provinces with the highest leprosy burden in Indonesia, with a high percentage of children cases. Many factors are thought to affect leprosy transmission. Among them are nutritional status, personal hygiene, BCG vaccination history, and occupancy density. The purpose of this study was to determine the relationship between nutritional status, personal hygiene, BCG vaccination history, and occupancy density with the incidence of leprosy in children in the Gresik Regency. This is an analytic observational research with a case-control approach. This research was conducted in December 2019. The number of samples were 60 respondents, consisting of 30 cases and 30 controls. The results of multivariate analysis showed that there was a relationship between nutritional status (p = 0.041; OR = 9,628), history of BCG vaccination (p = 0.032; OR = 22,164) and occupancy density (p = 0.003; OR = 14,810) with leprosy in children. Nutritional status, personal hygiene, BCG vaccination history, and occupancy density are significantly associated with the incidence of leprosy in children, with occupancy density as the most significant factor and history of BCG vaccination as the strongest risk predictor associated with the development of leprosy in the pediatric population. [ABSTRACT FROM AUTHOR]

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional mutation in NOD2 was detected by a genetic analysis, and he was diagnosed as sporadic Blau syndrome. Since NOD2 acts as a sensor for the BCG component, it is possible that BCG vaccination may trigger granuloma formation in Blau syndrome patients with such genetic background. [ABSTRACT FROM AUTHOR]

Long-term immunoreactivity to mycobacterial antigens in Bovis Calmette-Guérin (BCG)-vaccinated population is not well investigated. Herein, 361 volunteer healthy donors (HDs) with neonatal BCG vaccination from Shanghai region (China) were enrolled. They were subdivided into ESAT-6/CFP10- (E6C10-) and ESAT-6/CFP10+ (E6C10+) groups based on gamma-interferon release assays (IGRAs). Three mycobacterial antigens, including Rv0934, Rv3006, and Rv3841, were subjected to the determination of immunoreactivity by ELISPOT assay. The immunoreactivities to three mycobacterial antigens were firstly compared among TB patients (N=39), E6C10+ HDs (N=78, 21.61% of HDs) and E6C10- HDs (N=283, 78.39% of HDs). It was revealed that Rv3006 was dominant upon M.tb infection, while Rv3841 was likely to be more responsive upon latent TB infection. In E6C10- population, the immunoreactivity to Rv3841 maintained along with aging, whereas those to Rv3006 and Rv0934 attenuated in E6C10- HDs older than 45 years old. Our study implies the shift of dominant antigens at different infection statuses, providing the clues for the selection of mycobacterial antigens in vaccine development and precision revaccination in the future. [ABSTRACT FROM AUTHOR]

Purpose: Bacillus Calmette–Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients. Methods: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019. Results: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell–deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective. Conclusion: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell–deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication. [ABSTRACT FROM AUTHOR]

The wide spectrum of symptoms observed in coronavirus disease 2019 appears to defy explanation. Apart from geographic limitation to people with prior exposure to other coronaviruses and air pollutants, inflammatory comorbidities and older ages are also among the main factors of susceptibility to severe illness. The unusual epidemiological data pointed out in children and African territories have revealed new insights in host‐pathogen interplay with more focus on epigenetic regulation of cognitive compartments belonging to innate immunity. Should trained immunity be proven to be involved in timely immune responsiveness against severe acute respiratory syndrome coronavirus 2 and that adaptive memory could be detrimental, both treatment regimens and vaccine design will tremendously change accordingly with more focus on upper respiratory tissue innate immunity to subdue this threat underway. Research Highlights: Humanity is hanging onto its hope of rescue from the pharmaceutical companies that develop vaccines. But the medical expertise acquired since the first outbreak of the coronavirus in 2003 teaches us that the classic vision of vaccination based on adaptive immunity is unlikely to work against coronaviruses. In this piece we discuss the epidemiological, clinical and mechanistic elements that encourage us to go towards the development of a new generation of vaccine against SARS‐CoV‐2 which is based essentially on the memory of innate immunity. [ABSTRACT FROM AUTHOR]

The global control of Tuberculosis remains elusive, and Bacillus Calmette-Guérin (BCG) -the most widely used vaccine in history—has proven insufficient for reversing this epidemic. Several authors have suggested that the mass presence of vaccinated hosts might have affected the Mycobacterium tuberculosis (MTB) population structure, and this could in turn be reflected in a prevalence of strains with higher ability to circumvent BCG-induced immunity, such as the recent Beijing genotype. The effect of vaccination on vaccine-escape variants has been well-documented in several bacterial pathogens; however the effect of the interaction between MTB strains and vaccinated hosts has never been previously described. In this study we show for the first time the interaction between MTB Beijing-genotype strains and BCG-vaccinated hosts. Using a well-controlled murine model of progressive pulmonary tuberculosis, we vaccinated BALB/c mice with two different sub-strains of BCG (BCG-Phipps and BCG-Vietnam). Following vaccination, the mice were infected with either one of three selected MTB strains. Strains were selected based on lineage, and included two Beijing-family clinical isolates (strains 46 and 48) and a well-characterized laboratory strain (H37Rv). Two months after infection, mice were euthanized and the bacteria extracted from their lungs. We characterized the genomic composite of the bacteria before and after exposure to vaccinated hosts, and also characterized the local response to the bacteria by sequencing the lung transcriptome in animals during the infection. Results from this study show that the interaction within the lungs of the vaccinated hosts results in the selection of higher-virulence bacteria, specifically for the Beijing genotype strains 46 and 48. After exposure to the BCG-induced immune response, strains 46 and 48 acquire genomic mutations associated with several virulence factors. As a result, the bacteria collected from these vaccinated hosts have an increased ability for immune evasion, as shown in both the host transcriptome and the histopathology studies, and replicates far more efficiently compared to bacteria collected from unvaccinated hosts or to the original-stock strain. Further research is warranted to ascertain the pathways associated with the genomic alterations. However, our results highlight novel host-pathogen interactions induced by exposure of MTB to BCG vaccinated hosts.

Objective: To study the frequency of detection of severe forms of tuberculosis in vaccinated and unvaccinated BCG vaccine in children from foci of infection. Methods: There were 279 children with tuberculosis from the foci of infection: 178 (group I) of unvaccinated BCG and 101 (group II) vaccinated with BCG vaccine. In turn, these two groups were divided into two subgroups: non-vaccinated children from foci of infection (Ia) and unvaccinated children with unidentified contact (Ib) and vaccinated children from foci of infection (IIa) and with unidentified contact (IIb). An assessment was made of the forms of the disease, the frequency and nature of the complicated course of tuberculosis in vaccinated and non-vaccinated children. Results: Severe forms such as tuberculous meningitis and disseminated tuberculosis were more likely to occur in the group of children not vaccinated with BCG vaccine at birth – 17.2% (p

The global control of Tuberculosis remains elusive, and Bacillus Calmette-Guérin (BCG) -the most widely used vaccine in history—has proven insufficient for reversing this epidemic. Several authors have suggested that the mass presence of vaccinated hosts might have affected the Mycobacterium tuberculosis (MTB) population structure, and this could in turn be reflected in a prevalence of strains with higher ability to circumvent BCG-induced immunity, such as the recent Beijing genotype. The effect of vaccination on vaccine-escape variants has been well-documented in several bacterial pathogens; however the effect of the interaction between MTB strains and vaccinated hosts has never been previously described. In this study we show for the first time the interaction between MTB Beijing-genotype strains and BCG-vaccinated hosts. Using a well-controlled murine model of progressive pulmonary tuberculosis, we vaccinated BALB/c mice with two different sub-strains of BCG (BCG-Phipps and BCG-Vietnam). Following vaccination, the mice were infected with either one of three selected MTB strains. Strains were selected based on lineage, and included two Beijing-family clinical isolates (strains 46 and 48) and a well-characterized laboratory strain (H37Rv). Two months after infection, mice were euthanized and the bacteria extracted from their lungs. We characterized the genomic composite of the bacteria before and after exposure to vaccinated hosts, and also characterized the local response to the bacteria by sequencing the lung transcriptome in animals during the infection. Results from this study show that the interaction within the lungs of the vaccinated hosts results in the selection of higher-virulence bacteria, specifically for the Beijing genotype strains 46 and 48. After exposure to the BCG-induced immune response, strains 46 and 48 acquire genomic mutations associated with several virulence factors. As a result, the bacteria collected from these vaccinated hosts have an increased ability for immune evasion, as shown in both the host transcriptome and the histopathology studies, and replicates far more efficiently compared to bacteria collected from unvaccinated hosts or to the original-stock strain. Further research is warranted to ascertain the pathways associated with the genomic alterations. However, our results highlight novel host-pathogen interactions induced by exposure of MTB to BCG vaccinated hosts. [ABSTRACT FROM AUTHOR]

Background: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance.Methods: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point.Results: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04).Conclusions: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development. [ABSTRACT FROM AUTHOR]

The SARS-Cov-2 virus that generates Covid-19 has generated an unprecedented medical crisis leading to more than 100,000 deaths worldwide in less than four months since its identification. The spreading pattern of the virus in the world countries is asymmetrical, with many factors that influence its pattern. Previous research have shown that BCG vaccination with can induce nonspecific protective effects against not only bacterial but also viral infections. This article aims to carry out a correlation analysis between the variables that define BCG vaccination policies and those that define the spread and deaths caused by Covid-19 and to study the spread pattern. In almost 55 days from the outbreak of the epidemic, a clear differentiation can be observed among the clusters of countries defined according to the BCG vaccination policy concerning disease rates and mortality, which leads us to the conclusion that the BCG vaccine generated non-specific immune protection. [ABSTRACT FROM AUTHOR]

Objectives: To determine the frequency of BCG vaccination in children with tuberculous meningitis of age 01 to 12 years at Liaquat University Hospital Hyderabad. Study Design: Cross sectional descriptive study. Setting: Department of Pediatrics, Liaquat University Hospital, Jamshoro / Hyderabad. Period: Six months from 20-08-2016 to 20-02-2017. Material and Methods: A total of 189 children with history of fever (axillary temperature >37.2°C) for ≥14 days duration with presentation, CT scan and CSF findings consistent with tuberculous meningitis were selected in this study. The data was collected on pre-structured proforma (attached). Results: There were 86(45.5%) male and 103(54.5%) female. Frequency of BCG vaccination in children with tuberculosis meningitis was found in 130(68.78%) cases. Conclusion: Our results show effectiveness of BCG vaccine in preventing TBM. Regardless of the protective efficacy of BCG in preventing pulmonary tuberculosis, in areas in which tuberculosis affects a significant percentage of the population, continued use of BCG may be warranted to prevent tuberculous meningitis. [ABSTRACT FROM AUTHOR]

Background: Interferon‐γ (IFN‐γ) and interleukin‐12 (IL‐12) play a crucial role in the defense against mycobacteria, and in the response to bacillus Calmette–Guérin (BCG) vaccination. We have previously reported clinical and outcome data of 222 BCG osteitis cases diagnosed in 1960–1988 in Finland. The immunological and genetic reports have been based on 132 blood samples obtained in 2007–2008. Methods: We compared IFNγrs2430561 and rs35314021, IL12Ars568408 and rs2243115, and IL12Brs3212227 single‐nucleotide polymorphisms (SNP) between 132 BCG osteitis patients and 99 population‐based controls. In addition, stimulated production of IFN‐γ and IL‐12 in cell culture was evaluated in relation to the presence of IFNγ and IL12 wild versus variant genotypes, respectively. Results: The distributions of IFNγrs2430561, IFNγrs35314021, IL12Ars568408, IL12Ars2243115 and IL12Brs3212227SNP did not differ between BCG osteitis patients and Finnish population‐based controls. For IFNγrs2430561, IFNγrs35314021 and IL12Ars2243115, the negative result was confirmed by comparing the minor allele frequencies (MAF) in BCG osteitis cases with those in the publicly available genome aggregation database, including data for 3,472 Finnish persons. Instead, for IL12Ars568408 and IL12Brs3212227, the comparison of MAF in BCG osteitis cases with those in population‐based and in aggregation‐based controls gave conflicting results. The presence of the wild versus variant genotype had no significant association with IL‐12 or IFN‐γ production in BCG‐stimulated cell cultures. Conclusion: IFNγ gene polymorphisms did not show any association with BCG osteitis after newborn vaccination. [ABSTRACT FROM AUTHOR]

We performed studies in B10.M H2 -congenic mouse strain whose H2 f haplotype is associated with defective BCG vaccination efficacy against TB challenge. No difference in mortality dynamics between BCG-vaccinated and primarily infected B10.M mice was observed, whereas in B10 (H2 b) congenic mice BCG vaccination significantly prolonged survival. At the early stages of infection, vaccinated mice of both strains controlled mycobacterial multiplication in lungs and draining lymph nodes better than non-vaccinated, however, in B10.M spleens no vaccination effect was evident. More activated cells expressing the CD4+CD44+CD62L− phenotype resided in spleens of vaccinated B10 compared to B10.M mice. Our results suggest that inability of BCG vaccination to prolong survival of TB-infected B10.M mice may be associated with defective response to disseminated rather than primary infection. [ABSTRACT FROM AUTHOR]

Abstract Background Previous research has provided evidence for the link between psychological processes and psychophysiological health outcomes. Psychological interventions, such as face-to-face or online cognitive behavioral therapy (CBT) and serious games aimed at improving health, have shown promising results in promoting health outcomes. Few studies so far, however, have examined whether Internet-based CBT combined with serious gaming elements is effective in modulating health outcomes. Moreover, studies often did not incorporate psychophysiological or immunological challenges in order to gain insight into physiological responses to real-life challenges after psychological interventions. The overall aim of this study is to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges. Methods/design In a randomized controlled trial, 60 healthy men are randomly assigned to either an experimental condition, receiving guided Internet-based (e-health) CBT combined with health-related serious gaming elements for 6 weeks, or a control condition receiving no intervention. After the psychological intervention, self-reported vitality is measured, and participants are given an immunological challenge in the form of a Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. One day after the vaccination, participants are asked to perform several psychophysiological tasks in order to explore the effects of the psychological intervention on participants’ stress response following the immune challenge. To assess the delayed effects of vaccination on self-reported and physiological health outcomes, a follow-up visit is planned 4 weeks later. Total study duration is approximately 14 weeks. The primary outcome measure is self-reported vitality measured directly after the intervention. Secondary outcome measures include inflammatory and endocrine markers, as well as psychophysiological measures of heart rate and skin conductance in response to the psychophysiological tasks after the BCG vaccination. Discussion The innovative design features of this study – e.g., combining guided e-health CBT with health-related serious gaming elements and incorporating immunological and psychophysiological challenges – will provide valuable information on the effects of a psychological intervention on both self-reported and physiological health outcomes. This study will offer further insights into the mechanisms underlying the link between psychological factors and health outcomes and is anticipated to contribute to the optimization of health care strategies. Trial registration Nederlands Trial Register, NTR5610 . Registered on 4 January 2016.

Objectives To assess BCG vaccination and nutritional states in children with tuberculous meningitis and their relations with the occurrence of tuberculous meningitis. Methods A case-control study was conducted at the Division of Neurology, Department of Child Health, Adam Malik Hospi- tal, Medan, from January 1997 to December 2000. Subjects of this study were all tuberculous meningitis patients and primary tuberculosis patients as the control group. Odds ratio (OR) was used to assess the risk of tuberculous meningitis in patients with positive BCG vaccination and (1-OR) was used to assess the efficacy of BCG to prevent tuberculous meningitis. Results Four out of sixteen tuberculous meningitis patients were vaccinated, while 10 of 16 primary tuberculosis patients were vac- cinated (p=0.03). OR of vaccinated patients to get tuberculous meningitis was 0.2 (95%CI 0.04;0.91). The efficacy of BCG vacci- nation to prevent tuberculous meningitis was 1-0.2 = 0.8. The risk of severe malnourished patients to get tuberculous meningitis was 2.33 (95%CI 0.52;10.48; p=0.26). Conclusion Most tuberculous meningitis patients were not BCG vaccinated. Severe malnutrition did not play role in the occurrence of this disease

World Health Organization (WHO) control policy for tuberculosis (TB) includes Bacillus Calmette-Guérin (BCG) vaccine at birth, case detection, and treatment of cases with directly observed therapy short-course (DOTS). This policy has been applied through the Ministry of Health and Population in Egypt for more than 30 years. The controversies about the efficacy of the BCG vaccination against TB in adults initiate some suggestions for its discontinuation from compulsory vaccinations in countries with low incidence of TB. The present work aimed to study the trend of applying the WHO control policy for TB in Egypt among the Egyptian population throughout the last 20 years (1992–2011). The documented database of the country, bibliographic review on MEDLINE, published studies and reports, WHO and EMRO databases that covered the period from 1992 to 2011 were used in this study. The incidence rate of all forms of TB (pulmonary and extrapulmonary) dropped by 50% from 34 cases to 17 cases per 100,000 population, as well as the prevalence rate declined by 60.6% from 71 cases per 100,000 population throughout the last 20 years. Case detection and treatment success rates have increased throughout the studied period while it flat-lined over the past 6 years which may need attention. The results of this study introduce an evidence-based recommendation for continuation of the WHO TB control policy in Egypt towards elimination of the disease.

We performed studies in B10.M H2-congenic mouse strain whose H2 f haplotype is associated with defective BCG vaccination efficacy against TB challenge. No difference in mortality dynamics between BCG-vaccinated and primarily infected B10.M mice was observed, whereas in B10 (H2 b ) congenic mice BCG vaccination significantly prolonged survival. At the early stages of infection, vaccinated mice of both strains controlled mycobacterial multiplication in lungs and draining lymph nodes better than non-vaccinated, however, in B10.M spleens no vaccination effect was evident. More activated cells expressing the CD4 + CD44 + CD62L - phenotype resided in spleens of vaccinated B10 compared to B10.M mice. Our results suggest that inability of BCG vaccination to prolong survival of TB-infected B10.M mice may be associated with defective response to disseminated rather than primary infection., Competing Interests: Declaration of competing interest The authors report no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

• BCG vaccine vials with 20 doses must be used within 6 hours of reconstitution. • To reduce vaccine wastage a vial of BCG is often not opened for every child. • We assessed missed opportunities of BCG vaccination and household cost of seeking BCG. • Infants were on average brought to health centers 1.26 times before obtaining BCG. • The household cost was 1.89 USD per vaccinated child - similar to the price of a BCG vial. In Guinea-Bissau, a vial of BCG vaccine is often not opened unless 10 infants are present for vaccination, with the aim of reducing vaccine wastage. This causes delays in vaccination, as previously demonstrated in Guinea-Bissau and other low-income countries. Reducing wastage of BCG vaccine to save money may deprive infants of important health benefits and transfer costs from the vaccination programme to mothers. Using the Bandim Health Project's rural Health and Demographic Surveillance System, we interviewed mothers of infants aged 1–11 months about household costs of seeking BCG vaccination. On average mothers took their infant for BCG vaccination 1.26 times before obtaining the vaccine. For mothers who had sought BCG vaccine for their infants the average cost was 1.89 USD for each BCG-vaccinated infant. Among BCG-unvaccinated infants at the time of interview, 42% had brought their infant for BCG vaccination in vain at an average cost of 2.83 USD. [ABSTRACT FROM AUTHOR]

There is no uniform method to conduct the epidemiological monitoring of BCG complications in the Russian Federation, Current indicators of BCG complications include the number of complication cases (cases registered within two years after vaccination) and the total number of the vaccinated children. Our aim is to discover a new indicator of BCG complications and to compare it with the indicators of the existing methods, The comparative analysis of new and existing methods of all complication cases (continuous sampling, n = 110) was conducted in the Irkutsk Region (Eastern Siberia) from 2005 to 2014, The calculating formula included the ratio of the number of children with complications vaccinated in the analyzed year to 100,000 children vaccinated in the same year, The new method shows the advantages over the existing methodological approaches, It demonstrates more adequate assessment, expressed in the highest approximation coefficient of trend model compared to the other methods, and stability of indicator over the years, The incidence of complications in the Irkutsk Region has a steady decreasing linear trend and a significant negative growth rate of the indicator (-17,9 %), The new method offers an adequate assessment and can be used as an epidemiological control system not only in the Russian Federation but in other high TB-burden countries with massive BCG vaccination of children,

Kusta masih menjadi masalah kesehatan masyarakat di berbagai negara umumnya negara berkembang, termasuk Indonesia. Tujuan dari penelitian ini adalah untuk mengetahui hubungan antara status vaksinasi BCG, riwayat kontak dan personal hygiene dengan kejadian kusta. Penelitian ini merupakan penelitian analitik observasional dengan pendekatan kasus kontrol secara retrospektif. Pada penelitian ini menggunakan total sampling pada kelompok kasus dan accidental sampling pada kelompok kontrol, dengan jumlah masing-masing 64 orang. Analisis data dilakukan secara univariat, bivariat dan berstrata dengan uji chi square (α=0,05) dan menghitung nilai Odds Ratio (OR). Dari hasil penelitian didapatkan bahwa faktor yang berhubungan dengan kejadian kusta adalah status vaksinasi BCG (p=0,000;OR=3,621), riwayat kontak (p=0,000;OR=5,800) dan lama kontak (p=0,000; OR=15,815). Sedangkan personal hygiene (p=0,077) tidak berhubungan dengan kejadian kusta. Variabel umur, tingkat pendidikan dan status sosial ekonomi tidak terbukti sebagai variabel perancu dalam hubungan antara status vaksinasi BCG. Akan tetapi pendidikan merupakan variabel perancu dalam hubungan antara personal hygiene dengan kejadian kusta. Saran bagi petugas bagian P2PL adalah meningkatkan kegiatan surveilans epidemiologi penyakit kusta. Bagi kepala puskesmas diharapkan untuk meningkatkan penemuan penderita secara aktif, meningkatkan penyuluhan kepada masyarakat tentang penyakit kusta dan meningkatkan cakupan vaksinasi BCG. Bagi peneliti selanjutnya untuk menghindari bias recall dan bias seleksi. Leprosy remains a public health problem in many developing countries, including Indonesia. The purpose of this study was to determine the relation between BCG vaccination status, contact with patient, and personal hygiene and leprosy. This study was an observational analytic study with approach case control restropectively. This study used total sampling in case group and accidental sampling in control group, in total 64 peoples each group. Data analysis used univariate, bivariate and stratified by chi square test (α = 0,05) and calculated the odd ratio (OR). The result showed that the factors related with the leprosy were BCG vaccination status (p=0,000;OR=3,621), contact with patient (p=0,000;OR=5,800) and duration of contact (p=0,000; OR=15,815). While personal hygiene was not associated with the leprosy (p=0,077). Variables of age, education and socioeconomic status did not proven as a confounding variable in relation between BCG vaccination status and leprosy. But education was confounding variable in relation between personal hygiene and leprosy. Recommendation for P2PL officer is to improve epidemiological surveillance of leprosy. For the head of the health center is expected to increase active case detection, improving counseling to society about leprosy defect and increasing the coverage of BCG vaccination. For the other researchers to avoid recall bias and selection bias.

Tuberculosis (TB) is one of the top 10 causes of death worldwide and is more common in developing countries. Isolated splenic TB is typically found in trauma, miliary TB and immunocompromised status. We present a very rare case of an immunocompetent child with an isolated primary TB in the spleen. The child only had fever of unknown origin (FUO), and mild anaemia. The diagnosis was not made until splenectomy was performed. The patient took the quadruple therapy for TB, and follow-ups showed no recurrence. This case is unique because this child was immunocompetent with no history of trauma or active TB. TB diagnosis should never be ignored in FUO as this might prevent unnecessary procedures to the patient. Although the child was vaccinated with Bacillus Calmette–Guérin that usually protects against severe TB in first 5 years of life, it did not prevent from affecting the spleen. [ABSTRACT FROM AUTHOR]

In recent years, BCG vaccination is routinely performed worldwide. The Ministry of Health, Labor and Welfare of Japan reported that the vaccination rate was as high as 92.9% in 2011. Majority of the reported local adverse reactions to BCG vaccination included lymph node swelling, keloid formation, and abscesses. Subcutaneous tuberculous granuloma is a rare local adverse reaction to BCG vaccination. Herein, we report two cases of developing subcutaneous tuberculous granuloma associated with BCG vaccination. Both of them were treated with isoniazid. There is no standard management for BCG-induced subcutaneous tuberculous granuloma, however, treatment with anti-tuberculosis drugs should be considered for cases of BCGinduced subcutaneous tuberculous granuloma with abscesses or ulcerations. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) infection is highly prevalent in Indonesia. The source of transmission of TB to a child is usually via an adult with sputum smear-positive pulmonary tuberculosis. The Mantoux test is a diagnostic tool for tuberculosis infection. The BCG vaccine has been used for the prevention of TB, but its efficacy is still debated. Objective To assess for an association between Mantoux test results and BCG vaccination in children who had contact with adult pulmonary tuberculosis and to assess for differences in Mantoux test induration with regards to nutritional status, age, type of TB contact, and time duration since BCG vaccination in BCG-vaccinated and BCG-unvaccinated children. Methods A cross-sectional study was conducted in FebruaryMarch 2011 on infants and children (aged 3 months to five years), who had household contact with adult pulmonary TB. We performed tuberculin (Mantoux) skin tests to detect TB infection in the children. Subjects were consisted of two groups: BCG-vaccinated and BCG-unvaccinated. Results Subjects were 100 children (50 BCG-vaccinated and 50 BCG-unvaccinated subjects). Positive Mantoux test results were observed in 9 vaccinated subjects and 33 unvaccinated subjects. The mean diameters of induration in the vaccinated and unvaccinated groups were 7.6 mm and 9.6 mm, respectively (95%CI of difference -4.25 to 0.20; P=0.074). In children who had household contact with sputum smear-positive adult pulmonary TB, BCG vaccination was a protective factor against TB infection, with an odds ratio (OR) of 0.113 (95%CI 0.045 to 0.286; P=0.0001). There were no significant differences in Mantoux test induration associated with nutritional status, age, type of TB contact, and duration since BCG vaccination, between the two groups. Conclusion BCG vaccination has a protective effect on TBexposed children, based on Mantoux test results. However, there are no differences in Mantoux test induration associated with nutritional status, age, type of TB contact, or duration since BCG vaccination, between the BCG-vaccinated and BCGunvaccinated groups.

Background The Mantoux method of tuberculin skin testing has been used in tuberculosis (TB) screening of healthcare workers (HCWs) in the UK National Health Service (NHS) for many years. More recently, there have been problems with the supply of the Mantoux test solution presenting a challenge to its continued use. Aims To review results of Mantoux testing and determine factors associated with positive Mantoux result, i.e. tuberculin reactivity, in NHS HCWs, with a view to streamlining the TB screening process. Methods A retrospective descriptive study. We extracted data on HCW demographics, country of birth, previous stay or work in a high TB prevalence country, TB contact, Bacillus Calmette-Guerin (BCG) vaccination, previous tuberculin skin test (TST) and Mantoux results from the occupational health records of HCWs who had a Mantoux test during 1 January 2007 to 31 December 2010 inclusive. Results We reviewed the records of 246 HCWs. Overall, 46% were Mantoux positive (defined as ≥6 mm skin induration). Factors associated with positive Mantoux result were BCG vaccination [odds ratio (OR) 2.30; 95% confidence interval (CI) 1.14-4.66]; stay or work in a high TB prevalence country (OR 7.52; CI 2.76-20.46) and previous TST (OR 2.78; CI 1.25-6.19). Conclusions BCG vaccination, stay or work in a high TB prevalence country and previous TST were associated with positive Mantoux results. These factors could be used to predict Mantoux results, with the potential of substituting Mantoux testing. [ABSTRACT FROM AUTHOR]

Summary: Bovine tuberculosis (bTB) is highly prevalent in intensive dairy farms of the urban “milk‐sheds” in Ethiopia, and vaccination could be a cost‐effective disease control strategy. In the present study, the efficacy of Bacillus Calmette–Guerin (BCG) to protect against bTB was assessed in Holstein–Friesian calves in a natural transmission setting. Twenty‐three 2‐week‐old calves were subcutaneously vaccinated with BCG Danish SSI strain 1331, and matched 26 calves were injected with placebo. Six weeks later, calves were introduced into a herd of M. bovis‐infected animals (reactors) and kept in contact with them for 1 year. In vitro and in vivo immunological tests were performed to assess immune responses post‐vaccination and during exposure. Successful vaccine uptake was confirmed by tuberculin skin test and IFN‐γ responses in vaccinated calves. The kinetics of IFN‐γ responses to early secretory antigen target 6 and culture filtrate protein 10 (ESAT6 and CFP10, respectively) and tuberculin skin test responses post‐exposure suggested that the animals were infected early after being placed in contact with the infected herd as immunological signs of infection were measurable between 2 and 4 months post‐initial exposure. Protection was determined by comparing gross and microscopic pathology and bacteriological burden between vaccinated and control calves. BCG vaccination reduced the proportions of tissues with visible pathology in vaccinates compared to control calves by 49% (p < .001) with 56%, 43%, 72%, and 38% reductions in the proportion of lesioned tisues in head, thoracic, abdominal lymph nodes, and lungs, respectively (p‐values .029–.0001). In addition, the lesions were less severe grossly and microscopically in vaccinated calves than in non‐vaccinated calves (p < .05). The reduction in the overall incidence rates of bTB was 23%, 28%, and 33% on the basis of the absence of gross pathology, M. bovis culture positivity, and histopathology, respectively, in vaccinated animals. In conclusion, BCG vaccination reduced the frequency and severity of the pathology of bTB significantly, which is likely to reduce onwards transmission of the disease. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB). Although every year M. tb infection affects millions of people worldwide, the only vaccine that is currently available is the Bacille Calmette−Guérin (BCG) vaccine. However, the BCG vaccine has varying efficacy. Additionally, the first line antibiotics administered to patients with active TB often cause severe complications and side effects. To improve upon the host response mechanism in containing M. tb infection, our lab has previously shown that the addition of the biological antioxidant glutathione (GSH) has profound antimycobacterial effects. The aim of this study is to understand the additive effects of BCG vaccination and ex-vivo GSH enhancement in improving the immune responses against M. tb in both groups; specifically, their ability to mount an effective immune response against M. tb infection, maintain CD4+ and CD8+ T cells in the granulomas, their response to liposomal glutathione (L-GSH), with varying suboptimal levels of the first line antibiotics isoniazid (INH) and pyrazinamide (PZA), the expressions of programmed death receptor 1 (PD-1), and their ability to induce autophagy. Our results revealed that BCG vaccination, along with GSH enhancement, can prevent the loss of CD4+ and CD8+ T cells in the granulomas and improve the control of M. tb infection by decreasing the expressions of PD-1 and increasing autophagy and production of the cytokines interferon gamma IFN-γ and tumor necrosis factor-α (TNF-α).