Impaired macrophage and memory T-cell responses to Bacillus Calmette-Guerin nonpolar lipid extract.

Introduction: The attenuation of BCG has led to the loss of not only immunogenic proteins but also lipid antigens. Methods: Thus, we compared the macrophage and T-cell responses to nonpolar lipid extracts harvested from BCG and Mycobacterium tuberculosis (Mtb) to better understand the role of BCG lipids in the already known diminished responses of the vaccine strain. Results: Relative to Mtb, nonpolar lipid extract from BCG presented a reduced capacity to trigger the expression of the genes encoding TNF, IL-1b, IL-6 and IL-10 in RAW 264.7 macrophages. Immunophenotyping of PBMCs isolated from healthy individuals revealed that lipids from both BCG and Mtb were able to induce an increased frequency of CD4+ and CD8+ T cells, but only the lipid extract from Mtb enhanced the frequency of CD4-CD8-double-negative, γσ+, CD4+HLA-DR+, and γσ+HLA-DR+ T cells relative to the nonstimulated control. Interestingly, only the Mtb lipid extract was able to increase the frequency of CD4+ memory (CD45RO+) T cells, whereas the BCG lipid extract induced a diminished frequency of CD4+ central memory (CD45RO+CCR7-) T cells after 48 h of culture compared to Mtb. Discussion: These findings show that the nonpolar lipids of the BCG bacilli presented diminished ability to trigger both proinflammatory and memory responses and suggest a potential use of Mtb lipids as adjuvants to increase the BCG vaccine efficacy.

In silico comparisons of lipid-related genes between Mycobacterium tuberculosis and BCG vaccine strains.

Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine's impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine's inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.

Distribution of HLA-DRB1 alleles in BRICS countries with a high tuberculosis burden: a systematic review and meta-analysis.

INTRODUCTION: Tuberculosis (TB) is the leading cause of death worldwide caused by a single infectious disease agent. Brazil, Russia, India, China, and South Africa (BRICS) account for more than half of the world's TB cases. Bacillus Calmette-Guérin (BCG) remains the only vaccine available despite its variable efficacy. Promising antigen-based vaccines have been proposed as prophylactic and/or immunotherapeutic approaches to boost BCG vaccination. Relevant antigens must interact with the range of human leukocyte antigen (HLA) molecules present in target populations; yet this information is currently not available. METHODS: MEDLINE and EMBASE were systematically searched for articles published during 2013-2020 to measure the allelic frequencies of HLA-DRB1 in the BRICS. RESULTS: In total, 67 articles involving 3,207,861 healthy individuals were included in the meta-analysis. HLA-DRB1 alleles *03, *04, *07, *11, *13, and *15 were consistently identified at high frequencies across the BRICS, with a combined estimated frequency varying from 52% to 80%. HLA-DRB1 alleles *01, *08, *09, *10, *12, and *14 were found to be relevant in only one or two BRICS populations. CONCLUSIONS: By combining these alleles, it is possible to ensure at least 80% coverage throughout the BRICS populations.

Comparing cytokine production and clinical response following vaccination with BCG Moreau and BCG Russia strains in a Brazilian infant population.

INTRODUCTION: BCG is the only licensed vaccine against tuberculosis (TB) and, in Brazil, comprises part of the recommended vaccine schedule within the first month of life. Due to a local manufacturing shortage of BCG Moreau, BCG Russia was introduced in 2017 by the Brazilian Ministry of Health. OBJECTIVE: To evaluate differences in immune responses induced by BCG Moreau and BCG Russia in infants, in addition to scar formation. METHODS: The present case series involved 15 healthy infants who were vaccinated within the first seven days of life with one of two strains of BCG, then followed for 12 weeks or longer. Cytokine levels were measured before and after vaccination in whole blood culture supernatants previously stimulated in vitro with either BCG strain, heat-killed M. tuberculosis H37Rv or in the absence of stimulation. BCG scarring was also documented. RESULTS: Infants vaccinated with BCG Moreau exhibited increased background IL-2, IL-10 and IL-4 production, yet no differences were found in those vaccinated with BCG Russia. Although both strains induced higher levels of IL-2 and IFN-γ, elevated IL-6, TNF and IL-10 production was also seen in response to BCG Russia. In contrast, no specific responses were observed against heat-killed M. tuberculosis H37Rv, with the exception of increased IL-2 following BCG Moreau vaccination. Although documented in both groups, scarring was milder and less frequent following BCG Russia vaccination. CONCLUSIONS: Similar Th1 profiles were found following immunization with either type of BCG vaccine evaluated herein, with more pronounced cytokine production detected in response to the Russia strain. Overall, vaccination was well-tolerated and scarring evolved as expected for both BCG strains.

Distribution of HLA-DRB1 alleles in BRICS countries with a high tuberculosis burden: a systematic review and meta-analysis

Abstract INTRODUCTION: Tuberculosis (TB) is the leading cause of death worldwide caused by a single infectious disease agent. Brazil, Russia, India, China, and South Africa (BRICS) account for more than half of the world's TB cases. Bacillus Calmette-Guérin (BCG) remains the only vaccine available despite its variable efficacy. Promising antigen-based vaccines have been proposed as prophylactic and/or immunotherapeutic approaches to boost BCG vaccination. Relevant antigens must interact with the range of human leukocyte antigen (HLA) molecules present in target populations; yet this information is currently not available. METHODS: MEDLINE and EMBASE were systematically searched for articles published during 2013-2020 to measure the allelic frequencies of HLA-DRB1 in the BRICS. RESULTS: In total, 67 articles involving 3,207,861 healthy individuals were included in the meta-analysis. HLA-DRB1 alleles *03, *04, *07, *11, *13, and *15 were consistently identified at high frequencies across the BRICS, with a combined estimated frequency varying from 52% to 80%. HLA-DRB1 alleles *01, *08, *09, *10, *12, and *14 were found to be relevant in only one or two BRICS populations. CONCLUSIONS: By combining these alleles, it is possible to ensure at least 80% coverage throughout the BRICS populations.