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Eradication of tuberculosis (TB), the world's leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in pre-clinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection, the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.

We performed a quantitative analysis of the HLA restriction, antigen and epitope specificity of human pathogen specific responses in healthy individuals infected with M. tuberculosis (Mtb), in a South African cohort as a test case. The results estimate the breadth of T cell responses for the first time in the context of an infection and human population setting. We determined the epitope repertoire of eleven representative Mtb antigens and a large panel of previously defined Mtb epitopes. We estimated that our analytic methods detected 50-75% of the total response in a cohort of 63 individuals. As expected, responses were highly heterogeneous, with responses to a total of 125 epitopes detected. The 66 top epitopes provided 80% coverage of the responses identified in our study. Using a panel of 48 HLA class II-transfected antigen-presenting cells, we determined HLA class II restrictions for 278 epitope/donor recognition events (36% of the total). The majority of epitopes were restricted by multiple HLA alleles, and 380 different epitope/HLA combinations comprised less than 30% of the estimated Mtb-specific response. Our results underline the complexity of human T cell responses at a population level. Efforts to capture and characterize this broad and highly HLA promiscuous Mtb-specific T cell epitope repertoire will require significant peptide multiplexing efforts. We show that a comprehensive \"megapool\" of Mtb peptides captured a large fraction of the Mtb-specific T cells and can be used to characterize this response.

Reversion of immune sensitization tests for Mycobacterium tuberculosis (M.tb) infection, such as interferon-gamma release assays or tuberculin skin test, has been reported in multiple studies. We hypothesized that QuantiFERON-TB Gold (QFT) reversion is associated with a decline of M.tb-specific functional T cell responses, and a distinct pattern of T cell and innate responses compared to persistent QFT+ and QFT- individuals. We compared groups of healthy adolescents (n=~30 each), defined by four, 6-monthly QFT tests: reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent positives (QFT+/+/+/+). We stimulated peripheral blood mononuclear cells with M.tb antigens (M.tb lysate; CFP-10/ESAT-6 and EspC/EspF/Rv2348 peptide pools) and measured M.tb-specific adaptive T cell memory, activation, and functional profiles; as well as functional innate (monocytes, natural killer cells), donor-unrestricted T cells (DURT: γδ T cells, mucosal-associated invariant T and natural killer T-like cells) and B cells by flow cytometry. Projection to latent space discriminant analysis was applied to determine features that best distinguished between QFT reverters, non-converters and persistent positives. No longitudinal changes in immune responses to M.tb were observed upon QFT reversion. M.tb-specific Th1 responses detected in reverters were of intermediate magnitude, higher than responses in QFT non-converters and lower than responses in persistent positives. About one third of reverters had a robust response to CFP-10/ESAT-6. Among those with measurable responses, lower proportions of T SCM (CD45RA+CCR7+CD27+) and early differentiated (CD45RA-) IFN-γ-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed in reverters compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in reverters compared to persistent-positives. No differences in M.tb-specific innate, DURT or B cell functional responses were observed between the groups. Statistical modelling misclassified the majority of reverters as non-converters more frequently than they were correctly classified as reverters or misclassified as persistent positives. These findings suggest that QFT reversion occurs in a heterogeneous group of individuals with low M.tb-specific T cell responses. In some individuals QFT reversion may result from assay variability, while in others the magnitude and differentiation status of M.tb-specific Th1 cells are consistent with well-controlled M.tb infection.

The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis ( M.tb ) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to mycobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the individual adaptive and innate datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical confirmation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC) = 0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC = 0.91), while the innate data EN model performed poorly (average AUROC = 0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test χ 2 = 6.09, p = 0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models. A single biomarker measuring M.tb -specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.

The factors determining the functional avidity and its relationship with the broad heterogeneity of antiviral T cell responses remain partially understood. We investigated HIV-specific CD8 T cell responses in 85 patients with primary HIV infection (PHI) or chronic (progressive and non-progressive) infection. The functional avidity of HIV-specific CD8 T cells was not different between patients with progressive and non-progressive chronic infection. However, it was significantly lower in PHI patients at the time of diagnosis of acute infection and after control of virus replication following one year of successful antiretroviral therapy. High-avidity HIV-specific CD8 T cells expressed lower levels of CD27 and CD28 and were enriched in cells with an exhausted phenotype, i.e. co-expressing PD-1/2B4/CD160. Of note, a significant increase in the functional avidity of HIV-specific CD8 T cells occurred in early-treated PHI patients experiencing a virus rebound after spontaneous treatment interruption. This increase in functional avidity was associated with the accumulation of PD-1/2B4/CD160 positive cells, loss of polyfunctionality and increased TCR renewal. The increased TCR renewal may provide the mechanistic basis for the generation of high-avidity HIV-specific CD8 T cells. These results provide insights on the relationships between functional avidity, viremia, T-cell exhaustion and TCR renewal of antiviral CD8 T cell responses.

In this phase 2 study, investigators evaluated the potential of two vaccines (H4:IC31 and BCG) to prevent the acquisition of tuberculosis infection and the subsequent development of sustained disease.

Most infections with Mycobacterium tuberculosis ( Mtb ) manifest as a clinically asymptomatic, contained state, known as latent tuberculosis infection, that affects approximately one-quarter of the global population 1 . Although fewer than one in ten individuals eventually progress to active disease 2 , tuberculosis is a leading cause of death from infectious disease worldwide 3 . Despite intense efforts, immune factors that influence the infection outcomes remain poorly defined. Here we used integrated analyses of multiple cohorts to identify stage-specific host responses to Mtb infection. First, using high-dimensional mass cytometry analyses and functional assays of a cohort of South African adolescents, we show that latent tuberculosis is associated with enhanced cytotoxic responses, which are mostly mediated by CD16 (also known as FcγRIIIa) and natural killer cells, and continuous inflammation coupled with immune deviations in both T and B cell compartments. Next, using cell-type deconvolution of transcriptomic data from several cohorts of different ages, genetic backgrounds, geographical locations and infection stages, we show that although deviations in peripheral B and T cell compartments generally start at latency, they are heterogeneous across cohorts. However, an increase in the abundance of circulating natural killer cells in tuberculosis latency, with a corresponding decrease during active disease and a return to baseline levels upon clinical cure are features that are common to all cohorts. Furthermore, by analysing three longitudinal cohorts, we find that changes in peripheral levels of natural killer cells can inform disease progression and treatment responses, and inversely correlate with the inflammatory state of the lungs of patients with active tuberculosis. Together, our findings offer crucial insights into the underlying pathophysiology of tuberculosis latency, and identify factors that may influence infection outcomes. Integrated analyses of multiple cohorts are used to obtain a better understanding of the immune state of latent infection with Mycobacterium tuberculosis , and factors that mediate and/or predict transitions from latent infection to active disease.

The Global Forum on Tuberculosis (TB) Vaccines was held virtually from 20 to 22 April 2021, marking its 20th anniversary. The Global Forum on TB Vaccines is the world's largest gathering of stakeholders striving to develop new vaccines to prevent TB. The program included more than 60 speakers in 11 scientific sessions, panel discussions, and workshops. It provided an overview of the state of the field, and an opportunity to share the latest research findings, as well as new and innovative approaches to TB vaccine research and development (R&D). This year, it was held against the backdrop of the COVID-19 pandemic and convened researchers, developers, funders, and other stakeholders remotely to discuss opportunities and challenges for TB vaccine R&D in these unprecedented times.

Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability. To improve the consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion. Sources of QuantiFERON-TB variability were assessed, and optimal procedures were identified. Distributions of IFN-γ response levels were analyzed in healthy adolescents, Mtb-unexposed control subjects, and patients with pulmonary tuberculosis. Individuals with no known Mtb exposure had IFN-γ values less than 0.2 IU/ml. Among individuals with IFN-γ values less than 0.2 IU/ml, 0.2-0.34 IU/ml, 0.35-0.7 IU/ml, and greater than 0.7 IU/ml, tuberculin skin test positivity results were 15%, 53%, 66%, and 91% (P < 0.005), respectively. Together, these findings suggest that values less than 0.2 IU/ml were true negatives. In short-term serial testing, \"uncertain\" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/ml), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFN-γ values from less than 0.2 to greater than 0.7 IU/ml had 10-fold higher tuberculosis incidence rates than those who maintained values less than 0.2 IU/ml over 2 years (P = 0.0003). By contrast, \"uncertain\" converters were not at higher risk than nonconverters (P = 0.229). Eighty-seven percent of patients with active tuberculosis had IFN-γ values greater than 0.7 IU/ml, suggesting that these values are consistent with established Mtb infection. Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-γ <0.2 to >0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease.

Discriminating between active and latent infection with Mycobacterium tuberculosis ( Mtb ) is a protracted and complicated process, which can affect the timeliness of treatment decisions. Harari et al . now report that the cytokine profiles of Mtb -specific CD4 + T cells characterized by a polychromatic flow cytometry assay can distinguish latent infection from active disease. Rapid diagnosis of active Mycobacterium tuberculosis ( Mtb ) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb -specific T cells by polychromatic flow cytometry. We studied Mtb -specific CD4 + T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb -specific CD4 + T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry–based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb -specific CD4 + T cells is a new tool for the rapid diagnosis of active tuberculosis disease.