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Global tuberculosis (TB) control requires effective vaccines in TB-endemic countries, where most adults are infected with Mycobacterium tuberculosis (M.tb). We sought to define optimal dose and schedule of H56:IC31, an experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected and M.tb-uninfected adults. We enrolled 98 healthy, HIV-uninfected, bacillus Calmette-Guérin-vaccinated, South African adults. M.tb infection was defined by QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations of different concentrations of H56 in 500 nmol of IC31 to enable dose selection for further vaccine development. Subsequently, QFT-positive and QFT-negative participants were randomized to receive two or three vaccinations to compare potential schedules. Participants were followed for safety and immunogenicity for 292 days. H56:IC31 showed acceptable reactogenicity profiles irrespective of dose, number of vaccinations, or M.tb infection. No vaccine-related severe or serious adverse events were observed. The three H56 concentrations tested induced equivalent frequencies and functional profiles of antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative participants who received three vaccinations. Two or three H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4 T-cell responses with acceptable safety and tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional studies should validate applicability of vaccine doses and regimens to both QFT-positive and QFT-negative individuals. Clinical trial registered with www.clinicaltrials.gov (NCT01865487).

Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (T ), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (T ) or effector (T ) T cells. Our knowledge of T derives primarily from studies of virus-specific CD8 T . We aimed to determine if infection with ( ), the etiological agent of tuberculosis, generates antigen-specific CD4 T and to characterize their functional ontology. We studied T cell responses to natural infection in a longitudinal adolescent cohort of recent QuantiFERON-TB Gold (QFT) converters and three cross-sectional QFT adult cohorts; and to bacillus Calmette-Guerin (BCG) vaccination in infants. and/or BCG-specific CD4 T cells were detected by flow cytometry using major histocompatibility complex class II tetramers bearing Ag85, CFP-10, or ESAT-6 peptides, or by intracellular cytokine staining. Transcriptomic analyses of -specific tetramer CD4 T (CD45RA CCR7 CD27 ) were performed by microfluidic qRT-PCR, and functional and phenotypic characteristics were confirmed by measuring expression of chemokine receptors, cytotoxic molecules and cytokines using flow cytometry. -specific T were not detected in QFT-negative persons. After QFT conversion frequencies of T increased to measurable levels and remained detectable thereafter, suggesting that primary infection induces T cells. Gene expression (GE) profiling of tetramer T showed that these cells were distinct from bulk CD4 naïve T cells (T ) and shared features of bulk T and -specific tetramer T and T cells. These T were predominantly CD95 and CXCR3 , markers typical of CD8 T . Tetramer T expressed significantly higher protein levels of CCR5, CCR6, CXCR3, granzyme A, granzyme K, and granulysin than bulk T and T cells. -specific T were also functional, producing IL-2, IFN-γ, and TNF-α upon antigen stimulation, and their frequencies correlated positively with long-term BCG-specific CD4 T cell proliferative potential after infant vaccination. Human infection with induced distinct, antigen-specific CD4 T cells endowed with effector functions, including expression of cytotoxic molecules and Th1 cytokines, and displayed chemokine receptor profiles consistent with memory Th1/17 cells. Induction of CD4 T should be considered for vaccination approaches that aim to generate long-lived memory T cells against .

Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis ( M. tb ) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1β stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed distinct responses between TB/LTBI at transcriptomic, proteomic and metabolomic levels. At baseline, we identified a novel immune-metabolic association between pregnane steroids, the PPARγ pathway and elevated plasma IL-1ra in TB. We observed dysregulated IL-1 responses after BCG stimulation in TB patients, with elevated IL-1ra responses being explained by upstream TNF differences. Additionally, distinct secretion of IL-1α/IL-1β in LTBI/TB after BCG stimulation was associated with downstream differences in granzyme mediated cleavage. Finally, IL-1β driven signalling was dramatically perturbed in TB disease but was completely restored after successful treatment. This study improves our knowledge of how immune responses are altered during TB disease, and may support the design of improved preventive and therapeutic tools, including host-directed strategies.

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.

Early secretory antigenic target-6 (ESAT-6) is an immunodominant Mycobacterium tuberculosis (M.tb) antigen included in novel vaccines against tuberculosis (TB) and in interferon-gamma (IFN-γ) release assays (IGRAs). Therefore, the availability of an ESAT-6-free IGRA is essential to determine M.tb infection status following vaccination with ESAT-6-containing vaccines. We aimed to qualify a recently developed ESAT-6-free IGRA and to assess its diagnostic performance in comparison to QuantiFERON-TB Gold In-tube (QFT). Participants with different levels of M.tb exposure and TB disease were enrolled to determine the ESAT-6-free IGRA cutoff, test assay performance in independent cohorts compared to standard QFT, and perform a technical qualification of antigen-coated blood collection tubes. ESAT-6-free IGRA antigen recognition was evaluated in QFT-positive and QFT-negative South African adolescents. The ESAT-6-free IGRA cutoff was established at 0.61 IU/mL, based on receiver operating characteristic analysis in M.tb-unexposed controls and microbiologically confirmed pulmonary TB patients. In an independent cohort of healthy adolescents, levels of IFN-γ released in QFT and ESAT-6-free IGRA were highly correlated (P < .0001, r = 0.83) and yielded comparable positivity rates, 41.5% and 43.5%, respectively, with 91% concordance between the tests (kappa = 0.82; 95% confidence interval, 0.74-0.90; McNemar test P = .48). ESAT-6-free IGRA blood collection tubes had acceptable lot-to-lot variability, precision, and stability. The novel ESAT-6-free IGRA had diagnostic accuracy comparable to QFT and is suitable for use in clinical trials to assess efficacy of candidate TB vaccines to prevent established M.tb infection.

BackgroundNew safe and effective TB vaccine strategies to replace infant BCG vaccination are needed urgently. We evaluated the safety, reactogenicity and immunogenicity of three doses of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate, MTBVAC, in comparison to BCG in South African newborns.MethodsHealthy infants, HIV-unexposed, BCG-naïve newborns without history of close TB contact were randomly allocated into three sequential cohorts to receive a single intradermal dose of BCG (SSI, 2.5×105 CFU) or MTBVAC (2.5×104; 2.5×105 CFU; or 2.5×106 CFU).Results228 pregnant women consented, and 99 newborns were enrolled. Seventy-eight infants across all 3 cohorts had local reactions, all rated mild, except one grade 2 erythema. Induration, swelling, and erythema was more common with increased MTBVAC dosage. Induration and swelling were more common in MTBVAC 2.5x106 than in BCG and reactogenicity in MTBVAC 2.5x105 was same as BCG. Twelve infants experienced 14 vaccine-unrelated SAEs including one death due to bronchopneumonia. Eight infants commenced TB treatment for unconfirmed pulmonary TB (BCG n=4 and MTBVAC 2.5x104 CFU n=4) and one for unconfirmed TB meningitis (BCG). MTBVAC was highly immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T-cells, which peaked at day 56 and waned thereafter. The 2.5×105 and 2.5×106 CFU MTBVAC doses were more immunogenic than BCG, inducing very similar response magnitudes and phenotypes. Vaccination with any MTBVAC dose resulted in QFT conversion in most infants at Day 56, but these responses waned and reverted to QFT-negative in more than half by the end of the 1-year follow-up period. ConclusionMTBVAC appeared safe and well tolerated and immunogenic at doses between 2.5×104 CFU and 2.5×106 CFU in South Africans newborns. The 2.5×105 CFU MTBVAC dose was selected for the ongoing phase 3 trial in a high TB prevalence setting.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem with an estimated 1.7 billion persons infected worldwide. Clinical challenges in TB include the lack of a blood-based test for active disease, and the absence of prognostic biomarkers for early treatment response. Current blood based tests, such as QuantiFERON-TB Gold (QFT), are based on an IFNγ readout following Mtb antigen stimulation. However, they do not distinguish active TB disease from asymptomatic Mtb infection. We hypothesized that the use of TruCulture, an improved immunomonitoring method for whole blood collection and immune stimulation, could improve the discrimination of active disease from latent Mtb infection. To test our hypothesis, we stimulated whole blood from active TB patients (before and after successful treatment), comparing them to asymptomatic latently infected individuals. Mtb-specific antigens (ESAT-6, CFP-10, TB7.7) and live bacillus Calmette-Guerin (BCG) were used for TruCulture stimulation conditions, with direct comparison to QFT. Protein analyses were performed on the culture supernatants using ELISA and Luminex multi-analyte profiling. TruCulture showed an ability to discriminate active TB cases from latent controls (p < 0.0001, AUC = 0.81, 95% CI: 0.69-0.93) as compared to QFT (p = 0.47 AUC = 0.56, 95% CI: 0.40-0.72), based on an IFNγ readout after Mtb antigen stimulation. The stratification of the two groups could be further improved by using the Mtb Ag/BCG IFNγ ratio response (p < 0.0001, AUC = 0.918, 95% CI: 0.84-0.98). We also identified additional cytokines that distinguished latent infection from TB disease; and show that the primary differences between the TruCulture and QFT systems were a result of higher levels of non-specific innate immune activation in QFT tubes, due to the lack of a buffering solution in the latter. We conclude that TruCulture offers a next-generation solution for whole blood stimulation and immunomonitoring with the possibility to discriminate active and latently infected persons.