Abstract Background H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial ...assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis ( M.tb ) infection. Methods Low dose (15 μg H56 protein in 500 nmol IC31) or high dose (50 μg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA. Results One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4+ T cells. M.tb -infected vaccinees had higher frequencies of H56-induced CD4+ T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ+ TNF-α+ IL-2+ ) and higher frequencies of H56-specific CD4+ T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4+ T cells, displaying a CD45RA− CCR7− effector memory phenotype, emerged after the second high-dose vaccination in M.tb -infected vaccinees. TNF-α+ IL-2+ H56-specific memory CD4+ T cells were detected mostly after low-dose H56 vaccination in M.tb -infected vaccinees, and predominantly expressed a CD45RA− CCR7+ central memory phenotype. Our results support further clinical testing of H56:IC31.
C-Tb, a novel Mycobacterium tuberculosis and 6-kDa early secretory antigenic target/10-kDa culture filtrate protein (ESAT-6/CFP-10)-specific skin test, has high specificity in bacille ...Calmette-Guerin-vaccinated healthy controls. However, the sensitivity of C-Tb has hitherto not been determined. The objective was to determine the sensitivity of C-Tb in patients with active tuberculosis (TB) in comparison with the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT).C-Tb and TST were randomly administered in a double-blinded fashion to one or the other forearm in 253 patients with active TB with or without HIV co-infection. QFT-GIT testing was performed prior to skin testing.Using a receiver operating characteristic curve-derived cut-point of 5 mm, C-Tb sensitivity was similar to QFT-GIT (73.9 (95% CI 67.8-79.3) versus 75.1 (95% CI 69.3-80.2)), and similar in HIV-infected and HIV-uninfected patients (76.7 (95% CI 69.0-83.3) versus 69.5 (95% CI 59.2-78.5)). However, sensitivity was significantly diminished in HIV-infected patients with CD4 counts <100 cells·mm(-3). C-Tb and QFT-GIT combined had significantly higher sensitivity than C-Tb alone (p<0.0001). C-Tb was safe with no significant adverse events. The 5 mm cut-point corresponded to that found in the previously published specificity study (TESEC-04).C-Tb has similar sensitivity compared with QFT-GIT for the diagnosis of M. tuberculosis infection. Sensitivity was reduced only in HIV-infected patients with severe immunosuppression. Further studies in different settings are required to validate the proposed 5 mm cut-point.
Understanding immune mechanisms, particularly the role of innate immune markers during latent TB infection remains elusive. The main objective of this study was to evaluate mRNA gene expression ...patterns of toll-like receptors (TLRs) as correlates of immunity during latent TB infection and further infer their roles as potential diagnostic biomarkers.
Messenger RNA (mRNA) levels were analysed in a total of 64 samples collected from apparently healthy children and adolescents latently infected with tuberculosis (n = 32) or non-infected (n = 32). Relative expression in peripheral blood of selected genes encoding TLRs (TLR-1, TLR-2, TLR-4, TLR-6 and TLR-9) was determined with a quantitative real-time polymerase chain reaction (qRT-PCR) using specific primers and florescent labelled probes and a comparative threshold cycle method to define fold change. Data were analysed using Graph-Pad Prism 7.01 for Windows and a p-value less than 0.05 was considered statistically significant.
An increased mean fold change in the relative expression of TLR-2 and TLR-6 mRNA was observed in LTBI groups relative to non-LTBI groups (p < 0.05), whereas a slight fold decrease was observed for TLR-1 gene.
An increased mRNA expression of TLR-2 and TLR-6 was observed in latently infected individuals relative to those non-infected, possibly indicating the roles these biomarkers play in sustenance of the steady state interaction between the dormant TB bacilli and host immunity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
C-Tb, an ESAT-6/CFP-10-based skin test, has similar sensitivity for active TB compared to tuberculin skin test (TST) and QuantiFERON-TB-Gold-In-Tube (QFT). However, data are limited in children and ...HIV-infected persons.
Asymptomatic South African contacts <5 years (n = 87; HIV-uninfected), or symptomatic individuals of all ages presenting to clinics with suspected TB (n = 1003; 30% HIV-infected) were recruited from eight South African centres. C-Tb and TST were allocated to either forearm double blinded. Samples for QFT were collected in parallel, and test-positivity rates were compared.
In participants with microbiologically confirmed TB (n = 75; 45% HIV-infected) sensitivity of C-Tb, TST and QFT were similar (72% versus 75% versus 73%; p>0.5). All 3 tests had similar positivity rates in HIV-infected participants with active TB, however, positivity rates were reduced when CD4 counts were <100 cells/μL. In participants where active TB was excluded (n = 920), C-Tb (41%), TST (43%), and QFT (44%) also had similar test-positivity rates. Among asymptomatic contacts aged below five, 32% (28/87) tested positive with C-Tb and 32% (28/87) with TST (concordance 89%). Overall, C-Tb and TST showed a similar safety profile.
C-Tb was safe and showed similar test-positivity rates, compared to TST and QFT, in children and HIV-infected persons with active or latent M. tuberculosis infection. These data inform the utility of C-Tb in clinical practice.
ClinicalTrials.gov NCT01642888. EudraCT 2011-005078-40.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients (pts) with T2D uncontrolled on metformin ± SGLT2i were randomized to oral semaglutide (sema) 14 mg once daily (N=285), liraglutide (lira) 1.8 mg (N=284) or placebo (pbo, N=142) in a phase ...3a, 52-week, double-blind, double-dummy trial (NCT02863419). Endpoints: Change (baseline to week 26) in HbA1c (primary) and body weight (BW, confirmatory secondary). Two estimands addressed two efficacy-related questions: Treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Treatment policy estimand: Oral sema was non-inferior (margin 0.4%) to lira and superior to pbo in reducing HbA1c, and superior to both in reducing BW at week 26 (Table). Differences in both HbA1c and BW were significant at week 52. Trial product estimand: Oral sema gave significant reductions in HbA1c and BW vs. lira and pbo at weeks 26 and 52. Oral sema had comparable tolerability to lira; 11% (oral sema) vs. 9% (lira) and 4% (pbo) prematurely discontinued trial product due to adverse events (primarily gastrointestinal; 5% oral sema vs. 3% lira discontinued due to nausea).
In conclusion, oral sema was well tolerated in pts with T2D on metformin ± SGLT2i, was non-inferior vs. lira and superior vs. pbo in reducing HbA1c, and was superior in reducing BW vs. both lira and pbo. The reduction in HbA1c was significantly better vs. lira when evaluated by the trial product estimand.
Disclosure
R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. A. Amod: Advisory Panel; Self; Aspen Pharmacare, AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. S.T. Hoff: Employee; Self; Novo Nordisk A/S. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Lingvay: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation. Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi, TARGET PharmaSolutions, Valeritas, Inc. Research Support; Self; Merck & Co., Inc., Mylan, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. K. Pedersen: Employee; Self; Novo Nordisk A/S. T. Saugstrup: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Zealand Pharma A/S. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi.
Funding
Novo Nordisk A/S
Background. New, simple, and better-performing diagnostic tools are needed for the diagnosis of tuberculosis (TB). Much effort has been invested in developing an antibody-based test for TB, but to ...date, no such test has performed with sufficient sensitivity and specificity. A key question remaining is the extent to which the disappointing performance of current tests is associated with a high background prevalence of latent TB. Methods. We compared Mycobacterium tuberculosis-specific ESAT-6 and CFP-10 antibody responses in a total of 565 human serum samples from M. tuberculosis-uninfected donors and donors with latent infection, as well as samples from patients with active TB. Our study included samples from 4 countries, representing environments with low, intermediate, and high TB incidences. Results. We demonstrated significant increases in antibody levels in latently infected contacts, compared with M. tuberculosis-uninfected individuals, and in patients with active TB disease, compared with latently infected contacts. Furthermore, we found a striking increase in the magnitude of the antibody responses in samples obtained from infected Ethiopian individuals (with and without disease), compared with Danish and Brazilian infected individuals; this was presumably the result of higher exposure levels. Conclusions. Our study confirms the presence of ESAT-6 and CFP-10 antibodies in patients with TB, and we demonstrate that significant antibody responses are not restricted to active TB disease but can reflect latent infection, particularly in areas with high levels of exposure to M. tuberculosis. This finding is important for the understanding of the poor discriminatory power of current serodiagnostic tests in regions of endemicity, and it may have major implications on the future development of serologic tests.
Summary Background The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures ...within the lung may influence host responses through regulation of the local cytokine environment. A candidate for such regulation could be the chemokine CXCL10. CXCL10 is mainly produced by human monocytes, but a few reports have also found CXCL10 production by human B cells. The objective of this study was to investigate CXCL10 production by human B cells in response to in vitro stimulation with Mtb antigens. Methodology/principal findings We analyzed human blood samples from 30 volunteer donors using multiparameter flow cytometry, and identified a subgroup of B cells producing CXCL10 in response to in vitro stimulation with antigens. T cells did not produce CXCL10, but CXCL10 production by B cells appeared to be mediated via IFN-γ and dependent on contact with antigen-specific T cells recognizing the antigen. Conclusion Human B cells are able to produce CXCL10 in an IFN-γ and T cell contact-dependent manner. The present findings suggest a possible mechanism through which B cells in part may influence granuloma formation in human tuberculosis (TB) and participate in infection control.
Highlights • Novel liposome based adjuvant formulation CAF01 safe in first-in-human clinical trial. • H1 antigen + CAF01 adjuvant induce T-cell responses in human. • T-cell immunity is very ...long-lasting, specific responses detectable up to 150 weeks.
CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells ...have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection.
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•Mtb antigen Ag85B-specific CD4 T cells maintain memory cell features during infection•Antigen availability limits immunity conferred by Ag85B-specific CD4 T cells•Mtb antigen ESAT-6-specific CD4 T cells are driven toward terminal differentiation•Functional exhaustion restricts ESAT-6-specific CD4 T cell-mediated immunity against Mtb
Moguche and Musvosvi et al. show that two leading Mycobacterium tuberculosis vaccine antigens, Ag85B and ESAT-6, are differentially expressed during infection. As a result, CD4 T cells recognizing these antigens exhibit distinct patterns of differentiation, and their capacities to mediate protective immunity are restricted in different ways.
CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses ...has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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