Explore the vast range of titles available.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors. Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.

The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here, we report a comparative immunological characterization of CTH522/CAF®01 in female mice and humans. We find a range of immune signatures that translate from mouse to human, including a Th1/Th17 cytokine profile and antibody functionality. We identify vaccine-induced T cell epitopes, conserved among Chlamydia serovars, and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice, and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study. Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.

Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime–boost immunisation schedule. This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19–45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109. Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH. CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development. European Commission and The Innovation Fund Denmark.

There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens. CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18–45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A–F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A–E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A–E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 μg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 μg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 μg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A–E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 μg CTH522-CAF01 than 15 μg, although not significantly (intention-to-treat median IgG titre ratio groups A–C:D=5·6; p=0·062), with no difference after three injections of 85 μg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522. CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 μg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials. The EU Horizon Program TRACVAC.

Clare Turnbull and colleagues report discovery of 19 new susceptibility loci for testicular germ cell tumor (TGCT) and provide evidence for a network of physical interactions between TGCT risk variants and candidate causal genes. Their findings implicate widespread disruption of developmental transcriptional regulators in TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis 1 . Defective microtubule assembly and dysregulation of KIT–MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

To evaluate Bordetella pertussis as a cause of persistent cough in adults, we examined 201 patients who had a cough for 2-12 weeks and no pulmonary disease. We obtained the following at presentation: medical history, chest radiograph, respiratory function measurement, nasopharyngeal aspirate for polymerase chain reaction (PCR), nasopharyngeal swab specimen for culture, and a blood sample (acute serum). Four weeks later a second blood sample (convalescent serum) was obtained. Control sera were obtained from 164 age-matched healthy blood donors with no history of cough during the previous 12 weeks. Four patients were B. pertussis culture-positive; 11 (including the culture-positive patients) were B. pertussis PCR-positive; and 33, including 10 of the 11 PCR-positive patients, had serological evidence of recent B. pertussis infection. Pertussis-positive and -negative patients could not be discriminated by a history of cough. We conclude that B. pertussis infection is a common cause of persistent cough in adults. This is of concern, because these patients may be B. pertussis reservoirs from which transmission may occur to infants, in whom the disease can be devastating.

We have discovered a triply eclipsing triple-star system, TIC 290061484, with the shortest known outer period, Pout, of only 24.5 days. This \"eclipses\" the previous record set by lambda Tauri at 33.02 days, which held for 68 yr. The inner binary, with an orbital period of Pin = 1.8 days, produces primary and secondary eclipses and exhibits prominent eclipse timing variations with the same periodicity as the outer orbit. The tertiary star eclipses, and is eclipsed by, the inner binary with pronounced asymmetric profiles. The inclinations of both orbits evolve on observable timescales such that the third-body eclipses exhibit dramatic depth variations in TESS data. A photodynamical model provides a complete solution for all orbital and physical parameters of the triple system, showing that the three stars have masses of 6.85, 6.11, and 7.90 MSun, radii near those corresponding to the main sequence, and Teff in the range of 21,000-23,700 K. Remarkably, the model shows that the triple is in fact a subsystem of a hierarchical 2+1+1 quadruple with a distant fourth star. The outermost star has a period of ~3200 days and a mass comparable to the stars in the inner triple. In ~20 Myr, all three components of the triple subsystem will merge, undergo a Type II supernova explosion, and leave a single remnant neutron star. At the time of writing, TIC 290061484 is the most compact triple system and one of the tighter known compact triples (i.e., Pout/Pin = 13.7).