Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: European Commission and The Innovation Fund Denmark

The kinetics of lactate production and removal during whole-body exercise

<p>Abstract</p> <p>Background</p> <p>Based on a literature review, the current study aimed to construct mathematical models of lactate production and removal in both muscles and blood during steady state and at varying intensities during whole-body exercise. In order to experimentally test the models in dynamic situations, a cross-country skier performed laboratory tests while treadmill roller skiing, from where work rate, aerobic power and blood lactate concentration were measured. A two-compartment simulation model for blood lactate production and removal was constructed.</p> <p>Results</p> <p>The simulated and experimental data differed less than 0.5 mmol/L both during steady state and varying sub-maximal intensities. However, the simulation model for lactate removal after high exercise intensities seems to require further examination.</p> <p>Conclusions</p> <p>Overall, the simulation models of lactate production and removal provide useful insight into the parameters that affect blood lactate response, and specifically how blood lactate concentration during practical training and testing in dynamical situations should be interpreted.</p

Digital vs screen-film mammography in population-based breast cancer screening:performance indicators and tumour characteristics of screen-detected and interval cancers

Background: Full-field digital mammography (FFDM) has replaced screen-film mammography (SFM) in most breast cancer screening programs due to technological advantages such as possibilities to adjust contrast, better image quality and transfer capabilities. This study describes the performance indicators during the transition from SFM to FFDM and the characteristics of screen-detected and interval cancers. Methods: Data of the Dutch breast cancer screening program, region North from 2004 to 2010 were linked to The Netherlands Cancer Registry (N = 902 868). Performance indicators and tumour characteristics of screen-detected and interval cancers were compared between FFDM and SFM. Results: After initial screens, recall rates were 2.1% (SFM) and 3.0% (FFDM; P <0.001). The positive predictive values (PPV) were 25.6% (SFM) and 19.9% (FFDM; P = 0.002). Detection rates were similar, as were all performance indicators after subsequent screens. Similar percentages of low-grade ductal carcinoma in situ (DCIS) were found for SFM and FFDM. Invasive cancers diagnosed after subsequent screens with FFDM were more often of high-grade (P = 0.024) and ductal type (P = 0.030). The incidence rates of interval cancers were similar for SFM and FFDM after initial (2.69/1000 vs 2.51/1000; P = 0.787) and subsequent screens (2.30 vs 2.41; P = 0.652), with similar tumour characteristics. Conclusions: FFDM resulted in similar rates of screen-detected and interval cancers, indicating that FFDM performs as well as SFM in a breast cancer screening program. No signs of an increase in low-grade DCIS (which might connote possible overdiagnosis) were seen. Nonetheless, after initial screening, which accounts for 12% of all screens, FFDM resulted in higher recall rate and lower PPV that requires attention

Vi-specific serological correlates of protection for typhoid fever

Typhoid Vi vaccines have been shown to be efficacious in children living in endemic regions; however, a widely accepted correlate of protection remains to be established. We applied a systems serology approach to identify Vi-specific serological correlates of protection using samples obtained from participants enrolled in an experimental controlled human infection study. Participants were vaccinated with Vi-tetanus toxoid conjugate (Vi-TT) or unconjugated Vi-polysaccharide (Vi-PS) vaccines and were subsequently challenged with Salmonella Typhi bacteria. Multivariate analyses identified distinct protective signatures for Vi-TT and Vi-PS vaccines in addition to shared features that predicted protection across both groups. Vi IgA quantity and avidity correlated with protection from S. Typhi infection, whereas higher fold increases in Vi IgG responses were associated with reduced disease severity. Targeted antibody-mediated functional responses, particularly neutrophil phagocytosis, were also identified as important components of the protective signature. These humoral markers could be used to evaluate and develop efficacious Vi-conjugate vaccines and assist with accelerating vaccine availability to typhoid-endemic regions

Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses

To tackle the complexity of cross-reactive and pathogen-specific T cell responses against related Salmonella serovars, we used mass cytometry, unbiased single-cell cloning, live fluorescence barcoding, and T cell-receptor sequencing to reconstruct the Salmonella-specific repertoire of circulating effector CD4+ T cells, isolated from volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). We describe the expansion of cross-reactive responses against distantly related Salmonella serovars and of clonotypes recognizing immunodominant antigens uniquely expressed by S. Typhi or S. Paratyphi A. In addition, single-amino acid variations in two immunodominant proteins, CdtB and PhoN, lead to the accumulation of T cells that do not cross-react against the different serovars, thus demonstrating how minor sequence variations in a complex microorganism shape the pathogen-specific T cell repertoire. Our results identify immune-dominant, serovar-specific, and cross-reactive T cell antigens, which should aid in the design of T cell-vaccination strategies against Salmonella