Fast vaccine design and development based on correlates of protection (COPs): influenza as a trendsetter

Drug Delivery Technolog

A Lipid Based Antigen Delivery System Efficiently Facilitates MHC Class-I Antigen Presentation in Dendritic Cells to Stimulate CD8+ T Cells

The most effective strategy for protection against intracellular infections such as Leishmania is vaccination with live parasites. Use of recombinant proteins avoids the risks associated with live vaccines. However, due to low immunogenicity, they fail to trigger T cell responses particularly of CD8+cells requisite for persistent immunity. Previously we showed the importance of protein entrapment in cationic liposomes and MPL as adjuvant for elicitation of CD4+ and CD8+ T cell responses for longterm protection. In this study we investigated the role of cationic liposomes on maturation and antigen presentation capacity of dendritic cells (DCs). We observed that cationic liposomes were taken up very efficiently by DCs and transported to different cellular sites. DCs activated with liposomal rgp63 led to efficient presentation of antigen to specific CD4+ and CD8+ T cells. Furthermore, lymphoid CD8+ T cells from liposomal rgp63 immunized mice demonstrated better proliferative ability when co-cultured ex vivo with stimulated DCs. Addition of MPL to vaccine enhanced the antigen presentation by DCs and induced more efficient antigen specific CD8+ T cell responses when compared to free and liposomal ntigen. These liposomal formulations presented to CD8+ T cells through TAP-dependent MHC-I pathway offer new possibilities for a safe subunit vaccine

CAF01 Potentiates Immune Responses and Efficacy of an Inactivated Influenza Vaccine in Ferrets

Trivalent inactivated vaccines (TIV) against influenza are given to 350 million people every year. Most of these are non-adjuvanted vaccines whose immunogenicity and protective efficacy are considered suboptimal. Commercially available non-adjuvanted TIV are known to elicit mainly a humoral immune response, whereas the induction of cell-mediated immune responses is negligible. Recently, a cationic liposomal adjuvant (dimethyldioctadecylammonium/trehalose 6,6′-dibehenate, CAF01) was developed. CAF01 has proven to enhance both humoral and cell-mediated immune responses to a number of different experimental vaccine candidates. In this study, we compared the immune responses in ferrets to a commercially available TIV with the responses to the same vaccine mixed with the CAF01 adjuvant. Two recently circulating H1N1 viruses were used as challenge to test the vaccine efficacy. CAF01 improved the immunogenicity of the vaccine, with increased influenza-specific IgA and IgG levels. Additionally, CAF01 promoted cellular-mediated immunity as indicated by interferon-gamma expressing lymphocytes, measured by flow cytometry. CAF01 also enhanced the protection conferred by the vaccine by reducing the viral load measured in nasal washes by RT-PCR. Finally, CAF01 allowed for dose-reduction and led to higher levels of protection compared to TIV adjuvanted with a squalene emulsion. The data obtained in this human-relevant challenge model supports the potential of CAF01 in future influenza vaccines

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Clinical outcomes of left atrial appendage occlusion versus direct oral anticoagulation in patients with atrial fibrillation and prior ischemic stroke: A propensity-score matched study.

BACKGROUND: This propensity-score matched study investigated clinical outcomes associated with left atrial appendage occlusion (LAAO) versus direct oral anticoagulation (DOAC) in patients with AF and prior ischemic stroke. METHODS: AF patients enrolled in the Amulet Observational Study with a history of ischemic stroke and successful LAAO (n = 299) were compared with a propensity-score matched cohort of incident AF patients with prior ischemic stroke and treated by DOAC (n = 301). The control cohort was identified through the Danish National Patient Registries. Propensity score matching was based on covariates of the CHA2DS2-VASc and HAS-BLED scores, with a 1:2 ratio and using Greedy 5:1 digit matching with replacement. The analysis included 2-years follow-up, with a primary composite outcome of ischemic stroke, major bleeding (BARC ≥ 3) or all-cause mortality. RESULTS: Mean (SD) CHA2DS2-VASc scores were 5.26 (1.42) and 5.40 (1.31) and HAS-BLED scores were 3.95 (0.91) and 4.03 (0.96), for the LAAO and DOAC group, respectively. Total number of primary composite outcome events were 61 (12.4 events/100 patient-years) and 117 (26.9 events/100 patient-years) in the LAAO and DOAC group, respectively. Risk of the primary composite outcome was significantly lower in the LAAO group, hazard rate ratio [HR] 0.48 (95% CI: 0.35-0.65). Ischemic stroke risk was comparable, HR 0.71 (95% CI: 0.34-1.45), while risk of major bleeding, HR 0.41 (95% CI: 0.25-0.67), and all-cause mortality, HR 0.48 (95% CI: 0.32-0.71), were significantly lower with LAAO. Cardiovascular mortality did not differ statistically between the LAAO and DOAC group, HR 0.75 (95% CI: 0.39-1.42). Results were consistent across sensitivity analyses. CONCLUSION: This study indicated significantly lower risk of the composite outcome of stroke, major bleeding and all-cause mortality with LAAO therapy compared to DOAC, in patients with AF and prior stroke. The stroke prevention effectiveness appeared similar, with a significantly lower risk of major bleeding events with LAAO. The suggested clinical benefit of LAAO over DOAC require confirmation in the ongoing randomized OCCLUSION-AF trial

The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes

Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes did not have an effect on the maturation of murine bone-marrow-derived dendritic cells (BM-DCs) related to the surface expression of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86. We found that ovalbumin (OVA) readily associated with the liposomes (> 90%) when mixed in equal concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4° and by an inhibitor of actin-dependent endocytosis, cytochalasin D. In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake by T cells in mixed splenocyte cultures. The adsorption of antigen onto the liposomes increased the efficiency of antigen presentation more than 100 times in a responder assay with MHC class II-restricted OVA-specific T-cell receptor transgenic DO11.10 T cells. Our data therefore suggest that the primary adjuvant mechanism of cationic DDA liposomes is to target the cell membrane of antigen-presenting cells, which subsequently leads to enhanced uptake and presentation of antigen

Does socioeconomic status in adolescence predict low back pain in adulthood? A repeated cross-sectional study of 4,771 Danish adolescents

Social and economic disadvantage is associated with general poor physical health. This relationship has been recognised for centuries, but it is unknown whether socioeconomic factors have a specific influence on low back pain (LBP). Furthermore, it is unknown how social and economic disadvantages in youth affect adult health. Therefore, the specific objectives of this study are to explore (1) the cross-sectional association between socioeconomic status (SES) and LBP in adolescence and (2) the longitudinal association between SES in adolescence and LBP in early adulthood. A database containing LBP data from 4,771 twins was merged with their parents’ social and economic data, available from Statistics Denmark. Low back pain data [‘any low back pain’ and ‘persistent low back pain (more than 30 days)’] were collected in 1994, when the subjects were 12–18 years of age, and collected again eight years later. Socioeconomic data of the parents (education, income, social class and long-term illness, all for both mother and father) were collected in 1994. Logistic regression analyses were used to estimate the associations between each parameter of parental SES in adolescence and LBP at baseline as well as at follow-up. Finally, the influence of a variable combining the different socioeconomic parameters was established. All estimates were controlled for smoking, alcohol consumption and body mass index at baseline. In the logistic regression models, only three of the 32 estimates were statistically significant. When merging the socioeconomic variables into a combined score, the results indicated that a good social background had a protective effect against the persistent LBP, while there was no association with any LBP. However, the statistical significance of this effect was unclear. We found no or very weak indications of possible relationships between social factors in adolescence and LBP at baseline and at follow-up

Experimentelle Untersuchung der Vorgaenge in engen Spalten zwischen den Unterkanaelen von Stabbuendeln bei turbulenter Stroemung

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman