Safety and Immunogenicity of Recombinant Strain VPM1002 and Its Derivatives in a Goat Model.

A more effective vaccine against tuberculosis than (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δ (PDX) and VPM1002 Δ (NUOG), were generated to further improve the safety profile or efficacy of the vaccine.

VPM1002 as Prophylaxis Against Severe Respiratory Tract Infections Including Coronavirus Disease 2019 in the Elderly: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study.

Background: Bacille Calmette-Guérin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including coronavirus disease 2019 (COVID-19) in an elderly population.

Methods: In this phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (N = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days.

Enhanced Susceptibility of ADAP-Deficient Mice to Infection Is Associated With an Altered Phagocyte Phenotype and Function.

The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date, only limited data exist regarding the role of ADAP in pathogen-specific immunity during infection, and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here, we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogen () by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality, and excessive infiltration of neutrophils and monocytes.

Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy.

: VPM1002BC is a modified mycobacterium Bacillus Calmette Guérin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC). The genetic modifications are expected to result in better immunogenicity and less side effects. We report on patient safety and immunology of the first intravesical application of VPM1002BC in human.

ADAP Promotes Degranulation and Migration of NK Cells Primed During Infection in Mice.

The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date only limited and moreover conflicting data exist regarding the role of ADAP in NK cells. To extend existing knowledge we investigated ADAP-dependency of NK cells in the context of infection with the intracellular pathogen ().

ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens.

The adhesion and degranulation promoting adaptor protein (ADAP) is a multifunctional scaffold involved in many different signaling pathways that are important for the function of T cells, including the inside-out and outside-in signaling of integrins, the activation of NF-κB, and the subsequent production of proinflammatory cytokines (e.g., IFN-γ and IL-2).

Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils.

Prostaglandin E2 (PGE2 ) protects against allergic responses via binding to prostanoid receptor EP4, which inhibits eosinophil migration in a PI3K/PKC-dependent fashion. The phosphoinositide-dependent protein kinase 1 (PDK1) is known to act as a downstream effector in PI3K signaling and has been implicated in the regulation of neutrophil migration. Thus, here we elucidate whether PDK1 mediates inhibitory effects of E-type prostanoid receptor 4 (EP4) receptors on eosinophil function.

Opposing roles of prostaglandin D2 receptors in ulcerative colitis.

Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals.

The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55.

The G protein-coupled receptor (GPCR) 55 (GPR55) and the cannabinoid receptor 1 (CB1R) are co-expressed in many tissues, predominantly in the central nervous system. Seven transmembrane spanning (7TM) receptors/GPCRs can form homo- and heteromers and initiate distinct signaling pathways. Recently, several synthetic CB1 receptor inverse agonists/antagonists, such as SR141716A, AM251, and AM281, were reported to activate GPR55.

Endothelial E-type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking.

Background: Increased vascular permeability is a fundamental characteristic of inflammation. Substances that are released during inflammation, such as prostaglandin (PG) E(2), can counteract vascular leakage, thereby hampering tissue damage.

Objective: In this study we investigated the role of PGE(2) and its receptors in the barrier function of human pulmonary microvascular endothelial cells and in neutrophil trafficking.

The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28.

Human cytomegalovirus (HCMV) encodes the seven transmembrane(7TM)/G-protein coupled receptor (GPCR) US28, which signals and endocytoses in a constitutive, ligand-independent manner. Here we show that, following endocytosis, US28 is targeted to the lysosomes for degradation as a consequence of its interaction with the GPCR-associated sorting protein-1 (GASP-1). We find that GASP-1 binds to US28 in vitro and that disruption of the GASP-1/US28 interaction by either (i) overexpression of dominant negative cGASP-1 or by (ii) shRNA knock-down of endogenous GASP-1 is sufficient to inhibit the lysosomal targeting of US28 and slow its post-endocytic degradation.