Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02A Candidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults ▿ †

Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02A (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02A. Mtb72F/AS02A recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02A vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02A induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4+ T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4+ T-cell response induced by the 10-μg and 40-μg Mtb72F/AS02A vaccines. The Mtb72F-specific CD4+ T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02A vaccine but did not persist. Vaccine-induced CD8+ T-cell responses were not detected, and no immune responses were elicited with AS02A alone. In conclusion, Mtb72F/AS02A is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-μg Mtb72F/AS02A vaccines show comparable safety and immunogenicity profiles

Phase I Dose Escalation Safety and Immunogenicity Trial of \u3cI\u3ePlasmodium falciparum \u3c/I\u3eApical Membrane Protein (AMA-1) FMP2.1, Adjuvanted with AS02A, in Malaria-Naive Adults at the Walter Reed Army Institute of Research

We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naıve volunteers who received 8, 20 or 40 _g of FMP2.1 in a fixed volume of 0.5mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-γ and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali

Optimal adjustment of the number of air changes of a smelter pot room by using mathematical optimization

The only large-scale, cost-effective way to exhaust contaminated air from the furnace pot room of an industrial plant is through natural ventilation. The effectiveness of the ventilation depends, amongst others, on the openings of the windows through which the air is allowed to enter and exit the workshop. The ventilation is also directly influenced by the prevailing weather outside the building. An appropriate measure that characterises the ventilation within the workshop is the number of air changes per hour, and ideally, it should be close to a prescribed value for all weather conditions. This requirement can be met by the appropriate adjustment of the opening angles of the inlet and outlet window slats. This paper reports on the feasibility of using mathematical optimisation to determine the ideal window slat angles for different prevailing wind conditions. The proposed optimisation methodology employs computational fluid dynamics software (FLUENT), coupled to a computationally economic optimisation algorithm (Dynamic-Q), to determine the optimal slat angles. Results of the successful application of the proposed optimisation procedure to an example problem of a large-scale aluminium smelter pot room are presented

In Vitro Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor TMC435▿ †

TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC50s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to ∼2,000-fold for those with the D168V or D168I mutation, compared to the EC50 for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC50s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC50s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies

Vlaams Indicatorenboek 2019

Het Vlaams Indicatorenboek 2019 is een uitgave van het Expertisecentrum O&O Monitoring van de Vlaamse Gemeenschap in opdracht van de Vlaamse minister van Werk, Economie, Innovatie, en Sport en van de Vlaamse minister van Onderwijsstatus: publishe