Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomised, double-blind, controlled trial

Background—Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vectorbased vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone. Methods—This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1–17 years were enrolled in three age cohorts (12–17 years, 4–11 years, and 1–3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 1010 viral particles; first dose) followed by MVA-BN-Filo (1 × 108 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494. Findings—From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1–3 years after placebo injection to 21% (30 of 144) of children aged 4–11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12–17 years and 4–11 years age cohorts after the first and second dose, and pyrexia in the 1–3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12–17 years (9929 ELISA units [EU]/mL [95% CI 8172–12 064]), in 119 (99%) of 120 aged 4–11 years (10 212 EU/mL [8419–12 388]), and in 118 (98%) of 121 aged 1–3 years (22 568 EU/mL [18 426–27 642]). Interpretation—The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1–17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children

Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial

Background The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. Methods The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5×1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1×108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant’s last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. Findings Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736–6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312–4383]) at 21 days after the second vaccination. Interpretation The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults

Vliv anizotropie na fyzikální a mechanické vlastnosti hornin.

Import 18/12/2013Vliv anizotropie na fyzikální a mechanické vlastnosti hornin. Disertační práce je zaměřena především na studium anizotropie základních mechanických a fyzikálních vybraných hornin. Studie byla provedena v laboratorních podmínkách s cílem testovat variabilitu vlastností hornin a jejich vzájemné vztahy. Pro pochopení vlivu anizotropního charakteru hornin na jejich fyzikální a mechanické vlastnosti byly realizována série následujících měření a analýz: měření velikosti horninových zrn, rychlosti šíření ultrazvukových vln, měření permeability pro kapaliny, zkoušky pevnosti v prostém tlaku, brazilská zkouška, zkoušky lomové houževnatosti a triaxiální pevnosti. Testovány byly 4 typy anizotropních hornin. Pro dosažení výše uvedeného cíle byly odebrány vzorky sedimentárních, metamorfovaných a magmatických hornin z lokalit na různých kontinentech (Česká republika, Japonsko, Jižní Korea, Jižní Afrika. Na každém z vybraných vzorků byly definovány základní osy anizotropie, označení jako Axis-1, Axis-2 and Axis-3. Roviny kolmé ke každé z os byly definovány jako Plane-1, Plane-2 and Plane-3. Pro účely této práce byla obdobně definována i použitá válcová tělesa, získaná orientovaným jádrovým vrtáním horninových bloků. Tělesa vrtaná kolmo na vrstevnatost nebo foliaci byla označena jako Type-1 and tělesa vrtaná paralelně, jako Type-3. Anizotropie stavby hornin, daná orientací zrn a mikrotrhlin, byla úspěšně vyhodnocena na mikroskopických výbrusech odebraných z horninových bloků ve třech navzájem kolmých rovinách. K tomu byl použit optický polarizační mikroskop. Anizotropie hornin byla vyšetřována také metodou měření rychlosti šíření ultrazvukových vln materiálem, kde byly určeny rozdíly v rychlosti ultrazvuku ve třech definovaných směrech. Výsledky z ultrazvukových testů jsou v dobré korelaci s měřením orientace zrn a mikrotrhlin. ...The main focus of this thesis is to study some basic rock mechanical and physical anisotropic properties of selected rocks. The study is mainly conducted in laboratory conditions to examine property variation in rocks and their inter-relationships. In order to present a clear contribution in understanding the influence of anisotropic characteristics of rocks on physical and mechanical properties, a series of average grain diameter examination, ultrasonic wave velocity test, fluid permeability test, uniaxial compressive strength test, Brazilian test, fracture toughness and triaxial compression test were conducted on four rock types known to be anisotropic. In order to achieve the mentioned experimental goals, sedimentary, metamorphic and igneous rock samples were randomly collected from different continent around the globe (Czech Republic, Japan, South Korea and South Africa). In each selected sample, a definition scheme was introduced based on directionality as Axis-1, Axis-2 and Axis-3 and planes perpendicular to each axis were defined as Plane-1, Plane-2 and Plane-3. In this thesis, classification scheme for cored samples obtained from directional coring was also introduced; samples from perpendicular direction are called Type-1 and those from Parallel direction are called Type-3. The anisotropic grain size distribution and micro-cracks orientation are successful describe by estimaing the average grain diameter distribution with microcracks orientation and propagation by observation made on thin sections in three perpendicular planes. This was performed for separate rock block using a polarization microscope. The rock blocks were also found to possess stronger degree of anisotropy of elastic wave velocity when compared between tested samples. With strong anisotropic wave velocity, I was able to determine the direction of higher and lesser propagation of wave. The results obtained from ultrasonic wave velocity test are in strong correlation with grain size distribution at measured axis orientation...Prezenční542 - Institut hornického inženýrství a bezpečnostivyhově

Practical Design and Evaluation Types of Various Engineering-geological Exploration Work

Import 29/09/2010Tato práce se zabývá praktickým provedením a vyhodnocením inženýrskogeologického průzkumu pro říční jezy a plošně a pilotově zakládané stavby. Analýza jednotlivých vybraných lokalit byla provedena určitou metodikou, nástroji a doporučenými laboratorními testy pro stanovení geologických podmínek. Proto se v práci zabývám technikami průzkumu, inženýrsko-geologickými podmínkami, efektivní soudržností, úhlem vnitřního tření, modulem přetvárnosti, standardní Proctorovou zkouškou a poměrem únosnosti zemin.This paper deals with the practical implementation and evaluation of engineering geological exploration for river weirs, flat and deep up buildings. The analysis, cover analysis for various localities, used methods and tools with recommended laboratory tests for determining the correct factors of safety. In order to achieve this, a special attention is given on exploration techniques, engineering geological conditions, effective cohesion, effective frictional angle, constrain modulus, proctor standard and Bering ratio of soilPrezenční541 - Institut geologického inženýrstvídobř

Analyzing geophysical signature of a hydrocarbon-contaminated soil using geoelectrical surveys

In February 1994, a major oil blow-out occurred as a consequence of an accident at an exploration drill-hole at Trecate (North-West, Italy). More than 15 years after the incident, a series of geophysical and hydrogeological surveys were conducted for investigating the hydrocarbon-contaminated soil. The hydrocarbon is still spatially distributed as residual phase in the unsaturated zone. A free phase exists between the transition zone and the vadose zone, in what is defined as a smear zone. Geoelectrical methods have shown their potential in contaminant detection, and are increasingly used for contaminated sites characterization. We carried out geoelectrical surveys over the most contaminated area of the site, in order to analyze the changes in geophysical signature due to the presence of contaminants, and furthermore to understand the role of biomass activity in degrading the hydrocarbon and altering petrophysical properties of the soil. Acquisition of time- and frequency-domain resistivity data allowed us to approach the same features with different methods, providing a better understanding of the problem. We further analyzed the role of soil properties on electrical resistivity; porosity, pore water specific resistivity and the influence of cation exchange capacity on the bulk resistivity at the site. The electrical resistivity observed at the site shows a clear relationship with water saturation, porosity and soil texture as well as with resistive hydrocarbon species. We also monitored soil polarizability in the same frequency range of electrical resistivity measures, allowing better delineation of the degrading processes underway in the contaminant, which constitutes an additional substrate for the proliferation of anaerobic degrader