Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

A Comparison of Flow Stress and Microstructure Development of Al Alloys in Plane Strain Compression and Multiple Forging

Publication suite à la conférence : 10th Intl. Conference on Aluminium Alloys (ICAA10) (Vancouver 2006)International audienceMultiple forging (MF) can be used to attain large plastic strains in bulk alloys by successive forging along three orthogonal directions to retain the initial sample shape. An original multiple forging technique enabling 3-D cross forging at constant temperature up to 500°C has been applied to two Al alloys (Al-1%Mn and Al-3%Mg-Sc,Zr). Their rheology, texture and microstructure evolution are compared with those obtained in plane strain compression (PSC). The results are interpreted in terms of slip activity behaviour during both deformation modes. They can also be correlated with the contributions of free dislocations and sub-boundaries

The Large Strain Flow Stress Behaviour of Aluminium Alloys as Measured by Channel-Die Compression (20-500°C)

International audienceTwo recent methods for obtaining flow stress-strain relations up to large strains of order 1.5 by channel-die compression are presented: i) for sheet metal formability tests, composite samples have been made of glued sheet layers and deformed at room temperature in a channel-die with the compression axis directed along one of the sheet metal edge directions, i.e. RD or TD. The sheet plane is parallel to the lateral compression die face. It is shown that, using a suitable lubricant, the sample deformation is homogeneous up to strains of 1.5. Tests carried out on 5xxx and 6xxx alloys to evaluate the stress-strain relations show that a generalized Voce law gives a good quantitative fit for the data. ii) for high temperature plate processing, quantitative flow stress data can be obtained up to 500°C with a rapid quench using a hot channel-die set-up. Some new results are presented here for high strain hot PSC tests on Al-Mn and Al-Mg alloys together with microstructure analyses

New orientation formation and growth during primary recrystallization in stable single crystals of three face-centred cubic metals

International audienceThe early stages of recrystallization have been systematically characterized in single crystal metals of medium and low stacking fault energy. Goss {1 1 0} [0 0 1] and brass {1 1 0} [1 1 2] oriented samples of Ni, Cu and Cu-2 wt.% Al alloy were deformed in a channel die to a logarithmic strain of 0.51 to develop a homogeneous structure composed of two sets of symmetrical primary microbands and then lightly annealed. Scanning electron microscopy/electron backscattered diffraction analyses demonstrate a strong relation between as-deformed orientations and the limited number of recrystallized grain orientations. The disorientation angles across the recrystallization front are mostly grouped in the ranges of 25-35 degrees and 45-55 degrees around axes located near, but not at, the normals of all four {1 1 1} planes. The original nuclei possess disorientation angles of 25-35 degrees. The orientation of the growing new grain quickly transforms through the formation of a first generation twin, leading to disorientations of 45-55 degrees. The most frequent situation occurs when the normal of the twinning face plane is situated near the rotation axis, around which the crystal lattice of the "primary nuclei" rotates. Based on the anisotropy of grain growth, a possible mechanism of orientation generation and grain growth by thermally activated movement of dislocation families on {1 1 1} planes is proposed. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved

Orientation-dependent recovery in strongly deformed Al-0.1% Mn crystals

Single crystals of Al-0.1% Mn were channel-die compressed to a true strain of 2.3 and their recovery behaviour at 240-320°C investigated by microhardness measurements, electron backscatter diffraction (EBSD) microtexture mapping and X-ray line broadening analysis. The crystal orientations were the nominally stable Goss {110}(001), brass {110}(112) and S {123}(634). For all three orientations the microhardness decreases with a logarithmic time dependence but the instantaneous recovery rates of the brass oriented crystals are systematically lower than those of the other two orientations by a factor of about 2. The dislocation densities decrease rapidly in the first stages of recovery (<1 min) by dislocation dipole annihilation and more slowly thereafter. In the Goss and S orientations the later stage of recovery is due to sub-grain growth. The orientation dependence is ascribed to the relatively low misorientations developed by plastic straining in the brass crystals (average about 4°) compared with the Goss and S orientations (about 7-8°). © 2011 Taylor & Francis

Boundary Mobilities in Binary Al-Mn Alloys

International audienceThis paper described new characterization methods and data to quantify the influence of solute atoms on grain boundary and sub-grain boundary mobilities in Al-Mn alloys with a view to their integration into recovery and recrystallization modelling. Detailed SEM measurements of grain boundary mobilities during recrystallization have been made by in-situ annealing experiments on cold deformed Al – 0.1 and 0.3wt.% Mn binary alloys. Stored energies are estimated from the sub-grain sizes and misorientations and the boundary velocities directly measured in the temperature range 200-450°C. It is shown that in many cases good agreement with the Cahn, Lücke, Stüwe model for solute drag is obtained, e.g. the activation energies are intermediate between those of boundary and volume solute diffusion. Some particular cases of rapid growth occur in Al-0.1%Mn indicating boundary breakaway from solute clouds. A complementary study of sub-grain boundary mobilities has started on the same alloys; in this case the average mobilities are estimated from FEG-SEM growth data for the average sub-grain size for temperatures in the range 150-300°C. The results are compared with some previous data on Al-Si and show similar rates

Sub-grain boundary mobilities during recovery of binary Al-Mn alloys

International audienceThe influence of Mn solute atoms on sub-grain boundary mobilities in Al has been determined by accurate electron backscatter diffraction analysis of the sub-grain sizes and misorientations during recovery annealing. High purity Al-0.1 and 0.3 wt.% Mn alloys were deformed by plane strain compression at room temperature to equivalent strains of 1.8 and annealed in the temperature range 150-300 °C. An original method of image analysis on sub-boundaries from electron backscatter diffraction maps was applied to quantify the sub-grain size distributions. The change in average sub-grain size with time at several temperatures was then used to estimate sub-grain boundary mobilities in both Al-Mn alloys. The activation energies for sub-grain mobility were found to be 48 and 52 and kJ.mol-1 for the 0.1 and 0.3 % Mn alloys respectively, with the higher Mn alloy exhibiting lower rates. The sub-boundary mobilities are higher than expected from previous similar work on deformed Al-Si crystals. The orientation dependence of sub-grain growth is also examined