Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Study of electrorheological fluids behavior under fatigue tests

ER fluids made of starch and CMC in silicone fluid were submitted to fatigue tests in a Material Testing System (MTS). Wohler curves were determined and the behavior of the electric current was studied. We concluded that it is possible to treat data on fatigue life of ER fluids by means of Weibull distribution and that it is possible to determine the time the "snap" begins in an ER material by monitoring the electric current. The ER fluids studied have fatigue lives similar to those of some polymers like polypropylene and polyethylene.91535

Modeling of the efficiency of fibrous filters through numerical simulation and X-ray tomography

This paper describes modeling of the efficiency of fibrous filters using numerical simulation and X-ray computerized tomography (XCT). Variations in the flow field within the filter due to particle accumulation and structural inhomogeneities are taken into account in the mathematical model. Both the theoretical results and the experimental XCT data (digital images) showed that in the depth filtration process analyzed there is graded particle accumulation, Larger particles form bridges and can improve the collection for smaller particles during the filtration time. It is also found that smaller particles tend to promote a more pronounced pressure drop.12331132

Influence of filtration conditions evaluated by X-ray computerized tomography

This research article investigates the effect of flow rate conditions on particle distribution within cartridge filters using X-Ray computerized tomography. Graphical analysis and an image reconstruction technique show that particle distribution and particle capture efficiency are significantly different for each flow condition.404454

Using X-ray computerized tomography for characterization of defects in cartridge filters

Cartridge filter manufacturers conventionally use air permeability, and bubble point tests for the evaluation of integrity and filtration rating of their filter elements. These tests reveal information only upstream and downstream of the filters. If a region of low density and a region of high density (compared to the mean density of the filter) exist in the interior of the element, these two regions may be superimposed and the results of the test may cause acceptance of an imperfect filter. The present paper shows the use of an X-ray computerized tomography scanner for visualization of internal defects in the cartridge filter elements used in industrial and domestic applications. Tomographic images with good contrast were obtained. The images clearly revealed cracks in the activated carbon filter and regions of high density in the fibrous filter (melt-blown type). Finally, the main objective of this paper is to show that X-ray computerized tomography can be used successfully within the filter industries as a potential tool in the evaluation of existing products, and as a support in new product development.301858

Electrorheological fluids response under mechanical testing

In most research, ER fluids have been studied and characterized as if they were extremely viscous liquids. In this work, electrorheological fluids were characterized as solids and their mechanical properties in tensile, compression and shear tests were determined. Two different fluids were studied: one of them was made of starch in silicone fluid and the other was composed of carboxymethylcelullose (CMC) in silicone fluid. From the results we concluded that fluids made of CMC have a better performance than those made of starch and also that ER materials are more resistant to compression, tensile and shear stress, in this order. More precisely, ER fluids made of CMC have an elasticity modulus similar to that of rubber. They have tensile strength 600 to 10(4) times lower than that of LDPE (low density polyethylene) and static yield stress 104 times lower than that of ABS (acrylonitrile-butadiene-styrene terpolymer).91445

Fiber-enriched double-setting calcium phosphate bone cement

Calcium phosphate bone cements are useful in orthopedics and traumatology, their main advantages being their biocompatibility and bioactivity, which render bone tissue osteoconductive, providing in situ hardening and easy handling. However, their low mechanical strength, which, in the best of cases, is equal to the trabecular bone, and their very low toughness are disadvantages. Calcium phosphate cement compositions with mechanical properties more closely resembling those of human bone would broaden the range of applications, which is currently limited to sites subjected to low loads. This study investigated the influence of added polypropylene, nylon, and carbon fibers on the mechanical properties of double setting alpha-tricalcium phosphate-based cement, using calcium phosphate cement added to an in situ polymerizable acrylamide-based system recently developed by the authors. Although the addition of fibers was found to reduce the compression strength of the double-setting calcium phosphate cement because of increased porosity, it strongly increased the cement's toughness (J(IC)) and tensile strength. The composites developed in this work, therefore, have a potential application in shapes subjected to flexure. (C) 2003 Wiley Periodicals, Inc.65A224425