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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Efeitos genéticos e de ambiente em um rebanho do ecótipo mantiqueira: II. Características produtivas Genetics and environment effects in mantiqueira type breed: II. Productive traits

Por meio de análises uni e bicaracterísticas entre a produção total de leite (PL), produção de gordura (PROG), porcentagem de gordura (PERG), duração da lactação (DL) e período seco (PSECO), objetivou-se, com este trabalho, estimar parâmetros genéticos utilizando-se registros provenientes das cinco primeiras lactações de 1.406 vacas do ecótipo Mantiqueira, filhas de 113 reprodutores, com partos entre os anos de 1977 e 1997, pertencentes ao programa de melhoramento do Pólo Regional do Vale do Paraíba da Agência Paulista de Tecnologia dos Agronegócios da Secretaria de Agricultura e Abastecimento do Estado de São Paulo (APTA/SAA-SP), no município de Pindamonhangaba. Os modelos usados para obtenção das médias dos quadrados mínimos incluíram os efeitos fixos de ano e estação de parto e idade ao parto, além dos efeitos aleatórios de reprodutor e do erro. Para a obtenção dos parâmetros genéticos pela metodologia REML foram utilizados os modelos que ajustavam os efeitos fixos de ano-estação e idade da vaca ao parto, além dos efeitos aleatórios de animal e do erro. As médias ajustadas ± erros-padrão foram: 1863,31 ± 1047,19 kg para a PL; 76,59 ± 31,92 kg para a PROG; 3,43 ± 0,64 % para PERG; 231,72 ± 91,30 dias para DL; e 256,40 ± 180,29 dias para o PSECO. As herdabilidades foram: 0,25; 0,09; 0,00; 0,16 e 0,06, respectivamente, para PL, PROG, PERG, DL e PSECO. As correlações genéticas entre PL e PROG ou PERG foram, respectivamente, de 0,36 e -0,02. De acordo com os resultados obtidos, pode-se inferir que há variação genética aditiva entre vacas para produção de leite.<br>Mantiqueira ecotype breed cows were analyzed to estimate genetic parameters for productive traits using single and multiple traits analysis of total milk production (PL), fat production (PROG), fat percentage (PERG), lactation length (DL) and days dry (PSECO). Records of the first five lactations of 1,406 cows from 113 sires with calving between 1977 and 1997 from the Paraiba Valley Regional Center of Research from São Paulo State (APTA/SAA-SP) breeding program were used. Models to obtain least square means included fixed effects for year and season of calving and age of calving, in addition to random effect of sire and error. The models to obtain the genetic parameters by REML methodology included fixed effects for year-season and age, in addition to random effects of animal and error. Least square means ± standard error were 1863,31 ± 1047,19 kg (PL); 76,59 ± 31,92 kg (PROG); 3,43 ± 0,64 % (PERG); 231,72 ± 91,30 days (DL); and 256,40 ± 180,29 days (PSECO). Estimated values of heritabilities were: 0.25 (PL); 0.09 (PROG); 0.00 (PERG); 0.16 (DL) and 0.06 (PSECO). Genetic correlations of PL with PROG and PERG were 0.36 and 0.02, respectively. These results suggest an additive genetic variation among cows to milk yield