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      Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial

      , FRCPath a , * , , PhD e , * , , DPhil a , , PhD f , , MD b , , PhD a , , BSc g , , PhD d , , DPhil b , , PhD h , , PhD a , , PhD i , , PhD j , , DPhil k , l , , PhD a , , DPhil b , , DPhil m , n , , PhD b , , DPhil b , , Prof, PhD o , p , , Prof, PhD i , , PhD a , , Prof, FRCPCH q , , MD b , , MSc b , , MBBS r , , FRCP s , t , , Prof, PhD c , , DPhil u , , MSc a , , PhD h , , Prof, FRCPCH r , , PhD v , w , , PhD i , , MRCP b , , MSc a , , DPhil ah , , Prof, FRCP y , z , , PhD aa , , PhD g , , MSc a , , DPhil b , , FRCPath ab , , MSc a , , MMath a , a , , PhD ac , ad , , RN a , , Prof, FRCPath ae , , MD a , , MD a , , FRCP af , , Prof, PhD ag , ah , aq , , MD ai , aj , ak , , Prof, PhD al , am , , PhD an , , PhD an , , FFPH ao , ap , , Prof, FMedSci b , * , , PhD a , * , , Prof, PhD b , * , , DPhil a , * , , DPhil a , * , * , , Prof, FMedSci a , * , COVID-19 Genomics UK consortium , the AMPHEUS Project , Oxford COVID-19 Vaccine Trial Group

      Lancet (London, England)

      The Author(s). Published by Elsevier Ltd.

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          Abstract

          Background

          A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant.

          Methods

          Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 − relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

          Findings

          Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18–55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2–11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6–84·5) for B.1.1.7 and 81·5% (67·9–89·4) for non-B.1.1.7 lineages.

          Interpretation

          ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.

          Funding

          UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

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          Most cited references 81

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          Is Open Access

          IQ-TREE: A Fast and Effective Stochastic Algorithm for Estimating Maximum-Likelihood Phylogenies

          Large phylogenomics data sets require fast tree inference methods, especially for maximum-likelihood (ML) phylogenies. Fast programs exist, but due to inherent heuristics to find optimal trees, it is not clear whether the best tree is found. Thus, there is need for additional approaches that employ different search strategies to find ML trees and that are at the same time as fast as currently available ML programs. We show that a combination of hill-climbing approaches and a stochastic perturbation method can be time-efficiently implemented. If we allow the same CPU time as RAxML and PhyML, then our software IQ-TREE found higher likelihoods between 62.2% and 87.1% of the studied alignments, thus efficiently exploring the tree-space. If we use the IQ-TREE stopping rule, RAxML and PhyML are faster in 75.7% and 47.1% of the DNA alignments and 42.2% and 100% of the protein alignments, respectively. However, the range of obtaining higher likelihoods with IQ-TREE improves to 73.3-97.1%.
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            Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

            Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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              Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

              Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet (London, England)
                The Author(s). Published by Elsevier Ltd.
                0140-6736
                1474-547X
                30 March 2021
                30 March 2021
                Affiliations
                [a ]Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK
                [b ]Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [c ]Clinical BioManufacturing Facility, University of Oxford, Oxford, UK
                [d ]Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [e ]Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [f ]Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
                [g ]COVID-19 Genomics UK, Department of Medicine, University of Cambridge, Cambridge, UK
                [h ]National Infection Service, Public Health England, Salisbury, UK
                [i ]Department of Clinical Sciences, Liverpool School of Tropical Medicine and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
                [j ]UK Biocentre, Milton Keynes, UK
                [k ]Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
                [l ]Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
                [m ]Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
                [n ]Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK
                [o ]NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust
                [p ]Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
                [q ]University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
                [r ]St George's Vaccine Institute, St George's, University of London, London, UK
                [s ]Department of Infection, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK
                [t ]MRC Clinical Trials Unit, University College London, London, UK
                [u ]NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [v ]University of Glasgow, Glasgow, UK
                [w ]Lighthouse Laboratory in Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
                [ah ]Severn Pathology, North Bristol NHS Trust, Bristol, UK
                [y ]NIHR UCLH Clinical Research Facility, London, UK
                [z ]NIHR UCLH Biomedical Research Centre, London, UK
                [aa ]Hull University Teaching Hospitals NHS Trust, Hull, UK
                [ab ]London Northwest University Healthcare, Harrow, UK
                [ac ]NIHR Imperial Clinical Research Facility, London, UK
                [ad ]NIHR Imperial Biomedical Research Centre, London, UK
                [ae ]College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital and School, University of Glasgow, Glasgow, UK
                [af ]Clinical Infection Research Group, Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
                [ag ]MRC University of Glasgow Centre for Virus Research, Glasgow, UK
                [ai ]Heart Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK
                [aj ]NIHR Cambridge Clinical Research Facility, Cambridge, UK
                [ak ]Cambridge University Hospital and Royal Papworth NHS Foundation Trusts, Cambridge, UK
                [al ]University of Nottingham, Nottingham, UK
                [am ]Nottingham University Hospitals NHS Trust, Nottingham, UK
                [an ]AstraZeneca BioPharmaceuticals, Gaithersburg, MD, USA
                [ao ]Public Health Wales, Cardiff, UK
                [ap ]Aneurin Bevan University Health Board, Newport, UK
                [aq ]Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK
                Author notes
                [* ]Correspondence to: Dr Maheshi N Ramasamy, Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK
                [*]

                Contributed equally

                [†]

                Full lists of group members are provided in the appendix (pp 24–33)

                Article
                S0140-6736(21)00628-0
                10.1016/S0140-6736(21)00628-0
                8009612
                © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

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