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      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

      research-article
      , DPhil a , * , , PhD c , d , * , , PhD f , * , , PhD g , * , , MD b , * , , PhD a , , MD b , , PhD h , , PhD i , , MSc j , , PhD a , , MBBCh k , , PhD b , , PhD m , , MSc a , , PhD h , , DPhil n , o , , FRCPCH p , , DPhil q , r , , BM BCh a , , PhD b , , FCPaeds l , , PhD s , t , , PhD a , , PhD m , , PhD u , , FRCP v , w , , PhD e , , DPhil x , , FRCPCH y , , BSc l , , PhD m , , PhD z , , DPhil b , , PhD aa , , MRCP b , , MRCP b , , PhD b , , MSc a , , MBChB aa , , PhD l , , DPhil ab , , PhD b , , BMBS a , , MD FRCP ac , , PhD ad , , MD z , , MD ae , af , , MD ag , , DPhil b , , FRCPath ah , , MRCP b , , MSc a , , MPharm k , , MBChBAO a , , MBChB ai , , MD aj , ak , al , a , , PhD am , , DPhil a , , MBChB a , , PhD an , , DPhil a , , FRCPath ao , , MD a , ap , , MD a , , MD aq , , FRCP ar , , PhD e , , FRCP PhD as , , FRCP at , au , , MD av , , PhD aw , , MD z , , PhD z , , PhD b , , DPH ax , ay , , DPhil b , * , , FMedSci b , * , , PhD b , * , , PhD b , * , , FMedSci a , * , * , Oxford COVID Vaccine Trial Group
      Lancet (London, England)
      The Author(s). Published by Elsevier Ltd.

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          Abstract

          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 × 10 10 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; p interaction =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.

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          Most cited references10

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            A modified poisson regression approach to prospective studies with binary data.

            G Zou (2004)
            Relative risk is usually the parameter of interest in epidemiologic and medical studies. In this paper, the author proposes a modified Poisson regression approach (i.e., Poisson regression with a robust error variance) to estimate this effect measure directly. A simple 2-by-2 table is used to justify the validity of this approach. Results from a limited simulation study indicate that this approach is very reliable even with total sample sizes as small as 100. The method is illustrated with two data sets.
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              Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

              Summary Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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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
                8 December 2020
                8 December 2020
                Affiliations
                [a ]Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK
                [b ]Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK
                [c ]Institute of Global Health, University of Siena, Siena, Brazil
                [d ]Department of Paediatrics, University of Oxford, Oxford, UK
                [e ]Clinical BioManufacturing Facility, University of Oxford, Oxford, UK
                [f ]MRC Vaccines and Infectious Diseases Analytics Research Unit, Johannesburg, South Africa
                [g ]Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil
                [g ]Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa
                [i ]Family Centre for Research with Ubuntu, Department of Paediatrics, University of Stellenbosch, Cape Town, South Africa
                [j ]Soweto Clinical Trials Centre, Soweto, South Africa
                [k ]Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
                [l ]Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
                [m ]Department of Clinical Sciences, Liverpool School of Tropical Medicine and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
                [n ]Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
                [o ]Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
                [p ]Division of Pulmonology, Groote Schuur Hospital and the University of Cape Town, South Africa
                [q ]Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
                [r ]Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK
                [s ]NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
                [t ]Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
                [u ]School of Population Health Sciences, University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
                [v ]Department of Infection, Guy's and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK
                [w ]MRC Clinical Trials Unit, University College London, London, UK
                [x ]NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [y ]St George's Vaccine Institute, St George's, University of London, London, UK
                [z ]AstraZeneca BioPharmaceuticals, Cambridge, UK
                [aa ]VIDA—Vaccines and Infectious Diseases Analytical Research Unit, Johannesburg, South Africa
                [ab ]Severn Pathology, North Bristol NHS Trust, Bristol, UK
                [ac ]NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK
                [ad ]Department of Infection, Hull University Teaching Hospitals NHS Trust, UK
                [ae ]Escola Bahiana de Medicina e Saúde Pública, Salvador, Braziland Hospital São Rafael, Salvador, Brazil
                [af ]Instituto D’Or, Salvador, Brazil
                [ag ]Department of Infectious Diseases, Universidade Federal do Rio Grande do Norte, Natal, Brazil
                [ah ]London Northwest University Healthcare, Harrow, UK
                [ai ]Setshaba Research Centre, Pretoria, South Africa
                [aj ]Department of Internal Medicine, Hospital Quinta D’Or, Rio de Janeiro, Brazil
                [ak ]Instituto D’Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil
                [al ]Department of Internal Medicine, Universidade UNIGRANRIO, Rio de Janeiro, Brazil
                [am ]NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
                [an ]Clinical Research Unit, Department of Clinical Medicine, Universidade Federal de Santa Maria, Santa Maria, Brazil
                [ao ]College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, University of Glasgow, Glasgow, UK
                [ap ]Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA
                [aq ]Infectious Diseases Service, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
                [ar ]Clinical Infection Research Group, Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
                [as ]MRC-University of Glasgow Centre for Virus Research & Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK
                [at ]Department of Medicine, University of Cambridge, UK
                [au ]Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
                [av ]Heart Lung Research Institute, Department of Medicine, University of Cambridge and Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
                [aw ]University of Nottingham and Nottingham University Hospitals NHS Trust, UK
                [ax ]Public Health Wales, Cardiff, Wales
                [ay ]Aneurin Bevan University Health Board, Newport, UK
                Author notes
                [* ]Correspondence to: Prof Andrew J Pollard, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK
                [*]

                Contributed equally

                [†]

                Members are listed in appendix 1 (pp 21–44)

                Article
                S0140-6736(20)32661-1
                10.1016/S0140-6736(20)32661-1
                7723445
                33306989
                8bb6b3df-e42e-415d-8013-df22df62e9a5
                © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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