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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

      , 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 references 2

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          • Article: not found

          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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            • Record: found
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            • Article: found
            Is Open Access

            Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial

            Objective To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed by a booster dose at age 12 months. Design Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 Setting Four centres in the United Kingdom and one centre in Malta. Participants Healthy infants aged 6-12 weeks followed up until age 24 months. Interventions In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months. Main outcome measure MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >−0.35. Results The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age. Conclusions MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib-MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children. Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov).
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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
              © 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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