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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.
Lancet. 2021 01 09; 397(10269):99-111.Lct

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 × 1010 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; pinteraction=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.

Authors+Show Affiliations

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Institute of Global Health, University of Siena, Siena, Brazil; Department of Paediatrics, University of Oxford, Oxford, UK.MRC Vaccines and Infectious Diseases Analytics Research Unit, Johannesburg, South Africa.Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa.Family Centre for Research with Ubuntu, Department of Paediatrics, University of Stellenbosch, Cape Town, South Africa.Soweto Clinical Trials Centre, Soweto, South Africa.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Department of Clinical Sciences, Liverpool School of Tropical Medicine and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa.Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.Division of Pulmonology, Groote Schuur Hospital and the University of Cape Town, South Africa; Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Department of Clinical Sciences, Liverpool School of Tropical Medicine and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.School of Population Health Sciences, University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.Department of Infection, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK; MRC Clinical Trials Unit, University College London, London, UK.Clinical BioManufacturing Facility, University of Oxford, Oxford, UK.NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.St George's Vaccine Institute, St George's, University of London, London, UK.Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.Department of Clinical Sciences, Liverpool School of Tropical Medicine and Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.VIDA-Vaccines and Infectious Diseases Analytical Research Unit, Johannesburg, South Africa.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.VIDA-Vaccines and Infectious Diseases Analytical Research Unit, Johannesburg, South Africa.Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.Severn Pathology, North Bristol NHS Trust, Bristol, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK.Department of Infection, Hull University Teaching Hospitals NHS Trust, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.Escola Bahiana de Medicina e Saúde Pública, Salvador, Braziland Hospital São Rafael, Salvador, Brazil; Instituto D'Or, Salvador, Brazil.Department of Infectious Diseases, Universidade Federal do Rio Grande do Norte, Natal, Brazil.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.London Northwest University Healthcare, Harrow, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Setshaba Research Centre, Pretoria, South Africa.Department of Internal Medicine, Hospital Quinta D'Or, Rio de Janeiro, Brazil; Instituto D'Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil; Department of Internal Medicine, Universidade UNIGRANRIO, Rio de Janeiro, Brazil.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Clinical Research Unit, Department of Clinical Medicine, Universidade Federal de Santa Maria, Santa Maria, Brazil.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, University of Glasgow, Glasgow, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Infectious Diseases Service, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.Clinical Infection Research Group, Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK.Clinical BioManufacturing Facility, University of Oxford, Oxford, UK.MRC-University of Glasgow Centre for Virus Research & Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK.Department of Medicine, University of Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.Heart Lung Research Institute, Department of Medicine, University of Cambridge and Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.University of Nottingham and Nottingham University Hospitals NHS Trust, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Public Health Wales, Cardiff, Wales; Aneurin Bevan University Health Board, Newport, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: andrew.pollard@paediatrics.ox.ac.uk.No affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33306989

Citation

Voysey, Merryn, et al. "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." Lancet (London, England), vol. 397, no. 10269, 2021, pp. 99-111.
Voysey M, Clemens SAC, Madhi SA, et al. 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. Lancet. 2021;397(10269):99-111.
Voysey, M., Clemens, S. A. C., Madhi, S. A., Weckx, L. Y., Folegatti, P. M., Aley, P. K., Angus, B., Baillie, V. L., Barnabas, S. L., Bhorat, Q. E., Bibi, S., Briner, C., Cicconi, P., Collins, A. M., Colin-Jones, R., Cutland, C. L., Darton, T. C., Dheda, K., Duncan, C. J. A., ... Pollard, A. J. (2021). 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. Lancet (London, England), 397(10269), 99-111. https://doi.org/10.1016/S0140-6736(20)32661-1
Voysey M, et al. 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. Lancet. 2021 01 9;397(10269):99-111. PubMed PMID: 33306989.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Voysey,Merryn, AU - Clemens,Sue Ann Costa, AU - Madhi,Shabir A, AU - Weckx,Lily Y, AU - Folegatti,Pedro M, AU - Aley,Parvinder K, AU - Angus,Brian, AU - Baillie,Vicky L, AU - Barnabas,Shaun L, AU - Bhorat,Qasim E, AU - Bibi,Sagida, AU - Briner,Carmen, AU - Cicconi,Paola, AU - Collins,Andrea M, AU - Colin-Jones,Rachel, AU - Cutland,Clare L, AU - Darton,Thomas C, AU - Dheda,Keertan, AU - Duncan,Christopher J A, AU - Emary,Katherine R W, AU - Ewer,Katie J, AU - Fairlie,Lee, AU - Faust,Saul N, AU - Feng,Shuo, AU - Ferreira,Daniela M, AU - Finn,Adam, AU - Goodman,Anna L, AU - Green,Catherine M, AU - Green,Christopher A, AU - Heath,Paul T, AU - Hill,Catherine, AU - Hill,Helen, AU - Hirsch,Ian, AU - Hodgson,Susanne H C, AU - Izu,Alane, AU - Jackson,Susan, AU - Jenkin,Daniel, AU - Joe,Carina C D, AU - Kerridge,Simon, AU - Koen,Anthonet, AU - Kwatra,Gaurav, AU - Lazarus,Rajeka, AU - Lawrie,Alison M, AU - Lelliott,Alice, AU - Libri,Vincenzo, AU - Lillie,Patrick J, AU - Mallory,Raburn, AU - Mendes,Ana V A, AU - Milan,Eveline P, AU - Minassian,Angela M, AU - McGregor,Alastair, AU - Morrison,Hazel, AU - Mujadidi,Yama F, AU - Nana,Anusha, AU - O'Reilly,Peter J, AU - Padayachee,Sherman D, AU - Pittella,Ana, AU - Plested,Emma, AU - Pollock,Katrina M, AU - Ramasamy,Maheshi N, AU - Rhead,Sarah, AU - Schwarzbold,Alexandre V, AU - Singh,Nisha, AU - Smith,Andrew, AU - Song,Rinn, AU - Snape,Matthew D, AU - Sprinz,Eduardo, AU - Sutherland,Rebecca K, AU - Tarrant,Richard, AU - Thomson,Emma C, AU - Török,M Estée, AU - Toshner,Mark, AU - Turner,David P J, AU - Vekemans,Johan, AU - Villafana,Tonya L, AU - Watson,Marion E E, AU - Williams,Christopher J, AU - Douglas,Alexander D, AU - Hill,Adrian V S, AU - Lambe,Teresa, AU - Gilbert,Sarah C, AU - Pollard,Andrew J, AU - ,, Y1 - 2020/12/08/ PY - 2020/11/24/received PY - 2020/12/01/revised PY - 2020/12/03/accepted PY - 2020/12/12/pubmed PY - 2021/2/2/medline PY - 2020/12/11/entrez SP - 99 EP - 111 JF - Lancet (London, England) JO - Lancet VL - 397 IS - 10269 N2 - 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 × 1010 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; pinteraction=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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/33306989/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(20)32661-1 DB - PRIME DP - Unbound Medicine ER -