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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.
Lancet. 2021 03 06; 397(10277):881-891.Lct

Abstract

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.

Authors+Show Affiliations

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Institute of Global Health, University of Siena, Siena, Italy; Department of Paediatrics, University of Oxford, Oxford, UK.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg, South Africa.Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases 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, Oxford, 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.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases 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, Cape Town, South Africa; Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, 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, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, 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, University of Southampton, 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, UK.St George's Vaccine Institute, St George's, University of London, London, 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.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, 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.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg, South Africa.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg, South Africa.South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg, South Africa.Severn Pathology, North Bristol NHS Trust, Bristol, UK.NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK.Department of Infection, Hull University Teaching Hospitals NHS Trust, Hull, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.Escola Bahiana de Medicina e Saúde Pública, Salvador, Braziland Hospital São Rafael, Salvador, Brazil; Instituto D'Or, Salvador, Brazil.Universidade Federal do Rio Grande do Norte, Natal, Brazil.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.London Northwest University Healthcare, Harrow, 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.Setshaba Research Centre, Pretoria, South Africa.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Hospital Quinta D'Or, Rede D'Or, 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.Jenner Institute, Nuffield Department of Medicine, 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.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.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.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, Dept of Medicine, University of Cambridge and NIHR Cambridge Clinical Research Facility, Cambridge University Hospital and Royal Papworth NHS Foundation Trusts, Cambridge, UK.University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.AstraZeneca BioPharmaceuticals, Cambridge, UK.Public Health Wales, Cardiff, Wales; Aneurin Bevan University Health Board, Newport, Wales.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Jenner Institute, Nuffield Department of Medicine, University of Oxford, 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
Meta-Analysis
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33617777

Citation

Voysey, Merryn, et al. "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." Lancet (London, England), vol. 397, no. 10277, 2021, pp. 881-891.
Voysey M, Costa Clemens SA, Madhi SA, et al. 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. Lancet. 2021;397(10277):881-891.
Voysey, M., Costa Clemens, S. A., 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., Clutterbuck, E. A., Collins, A. M., Cutland, C. L., Darton, T. C., Dheda, K., Dold, C., ... Pollard, A. J. (2021). 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. Lancet (London, England), 397(10277), 881-891. https://doi.org/10.1016/S0140-6736(21)00432-3
Voysey M, et al. 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. Lancet. 2021 03 6;397(10277):881-891. PubMed PMID: 33617777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Voysey,Merryn, AU - Costa Clemens,Sue Ann, 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 - Clutterbuck,Elizabeth A, AU - Collins,Andrea M, AU - Cutland,Clare L, AU - Darton,Thomas C, AU - Dheda,Keertan, AU - Dold,Christina, AU - Duncan,Christopher J A, AU - Emary,Katherine R W, AU - Ewer,Katie J, AU - Flaxman,Amy, AU - Fairlie,Lee, AU - Faust,Saul N, AU - Feng,Shuo, AU - Ferreira,Daniela M, AU - Finn,Adam, AU - Galiza,Eva, AU - Goodman,Anna L, AU - Green,Catherine M, AU - Green,Christopher A, AU - Greenland,Melanie, AU - Hill,Catherine, AU - Hill,Helen C, AU - Hirsch,Ian, AU - Izu,Alane, AU - Jenkin,Daniel, AU - Joe,Carina C D, AU - Kerridge,Simon, AU - Koen,Anthonet, AU - Kwatra,Gaurav, AU - Lazarus,Rajeka, AU - Libri,Vincenzo, AU - Lillie,Patrick J, AU - Marchevsky,Natalie G, AU - Marshall,Richard P, AU - Mendes,Ana V A, AU - Milan,Eveline P, AU - Minassian,Angela M, AU - McGregor,Alastair, AU - Mujadidi,Yama F, AU - Nana,Anusha, AU - Padayachee,Sherman D, AU - Phillips,Daniel J, AU - Pittella,Ana, AU - Plested,Emma, AU - Pollock,Katrina M, AU - Ramasamy,Maheshi N, AU - Ritchie,Adam J, AU - Robinson,Hannah, AU - Schwarzbold,Alexandre V, AU - Smith,Andrew, AU - Song,Rinn, AU - Snape,Matthew D, AU - Sprinz,Eduardo, AU - Sutherland,Rebecca K, AU - Thomson,Emma C, AU - Török,M Estée, AU - Toshner,Mark, AU - Turner,David P J, AU - Vekemans,Johan, AU - Villafana,Tonya L, AU - White,Thomas, 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 - 2021/02/19/ PY - 2021/01/27/received PY - 2021/02/10/revised PY - 2021/02/11/accepted PY - 2021/2/23/pubmed PY - 2021/3/18/medline PY - 2021/2/22/entrez SP - 881 EP - 891 JF - Lancet (London, England) JO - Lancet VL - 397 IS - 10277 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/33617777/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(21)00432-3 DB - PRIME DP - Unbound Medicine ER -