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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

37 Pages Posted: 1 Feb 2021

See all articles by Merryn Voysey

Merryn Voysey

University of Oxford - Oxford Vaccine Group

Sue Ann Costa Clemens

University of Siena - Institute of Global Health

Shabir A. Madhi

University of the Witwatersrand - South African Medical Research Council Vaccines and Infectious Diseases Analytical Research Unit

Lily Yin Weckx

Federal University of Sao Paulo

Pedro M. Folegatti

University of Oxford - Jenner Institute

Parvinder K. Aley

University of Oxford - Oxford Vaccine Group

Brian John Angus

University of Oxford - Jenner Institute

Vicky Baillie

University of the Witwatersrand

Shaun L. Barnabas

Soweto Clinical Trials Centre

Qasim E. Bhorat

Soweto Clinical Trials Centre

Sagida Bibi

University of Oxford - Oxford Vaccine Group

Carmen Briner

Setshaba Research Centre

Paola Cicconi

University of Oxford - Jenner Institute

Elizabeth Clutterbuck

University of Oxford - Oxford Vaccine Group

Andrea M. Collins

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Clare Cutland

University of the Witwatersrand - South African Medical Research Council Vaccines and Infectious Diseases Analytical Research Unit

Thomas Darton

University of Sheffield - Department of Infection, Immunity and Cardiovascular Disease

Keertan Dheda

University of Cape Town - Centre for Lung Infection and Immunology

Alexander D. Douglas

University of Oxford - Jenner Institute

Christopher J. A. Duncan

Newcastle upon Tyne Hospitals NHS Foundation Trust - Department of Infection and Tropical Medicine

Katherine R. W. Emary

University of Oxford - Oxford Vaccine Group

Katie Ewer

University of Oxford - Jenner Institute

Amy Flaxman

University of Oxford - Jenner Institute

Lee Fairlie

Wits Reproductive Health & HIV Institute (WRHI)

Saul N. Faust

University of Southampton - NIHR Southampton Clinical Research Facility and Biomedical Research Centre

Shuo Feng

University of Oxford - Oxford Vaccine Group

Daniela M. Ferreira

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Adam Finn

University Hospitals Bristol and Weston NHS Foundation Trust; University of Bristol - Cellular and Molecular Medicine

Eva Galiza

University of London - St George's Vaccine Institute

Anna L. Goodman

University College London - Department of Infection

Catherine M. Green

University of Oxford - Clinical BioManufacturing Facility

Christopher A. Green

University Hospitals Birmingham NHS Foundation Trust

Melanie Greenland

University of Oxford - Oxford Vaccine Group

Catherine Hill

University of the Witwatersrand - South African Medical Research Council

Helen C. Hill

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Ian Hirsch

AstraZeneca Pharmaceuticals

Alane Izu

University of the Witwatersrand - South African Medical Research Council

Daniel Jenkin

University of Oxford - Jenner Institute

Simon Kerridge

University of Oxford - Oxford Vaccine Group

Anthonet Koen

University of the Witwatersrand - South African Medical Research Council

Gaurav Kwatra

University of the Witwatersrand - South African Medical Research Council

Rajeka Lazarus

North Bristol NHS Trust - Severn Pathology

Vincenzo Libri

NIHR UCLH Clinical Research Facility

Patrick J. Lillie

Hull University Teaching Hospitals NHS Trust

Natalie G. Marchevsky

University of Oxford - Oxford Vaccine Group

Richard P. Marshall

AstraZeneca Pharmaceuticals

Ana Verena Almeida Mendes

Braziland Hospital São Rafael - Escola Bahiana de Medicina e Saúde Pública

Eveline P. Milan

Universidade Federal do Rio Grande do Norte (UFRN)

Angela M. Minassian

University of Oxford - Jenner Institute

Alastair C. McGregor

London Northwest University Healthcare

Yama Farooq Mujadidi

University of Oxford - Oxford Vaccine Group

Anusha Nana

University of the Witwatersrand - Perinatal HIV Research Unit

Sherman D. Payadachee

Setshaba Research Centre

Daniel J. Phillips

University of Oxford - Oxford Vaccine Group

Ana Pittella

Hospital Quinta D'OR

Emma Plested

University of Oxford - Oxford Vaccine Group

Katrina M. Pollock

NIHR Imperial Clinical Research Facility

Maheshi N. Ramasamy

University of Oxford - Oxford Vaccine Group

Hannah Robinson

University of Oxford - Oxford Vaccine Group

Alexandre V. Schwarzbold

Federal University of Santa Maria (UFSM) - Clinical Research Unit

Andrew Smith

University of Glasgow - College of Medical, Veterinary & Life Sciences

Rinn Song

University of Oxford - Oxford Vaccine Group

Matthew D. Snape

University of Oxford - Oxford Vaccine Group

Eduardo Sprinz

Universidade Federal do Rio Grande do Sul

Rebecca K. Sutherland

Western General Hospital - Clinical Infection Research Group

Emma C. Thomson

Queen Elizabeth University Hospital

Mili Torok

University of Cambridge - Department of Medicine

Mark Toshner

Royal Papworth Hospital - Heart Lung Research Institute

David P. J. Turner

University of Nottingham

Johan Vekemans

AstraZeneca Pharmaceuticals

Tonya L. Villafana

AstraZeneca Pharmaceuticals

Thomas White

AstraZeneca Pharmaceuticals

Christopher J. Williams

Anuerin Bevan University Health Board

Adrian V. S. Hill

University of Oxford - Wellcome Trust Centre for Human Genetics; University of Oxford - Centre for Clinical Vaccinology and Tropical Medicine

Teresa Lambe

University of Oxford - Jenner Institute

Sarah C. Gilbert

University of Oxford - The Jenner Institute

Andrew Pollard

University of Oxford - Oxford Vaccine Group

Oxford COVID Vaccine Trial Group

More...

Abstract

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, MHRA, with a regimen of two standard doses given with an interval of between 4 and 12 weeks. The planned rollout 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 phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and phase I/II clinical trials in the UK and South Africa, against symptomatic disease caused by SARS-CoV-2. The data cut-off date for these analyses was 7th December 2020. The accumulated cases of COVID-19 disease at this cut-off date exceeds the number required for a pre-specified final analysis, which is also presented. As previously described, individuals over 18 years of age were randomised 1:1 to receive two standard doses (SD) of ChAdOx1 nCoV-19 (5x1010 viral particles) or a control vaccine/saline placebo. In the UK trial efficacy cohort a subset of participants received a lower dose (LD, 2.2x1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. All cases with a nucleic acid amplification test (NAAT) were adjudicated for inclusion in the analysis, by a blinded independent endpoint review committee. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.

Findings: 17,177 baseline seronegative trial participants were eligible for inclusion in the efficacy analysis, 8948 in the UK, 6753 in Brazil and 1476 in South Africa, with 619 documented NAAT +ve infections of which 332 met the primary endpoint of symptomatic infection >14 days post dose 2.The primary analysis of overall vaccine efficacy >14 days after the second dose including LD/SD and SD/SD groups, based on the prespecified criteria was 66.7% (57.4%,  74.0%). There were no hospitalisations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control group.Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and modelled 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 day (GMR 0.66, 95% CI 0.59, 0.74).In the SD/SD group, after the second dose, efficacy was higher with a longer prime-boost interval: VE 82.4% 95%CI 62.7%, 91.7% at 12+ weeks, compared with VE 54.9%, 95%CI 32.7%, 69.7% at <6 weeks. These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 2.19 (2.12, 2.26) in those who were 18-55 years of age.

Interpretation: ChAdOx1 nCoV-19 vaccination programmes aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.

Trial Registration: Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.

Funding: UKRI, NIHR, CEPI, 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 Astra Zeneca.

Conflict of Interest: Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19. SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine. TL is named as aninventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project. PMF is a consultant to Vaccitech. AJP is Chair of UK Dept.Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO’sSAGE. AJP and SNF are NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO. AVSH reports personal feesfrom Vaccitech, outside the submitted work and has a patent on ChAdOx1 licensed to Vaccitech, and may benefit from royalty income to the University of Oxford from sales of this vaccine by AstraZeneca and sublicensees. MS reports grants from NIHR, non-financial support fromAstraZeneca, during the conduct of the study; grants from Janssen, grants fromGlaxoSmithKline, grants from Medimmune, grants from Novavax, grants and non-financialsupport from Pfizer, grants from MCM, outside the submitted work. CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work. SNF reports grants from Janssen and Valneva, outside the submitted work. ADD reports grants and personal fees from AstraZeneca, outside of the submitted work. In addition, ADD has a patent manufacturingprocess for ChAdOx vectors with royalties paid to AstraZeneca, and a patent ChAdOx2 vector with royalties paid to AstraZeneca. The other authors declare no competing interests.

Suggested Citation

Voysey, Merryn and Costa Clemens, Sue Ann and Madhi, Shabir A. and Weckx, Lily Yin and Folegatti, Pedro M. and Aley, Parvinder K. and Angus, Brian John and Baillie, Vicky and Barnabas, Shaun L. and Bhorat, Qasim E. and Bibi, Sagida and Briner, Carmen and Cicconi, Paola and Clutterbuck, Elizabeth and Collins, Andrea M. and Cutland, Clare and Darton, Thomas and Dheda, Keertan and Douglas, Alexander D. and Duncan, Christopher J. A. and Emary, Katherine R. W. and Ewer, Katie and Flaxman, Amy and Fairlie, Lee and Faust, Saul N. and Feng, Shuo and Ferreira, Daniela M. and Finn, Adam and Galiza, Eva and Goodman, Anna L. and Green, Catherine M. and Green, Christopher A. and Greenland, Melanie and Hill, Catherine and Hill, Helen C. and Hirsch, Ian and Izu, Alane and Jenkin, Daniel and Kerridge, Simon and Koen, Anthonet and Kwatra, Gaurav and Lazarus, Rajeka and Libri, Vincenzo and Lillie, Patrick J. and Marchevsky, Natalie G. and Marshall, Richard P. and Mendes, Ana Verena Almeida and Milan, Eveline P. and Minassian, Angela M. and McGregor, Alastair C. and Farooq Mujadidi, Yama and Nana, Anusha and Payadachee, Sherman D. and Phillips, Daniel J. and Pittella, Ana and Plested, Emma and Pollock, Katrina M. and Ramasamy, Maheshi N. and Robinson, Hannah and Schwarzbold, Alexandre V. and Smith, Andrew and Song, Rinn and Snape, Matthew D. and Sprinz, Eduardo and Sutherland, Rebecca K. and Thomson, Emma C. and Torok, Mili and Toshner, Mark and Turner, David P. J. and Vekemans, Johan and Villafana, Tonya L. and White, Thomas and Williams, Christopher J. and Hill, Adrian V. S. and Lambe, Teresa and Gilbert, Sarah C. and Pollard, Andrew and Group, Oxford COVID Vaccine Trial, Single Dose Administration, And The Influence Of The Timing Of The Booster Dose On Immunogenicity and Efficacy Of ChAdOx1 nCoV-19 (AZD1222) Vaccine. Available at SSRN: https://ssrn.com/abstract=3777268 or http://dx.doi.org/10.2139/ssrn.3777268

Merryn Voysey

University of Oxford - Oxford Vaccine Group

Sue Ann Costa Clemens

University of Siena - Institute of Global Health

Via Banchi di Sotto, 55
Siena, 53100
Italy

Shabir A. Madhi

University of the Witwatersrand - South African Medical Research Council Vaccines and Infectious Diseases Analytical Research Unit ( email )

Johannesburg
South Africa

Lily Yin Weckx

Federal University of Sao Paulo ( email )

Pedro M. Folegatti

University of Oxford - Jenner Institute

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Parvinder K. Aley

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Brian John Angus

University of Oxford - Jenner Institute

Vicky Baillie

University of the Witwatersrand

1 Jan Smuts Avenue
Johannesburg, GA 2000
South Africa

Shaun L. Barnabas

Soweto Clinical Trials Centre ( email )

Qasim E. Bhorat

Soweto Clinical Trials Centre ( email )

Sagida Bibi

University of Oxford - Oxford Vaccine Group ( email )

United Kingdom

Carmen Briner

Setshaba Research Centre

1 Jan Smuts Avenue
Johannesburg, GA 2000
South Africa

Paola Cicconi

University of Oxford - Jenner Institute

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Elizabeth Clutterbuck

University of Oxford - Oxford Vaccine Group

Andrea M. Collins

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Clare Cutland

University of the Witwatersrand - South African Medical Research Council Vaccines and Infectious Diseases Analytical Research Unit ( email )

7 York Rd
Parktown, Johannesburg 2193
South Africa

Thomas Darton

University of Sheffield - Department of Infection, Immunity and Cardiovascular Disease ( email )

17 Mappin Street
Sheffield, Sheffield S1 4DT
United Kingdom

Keertan Dheda

University of Cape Town - Centre for Lung Infection and Immunology

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

Alexander D. Douglas

University of Oxford - Jenner Institute

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Christopher J. A. Duncan

Newcastle upon Tyne Hospitals NHS Foundation Trust - Department of Infection and Tropical Medicine ( email )

Newcastle
United Kingdom

Katherine R. W. Emary

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Katie Ewer

University of Oxford - Jenner Institute ( email )

Old Road Campus Research Building Roosevelt Drive
Oxford, Oxfordshire OX3 7DQ
United Kingdom

Amy Flaxman

University of Oxford - Jenner Institute

Lee Fairlie

Wits Reproductive Health & HIV Institute (WRHI)

Klein St & Esselen St
Hillbrow, Johannesburg
South Africa

Saul N. Faust

University of Southampton - NIHR Southampton Clinical Research Facility and Biomedical Research Centre

Shuo Feng

University of Oxford - Oxford Vaccine Group

Oxford
United Kingdom

Daniela M. Ferreira

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Adam Finn

University Hospitals Bristol and Weston NHS Foundation Trust

University of Bristol,
Senate House, Tyndall Avenue
Bristol, BS8 ITH
United Kingdom

University of Bristol - Cellular and Molecular Medicine ( email )

United Kingdom

Eva Galiza

University of London - St George's Vaccine Institute ( email )

Senate House
Malet Street
London, WC1E 7HU
United Kingdom

Anna L. Goodman

University College London - Department of Infection ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Catherine M. Green

University of Oxford - Clinical BioManufacturing Facility

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Christopher A. Green

University Hospitals Birmingham NHS Foundation Trust

Mindelsohn Way
Edgbaston
Birmingham, B15 2TH
United Kingdom

Melanie Greenland

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Catherine Hill

University of the Witwatersrand - South African Medical Research Council

296 Umbilo Rd.
Durban 4000
South Africa

Helen C. Hill

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Ian Hirsch

AstraZeneca Pharmaceuticals ( email )

1800 Concord Pike
Wilmington, DE 19803
United States

Alane Izu

University of the Witwatersrand - South African Medical Research Council

296 Umbilo Rd.
Durban 4000
South Africa

Daniel Jenkin

University of Oxford - Jenner Institute

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Simon Kerridge

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Anthonet Koen

University of the Witwatersrand - South African Medical Research Council

296 Umbilo Rd.
Durban 4000
South Africa

Gaurav Kwatra

University of the Witwatersrand - South African Medical Research Council

Rajeka Lazarus

North Bristol NHS Trust - Severn Pathology ( email )

Vincenzo Libri

NIHR UCLH Clinical Research Facility

London
United Kingdom

Patrick J. Lillie

Hull University Teaching Hospitals NHS Trust ( email )

Natalie G. Marchevsky

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Richard P. Marshall

AstraZeneca Pharmaceuticals ( email )

1800 Concord Pike
Wilmington, DE 19803
United States

Ana Verena Almeida Mendes

Braziland Hospital São Rafael - Escola Bahiana de Medicina e Saúde Pública ( email )

Eveline P. Milan

Universidade Federal do Rio Grande do Norte (UFRN) ( email )

PO Box 1524
Natal-RN, 59078970
Brazil

Angela M. Minassian

University of Oxford - Jenner Institute

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Alastair C. McGregor

London Northwest University Healthcare ( email )

Yama Farooq Mujadidi

University of Oxford - Oxford Vaccine Group

Anusha Nana

University of the Witwatersrand - Perinatal HIV Research Unit ( email )

1 Jan Smuts Avenue
Johannesburg, GA Gauteng 2000
South Africa

Sherman D. Payadachee

Setshaba Research Centre ( email )

Soshanguve
South Africa

Daniel J. Phillips

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Ana Pittella

Hospital Quinta D'OR ( email )

Emma Plested

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Katrina M. Pollock

NIHR Imperial Clinical Research Facility

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Maheshi N. Ramasamy

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Hannah Robinson

University of Oxford - Oxford Vaccine Group

Oxford
United Kingdom

Alexandre V. Schwarzbold

Federal University of Santa Maria (UFSM) - Clinical Research Unit ( email )

Santa Maria
Brazil

Andrew Smith

University of Glasgow - College of Medical, Veterinary & Life Sciences

Adam Smith Business School
Glasgow, Scotland G12 8LE
United Kingdom

Rinn Song

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Matthew D. Snape

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Eduardo Sprinz

Universidade Federal do Rio Grande do Sul

Rua Washington Luiz #855
Porto Alegre, 90010460
Brazil

Rebecca K. Sutherland

Western General Hospital - Clinical Infection Research Group ( email )

Edinburgh
United Kingdom

Emma C. Thomson

Queen Elizabeth University Hospital

Glasgow, G51 4TF
United Kingdom

Mili Torok

University of Cambridge - Department of Medicine ( email )

United Kingdom

Mark Toshner

Royal Papworth Hospital - Heart Lung Research Institute

David P. J. Turner

University of Nottingham ( email )

University Park
Nottingham, NG8 1BB
United Kingdom

Johan Vekemans

AstraZeneca Pharmaceuticals ( email )

1800 Concord Pike
Wilmington, DE 19803
United States

Tonya L. Villafana

AstraZeneca Pharmaceuticals ( email )

1800 Concord Pike
Wilmington, DE 19803
United States

Thomas White

AstraZeneca Pharmaceuticals

1800 Concord Pike
Wilmington, DE 19803
United States

Christopher J. Williams

Anuerin Bevan University Health Board ( email )

Newport
United Kingdom

Adrian V. S. Hill

University of Oxford - Wellcome Trust Centre for Human Genetics ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - Centre for Clinical Vaccinology and Tropical Medicine ( email )

Oxford
United Kingdom

Teresa Lambe

University of Oxford - Jenner Institute ( email )

Sarah C. Gilbert

University of Oxford - The Jenner Institute ( email )

Old Road Campus Research Building Roosevelt Drive
Oxford, Oxfordshire OX3 7DQ
United Kingdom

Andrew Pollard (Contact Author)

University of Oxford - Oxford Vaccine Group ( email )

United Kingdom

No contact information is available for Oxford COVID Vaccine Trial Group

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