Abstract
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 (R2=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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 467-478 |
| Number of pages | 12 |
| Journal | The Lancet |
| Volume | 396 |
| Issue number | 10249 |
| DOIs | |
| State | Published - Aug 15 2020 |
ASJC Scopus subject areas
- Medicine(all)
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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. / Folegatti, Pedro M.; Ewer, Katie J.; Aley, Parvinder K.; Angus, Brian; Becker, Stephan; Belij-Rammerstorfer, Sandra; Bellamy, Duncan; Bibi, Sagida; Bittaye, Mustapha; Clutterbuck, Elizabeth A.; Dold, Christina; Faust, Saul N.; Finn, Adam; Flaxman, Amy L.; Hallis, Bassam; Heath, Paul; Jenkin, Daniel; Lazarus, Rajeka; Makinson, Rebecca; Minassian, Angela M.; Pollock, Katrina M.; Ramasamy, Maheshi; Robinson, Hannah; Snape, Matthew; Tarrant, Richard; Voysey, Merryn; Green, Catherine; Douglas, Alexander D.; Hill, Adrian V.S.; Lambe, Teresa; Gilbert, Sarah C.; Pollard, Andrew J.; Aboagye, Jeremy; Adams, Kelly; Ali, Aabidah; Allen, Elizabeth; Allison, Jennifer L.; Anslow, Rachel; Arbe-Barnes, Edward H.; Babbage, Gavin; Baillie, Kenneth; Baker, Megan; Baker, Natalie; Baker, Philip; Baleanu, Ioana; Ballaminut, Juliana; Barnes, Eleanor; Barrett, Jordan; Bates, Louise; Batten, Alexander; Beadon, Kirsten; Beckley, Rebecca; Berrie, Eleanor; Berry, Lisa; Beveridge, Amy; Bewley, Kevin R.; Bijker, Else Margreet; Bingham, Tracey; Blackwell, Luke; Blundell, Caitlin L.; Bolam, Emma; Boland, Elena; Borthwick, Nicola; Bower, Thomas; Boyd, Amy; Brenner, Tanja; Bright, Philip D.; Brown-O'Sullivan, Charlie; Brunt, Emily; Burbage, Jamie; Burge, Sharon; Buttigieg, Karen R.; Byard, Nicholas; Cabera Puig, Ingrid; Calvert, Anna; Camara, Susana; Cao, Michelangelo; Cappuccini, Federica; Carr, Melanie; Carroll, Miles W.; Carter, Victoria; Cathie, Katrina; Challis, Ruth J.; Charlton, Sue; Chelysheva, Irina; Cho, Jee Sun; Cicconi, Paola; Cifuentes, Liliana; Clark, Helen; Clark, Elizabeth; Cole, Tom; Colin-Jones, Rachel; Conlon, Christopher P.; Cook, Aislinn; Coombes, Naomi S.; Cooper, Rachel; Cosgrove, Catherine A.; Coy, Karen; Crocker, Wendy E.M.; Cunningham, Christina J.; Damratoski, Brad E.; Dando, Lynne; Datoo, Mehreen S.; Davies, Hannah; De Graaf, Hans; Demissie, Tesfaye; Di Maso, Claudio; Dietrich, Isabelle; Dong, Tao; Donnellan, Francesca R.; Douglas, Naomi; Downing, Charlotte; Drake, Jonathan; Drake-Brockman, Rachael; Drury, Ruth Elizabeth; Dunachie, Susanna Jane; Edwards, Nick J.; Edwards, Frances D.L.; Edwards, Chris J.; Elias, Sean C.; Elmore, Michael J.; Emary, Katherine R.W.; English, Marcus Rex; Fagerbrink, Susanne; Felle, Sally; Feng, Shuo; Field, Samantha; Fixmer, Carine; Fletcher, Clare; Ford, Karen J.; Fowler, Jamie; Fox, Polly; Francis, Emma; Frater, John; Furze, Julie; Fuskova, Michelle; Galiza, Eva; Gbesemete, Diane; Gilbride, Ciaran; Godwin, Kerry; Gorini, Giacomo; Goulston, Lyndsey; Grabau, Caroline; Gracie, Lara; Gray, Zoe; Guthrie, Lucy Belle; Hackett, Mark; Halwe, Sandro; Hamilton, Elizabeth; Hamlyn, Joseph; Hanumunthadu, Brama; Harding, Irasha; Harris, Stephanie A.; Harris, Andrew; Harrison, Daisy; Harrison, Clare; Hart, Thomas C.; Haskell, Louise; Hawkins, Sophia; Head, Ian; Henry, John Aaron; Hill, Jennifer; Hodgson, Susanne H.C.; Hou, Mimi M.; Howe, Elizabeth; Howell, Nicola; Hutlin, Cecilia; Ikram, Sabina; Isitt, Catherine; Iveson, Poppy; Jackson, Susan; Jackson, Frederic; James, Sir William; Jenkins, Megan; Jones, Elizabeth; Jones, Kathryn; Jones, Christine E.; Jones, Bryony; Kailath, Reshma; Karampatsas, Konstantinos; Keen, Jade; Kelly, Sarah; Kelly, Dearbhla; Kerr, David; Kerridge, Simon; Khan, Liaquat; Khan, Uzma; Killen, Annabel; Kinch, Jasmin; King, Thomas B.; King, Lloyd; King, Jade; Kingham-Page, Lucy; Klenerman, Paul; Knapper, Francesca; Knight, Julian C.; Knott, Daniel; Koleva, Stanislava; Kupke, Alexandra; Larkworthy, Colin W.; Larwood, Jessica P.J.; Laskey, Anna; Lawrie, Alison M.; Lee, Arlene; Ngan Lee, Kim Yee; Lees, Emily A.; Legge, Helen; Lelliott, Alice; Lemm, Nana Marie; Lias, Amelia M.; Linder, Aline; Lipworth, Samuel; Liu, Xinxue; Liu, Shuchang; Lopez Ramon, Raquel; Lwin, May; Mabesa, Francesca; Madhavan, Meera; Mallett, Garry; Mansatta, Kushal; Marcal, Ines; Marinou, Spyridoula; Marlow, Emma; Marshall, Julia L.; Martin, Jane; McEwan, Joanne; McInroy, Lorna; Meddaugh, Gretchen; Mentzer, Alexander J.; Mirtorabi, Neginsadat; Moore, Maria; Moran, Edward; Morey, Ella; Morgan, Victoria; Morris, Susan Jane; Morrison, Hazel; Morshead, Gertraud; Morter, Richard; Mujadidi, Yama F.; Muller, Jilly; Munera-Huertas, Tatiana; Munro, Claire; Munro, Alasdair; Murphy, Sarah; Munster, Vincent J.; Mweu, Philomena; Noé, Andrés; Nugent, Fay L.; Nuthall, Elizabeth; O'Brien, Katie; O'Connor, Daniel; Oguti, Blanché; Oliver, Jennifer L.; Oliveira, Catarina; O'Reilly, Peter John; Osborn, Mairead; Osborne, Piper; Owen, Cathy; Owens, Daniel; Owino, Nelly; Pacurar, Mihaela; Parker, Kaye; Parracho, Helena; Patrick-Smith, Maia; Payne, Victoria; Pearce, Jennifer; Peng, Yanchun; Peralta Alvarez, Marco Polo; Perring, James; Pfafferott, Katja; Pipini, Dimitra; Plested, Emma; Pluess-Hall, Helen; Pollock, Katrina; Poulton, Ian; Presland, Laura; Provstgaard-Morys, Samuel; Pulido, David; Radia, Kajal; Ramos Lopez, Fernando; Rand, Jade; Ratcliffe, Helen; Rawlinson, Thomas; Rhead, Sarah; Riddell, Amy; Ritchie, Adam John; Roberts, Hannah; Robson, Joanna; Roche, Sophie; Rohde, Cornelius; Rollier, Christine S.; Romani, Rossana; Rudiansyah, Indra; Saich, Stephen; Sajjad, Sara; Salvador, Stephannie; Sanchez Riera, Lidia; Sanders, Helen; Sanders, Katherine; Sapaun, Shari; Sayce, Chloe; Schofield, Ella; Screaton, Gavin; Selby, Beatrice; Semple, Calum; Sharpe, Hannah R.; Shaik, Imam; Shea, Adam; Shelton, Holly; Silk, Sarah; Silva-Reyes, Laura; Skelly, Donal T.; Smee, Heather; Smith, Catherine C.; Smith, David J.; Song, Rinn; Spencer, Alexandra J.; Stafford, Elizabeth; Steele, Amy; Stefanova, Elena; Stockdale, Lisa; Szigeti, Anna; Tahiri-Alaoui, Abdessamad; Tait, Moira; Talbot, Helen; Tanner, Rachel; Taylor, Iona Jennifer; Taylor, Victoria; Te Water Naude, Rebecca; Thakur, Nazia; Themistocleous, Yrene; Themistocleous, Andreas; Thomas, Merin; Thomas, Tonia M.; Thompson, Amber; Thomson-Hill, Samantha; Tomlins, Jennifer; Tonks, Susan; Towner, James; Tran, Nguyen; Tree, Julia A.; Truby, Adam; Turkentine, Kate; Turner, Cheryl; Turner, Nicola; Turner, Sally; Tuthill, Toby; Ulaszewska, Marta; Varughese, Rachel; Van Doremalen, Neeltje; Veighey, Kristin; Verheul, Marije K.; Vichos, Iason; Vitale, Elia; Walker, Laura; Watson, Marion E.E.; Welham, Benjamin; Wheat, Julie; White, Caroline; White, Rachel; Worth, Andrew T.; Wright, Danny; Wright, Suzie; Yao, Xin Li; Yau, Yasmine.
In: The Lancet, Vol. 396, No. 10249, 15.08.2020, p. 467-478.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2
T2 - a preliminary report of a phase 1/2, single-blind, randomised controlled trial
AU - Folegatti, Pedro M.
AU - Ewer, Katie J.
AU - Aley, Parvinder K.
AU - Angus, Brian
AU - Becker, Stephan
AU - Belij-Rammerstorfer, Sandra
AU - Bellamy, Duncan
AU - Bibi, Sagida
AU - Bittaye, Mustapha
AU - Clutterbuck, Elizabeth A.
AU - Dold, Christina
AU - Faust, Saul N.
AU - Finn, Adam
AU - Flaxman, Amy L.
AU - Hallis, Bassam
AU - Heath, Paul
AU - Jenkin, Daniel
AU - Lazarus, Rajeka
AU - Makinson, Rebecca
AU - Minassian, Angela M.
AU - Pollock, Katrina M.
AU - Ramasamy, Maheshi
AU - Robinson, Hannah
AU - Snape, Matthew
AU - Tarrant, Richard
AU - Voysey, Merryn
AU - Green, Catherine
AU - Douglas, Alexander D.
AU - Hill, Adrian V.S.
AU - Lambe, Teresa
AU - Gilbert, Sarah C.
AU - Pollard, Andrew J.
AU - Aboagye, Jeremy
AU - Adams, Kelly
AU - Ali, Aabidah
AU - Allen, Elizabeth
AU - Allison, Jennifer L.
AU - Anslow, Rachel
AU - Arbe-Barnes, Edward H.
AU - Babbage, Gavin
AU - Baillie, Kenneth
AU - Baker, Megan
AU - Baker, Natalie
AU - Baker, Philip
AU - Baleanu, Ioana
AU - Ballaminut, Juliana
AU - Barnes, Eleanor
AU - Barrett, Jordan
AU - Bates, Louise
AU - Batten, Alexander
AU - Beadon, Kirsten
AU - Beckley, Rebecca
AU - Berrie, Eleanor
AU - Berry, Lisa
AU - Beveridge, Amy
AU - Bewley, Kevin R.
AU - Bijker, Else Margreet
AU - Bingham, Tracey
AU - Blackwell, Luke
AU - Blundell, Caitlin L.
AU - Bolam, Emma
AU - Boland, Elena
AU - Borthwick, Nicola
AU - Bower, Thomas
AU - Boyd, Amy
AU - Brenner, Tanja
AU - Bright, Philip D.
AU - Brown-O'Sullivan, Charlie
AU - Brunt, Emily
AU - Burbage, Jamie
AU - Burge, Sharon
AU - Buttigieg, Karen R.
AU - Byard, Nicholas
AU - Cabera Puig, Ingrid
AU - Calvert, Anna
AU - Camara, Susana
AU - Cao, Michelangelo
AU - Cappuccini, Federica
AU - Carr, Melanie
AU - Carroll, Miles W.
AU - Carter, Victoria
AU - Cathie, Katrina
AU - Challis, Ruth J.
AU - Charlton, Sue
AU - Chelysheva, Irina
AU - Cho, Jee Sun
AU - Cicconi, Paola
AU - Cifuentes, Liliana
AU - Clark, Helen
AU - Clark, Elizabeth
AU - Cole, Tom
AU - Colin-Jones, Rachel
AU - Conlon, Christopher P.
AU - Cook, Aislinn
AU - Coombes, Naomi S.
AU - Cooper, Rachel
AU - Cosgrove, Catherine A.
AU - Coy, Karen
AU - Crocker, Wendy E.M.
AU - Cunningham, Christina J.
AU - Damratoski, Brad E.
AU - Dando, Lynne
AU - Datoo, Mehreen S.
AU - Davies, Hannah
AU - De Graaf, Hans
AU - Demissie, Tesfaye
AU - Di Maso, Claudio
AU - Dietrich, Isabelle
AU - Dong, Tao
AU - Donnellan, Francesca R.
AU - Douglas, Naomi
AU - Downing, Charlotte
AU - Drake, Jonathan
AU - Drake-Brockman, Rachael
AU - Drury, Ruth Elizabeth
AU - Dunachie, Susanna Jane
AU - Edwards, Nick J.
AU - Edwards, Frances D.L.
AU - Edwards, Chris J.
AU - Elias, Sean C.
AU - Elmore, Michael J.
AU - Emary, Katherine R.W.
AU - English, Marcus Rex
AU - Fagerbrink, Susanne
AU - Felle, Sally
AU - Feng, Shuo
AU - Field, Samantha
AU - Fixmer, Carine
AU - Fletcher, Clare
AU - Ford, Karen J.
AU - Fowler, Jamie
AU - Fox, Polly
AU - Francis, Emma
AU - Frater, John
AU - Furze, Julie
AU - Fuskova, Michelle
AU - Galiza, Eva
AU - Gbesemete, Diane
AU - Gilbride, Ciaran
AU - Godwin, Kerry
AU - Gorini, Giacomo
AU - Goulston, Lyndsey
AU - Grabau, Caroline
AU - Gracie, Lara
AU - Gray, Zoe
AU - Guthrie, Lucy Belle
AU - Hackett, Mark
AU - Halwe, Sandro
AU - Hamilton, Elizabeth
AU - Hamlyn, Joseph
AU - Hanumunthadu, Brama
AU - Harding, Irasha
AU - Harris, Stephanie A.
AU - Harris, Andrew
AU - Harrison, Daisy
AU - Harrison, Clare
AU - Hart, Thomas C.
AU - Haskell, Louise
AU - Hawkins, Sophia
AU - Head, Ian
AU - Henry, John Aaron
AU - Hill, Jennifer
AU - Hodgson, Susanne H.C.
AU - Hou, Mimi M.
AU - Howe, Elizabeth
AU - Howell, Nicola
AU - Hutlin, Cecilia
AU - Ikram, Sabina
AU - Isitt, Catherine
AU - Iveson, Poppy
AU - Jackson, Susan
AU - Jackson, Frederic
AU - James, Sir William
AU - Jenkins, Megan
AU - Jones, Elizabeth
AU - Jones, Kathryn
AU - Jones, Christine E.
AU - Jones, Bryony
AU - Kailath, Reshma
AU - Karampatsas, Konstantinos
AU - Keen, Jade
AU - Kelly, Sarah
AU - Kelly, Dearbhla
AU - Kerr, David
AU - Kerridge, Simon
AU - Khan, Liaquat
AU - Khan, Uzma
AU - Killen, Annabel
AU - Kinch, Jasmin
AU - King, Thomas B.
AU - King, Lloyd
AU - King, Jade
AU - Kingham-Page, Lucy
AU - Klenerman, Paul
AU - Knapper, Francesca
AU - Knight, Julian C.
AU - Knott, Daniel
AU - Koleva, Stanislava
AU - Kupke, Alexandra
AU - Larkworthy, Colin W.
AU - Larwood, Jessica P.J.
AU - Laskey, Anna
AU - Lawrie, Alison M.
AU - Lee, Arlene
AU - Ngan Lee, Kim Yee
AU - Lees, Emily A.
AU - Legge, Helen
AU - Lelliott, Alice
AU - Lemm, Nana Marie
AU - Lias, Amelia M.
AU - Linder, Aline
AU - Lipworth, Samuel
AU - Liu, Xinxue
AU - Liu, Shuchang
AU - Lopez Ramon, Raquel
AU - Lwin, May
AU - Mabesa, Francesca
AU - Madhavan, Meera
AU - Mallett, Garry
AU - Mansatta, Kushal
AU - Marcal, Ines
AU - Marinou, Spyridoula
AU - Marlow, Emma
AU - Marshall, Julia L.
AU - Martin, Jane
AU - McEwan, Joanne
AU - McInroy, Lorna
AU - Meddaugh, Gretchen
AU - Mentzer, Alexander J.
AU - Mirtorabi, Neginsadat
AU - Moore, Maria
AU - Moran, Edward
AU - Morey, Ella
AU - Morgan, Victoria
AU - Morris, Susan Jane
AU - Morrison, Hazel
AU - Morshead, Gertraud
AU - Morter, Richard
AU - Mujadidi, Yama F.
AU - Muller, Jilly
AU - Munera-Huertas, Tatiana
AU - Munro, Claire
AU - Munro, Alasdair
AU - Murphy, Sarah
AU - Munster, Vincent J.
AU - Mweu, Philomena
AU - Noé, Andrés
AU - Nugent, Fay L.
AU - Nuthall, Elizabeth
AU - O'Brien, Katie
AU - O'Connor, Daniel
AU - Oguti, Blanché
AU - Oliver, Jennifer L.
AU - Oliveira, Catarina
AU - O'Reilly, Peter John
AU - Osborn, Mairead
AU - Osborne, Piper
AU - Owen, Cathy
AU - Owens, Daniel
AU - Owino, Nelly
AU - Pacurar, Mihaela
AU - Parker, Kaye
AU - Parracho, Helena
AU - Patrick-Smith, Maia
AU - Payne, Victoria
AU - Pearce, Jennifer
AU - Peng, Yanchun
AU - Peralta Alvarez, Marco Polo
AU - Perring, James
AU - Pfafferott, Katja
AU - Pipini, Dimitra
AU - Plested, Emma
AU - Pluess-Hall, Helen
AU - Pollock, Katrina
AU - Poulton, Ian
AU - Presland, Laura
AU - Provstgaard-Morys, Samuel
AU - Pulido, David
AU - Radia, Kajal
AU - Ramos Lopez, Fernando
AU - Rand, Jade
AU - Ratcliffe, Helen
AU - Rawlinson, Thomas
AU - Rhead, Sarah
AU - Riddell, Amy
AU - Ritchie, Adam John
AU - Roberts, Hannah
AU - Robson, Joanna
AU - Roche, Sophie
AU - Rohde, Cornelius
AU - Rollier, Christine S.
AU - Romani, Rossana
AU - Rudiansyah, Indra
AU - Saich, Stephen
AU - Sajjad, Sara
AU - Salvador, Stephannie
AU - Sanchez Riera, Lidia
AU - Sanders, Helen
AU - Sanders, Katherine
AU - Sapaun, Shari
AU - Sayce, Chloe
AU - Schofield, Ella
AU - Screaton, Gavin
AU - Selby, Beatrice
AU - Semple, Calum
AU - Sharpe, Hannah R.
AU - Shaik, Imam
AU - Shea, Adam
AU - Shelton, Holly
AU - Silk, Sarah
AU - Silva-Reyes, Laura
AU - Skelly, Donal T.
AU - Smee, Heather
AU - Smith, Catherine C.
AU - Smith, David J.
AU - Song, Rinn
AU - Spencer, Alexandra J.
AU - Stafford, Elizabeth
AU - Steele, Amy
AU - Stefanova, Elena
AU - Stockdale, Lisa
AU - Szigeti, Anna
AU - Tahiri-Alaoui, Abdessamad
AU - Tait, Moira
AU - Talbot, Helen
AU - Tanner, Rachel
AU - Taylor, Iona Jennifer
AU - Taylor, Victoria
AU - Te Water Naude, Rebecca
AU - Thakur, Nazia
AU - Themistocleous, Yrene
AU - Themistocleous, Andreas
AU - Thomas, Merin
AU - Thomas, Tonia M.
AU - Thompson, Amber
AU - Thomson-Hill, Samantha
AU - Tomlins, Jennifer
AU - Tonks, Susan
AU - Towner, James
AU - Tran, Nguyen
AU - Tree, Julia A.
AU - Truby, Adam
AU - Turkentine, Kate
AU - Turner, Cheryl
AU - Turner, Nicola
AU - Turner, Sally
AU - Tuthill, Toby
AU - Ulaszewska, Marta
AU - Varughese, Rachel
AU - Van Doremalen, Neeltje
AU - Veighey, Kristin
AU - Verheul, Marije K.
AU - Vichos, Iason
AU - Vitale, Elia
AU - Walker, Laura
AU - Watson, Marion E.E.
AU - Welham, Benjamin
AU - Wheat, Julie
AU - White, Caroline
AU - White, Rachel
AU - Worth, Andrew T.
AU - Wright, Danny
AU - Wright, Suzie
AU - Yao, Xin Li
AU - Yau, Yasmine
N1 - Funding Information: This work is funded by UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), Coalition for Epidemic Preparedness Innovations (CEPI), the National Institute for Health Research (NIHR), the NIHR Oxford Biomedical Research Centre, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen. Additional resources for study delivery were provided by NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust; the NIHR Imperial Clinical Research Facility; and NIHR North West London, South London, Wessex, and West of England Local Clinical Research Networks and NIHR Oxford Health Biomedical Research Centre. PMF received funding from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (finance code 001). Development of SARS-CoV-2 reagents was partially supported by the US National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance contract HHSN272201400008C. The research reagent for SARS-CoV-2 RNA (NIBSC 20/130) was obtained from the National Institute for Biological Standards and Control, UK. The control vaccine was provided free of charge by the UK Department of Health and Social Care. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. The University of Oxford has entered into a partnership with AstraZeneca on vaccine development; the authors are grateful to the senior management at AstraZeneca for facilitating and funding the pseudovirus neutralisation assays and Meso Scale antibody assay included in this Article. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. The investigators express their gratitude for the contribution of all the trial participants, the invaluable advice of the international Data Safety Monitoring Board ( appendix p 46 ) and the independent members of the Trial Steering Committee. We additionally acknowledge the broader support from the various teams within the University of Oxford including Medical Sciences Division, Nuffield Department of Medicine and Department of Paediatrics, the Oxford Immunology Network COVID Consortium, Clinical Trials Research Governance, Research Contracts, Public Affairs Directorate and the Clinical Biomanufacturing Facility, as well as the Oxford University Hospitals NHS Foundation Trust and Oxford Health NHS Foundation Trust and the trial sites ( appendix pp 46–48 ). We are grateful for the input of the protein production team at the Jenner Institute and the team at the Pirbright Institute. Funding Information: SCG is co-founder and board member 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 an inventor on a patent application covering this SARS-CoV-2 vaccine and consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care's Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a co-founder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines. AF is a member of JCVI, Chair of the WHO European Technical Advisory Group of Experts on Immunisation, an ex-officio member of WHO SAGE working group on COVID-19 vaccines, and acting director of National Institute for Health Research West of England Local Clinical Research Network. KMP reports grants from the NIHR Imperial Biomedical Research Centre and Gilead Sciences, and personal fees from Sanofi Pasteur, outside of the submitted work. MS reports grants from Janssen, GlaxoSmithKline, Medimmune, Novavax, and MCM and grants and non-financial support from Pfizer, outside of the submitted work. CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work. ADD reports grants and personal fees from AstraZeneca, outside of the submitted work. In addition, ADD has a patent manufacturing process 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. Funding Information: This work is funded by UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), Coalition for Epidemic Preparedness Innovations (CEPI), the National Institute for Health Research (NIHR), the NIHR Oxford Biomedical Research Centre, and the German Center for Infection Research (DZIF), Partner site Gie?en-Marburg-Langen. Additional resources for study delivery were provided by NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust; the NIHR Imperial Clinical Research Facility; and NIHR North West London, South London, Wessex, and West of England Local Clinical Research Networks and NIHR Oxford Health Biomedical Research Centre. PMF received funding from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (finance code 001). Development of SARS-CoV-2 reagents was partially supported by the US National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance contract HHSN272201400008C. The research reagent for SARS-CoV-2 RNA (NIBSC 20/130) was obtained from the National Institute for Biological Standards and Control, UK. The control vaccine was provided free of charge by the UK Department of Health and Social Care. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. The University of Oxford has entered into a partnership with AstraZeneca on vaccine development; the authors are grateful to the senior management at AstraZeneca for facilitating and funding the pseudovirus neutralisation assays and Meso Scale antibody assay included in this Article. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. The investigators express their gratitude for the contribution of all the trial participants, the invaluable advice of the international Data Safety Monitoring Board (appendix p 46) and the independent members of the Trial Steering Committee. We additionally acknowledge the broader support from the various teams within the University of Oxford including Medical Sciences Division, Nuffield Department of Medicine and Department of Paediatrics, the Oxford Immunology Network COVID Consortium, Clinical Trials Research Governance, Research Contracts, Public Affairs Directorate and the Clinical Biomanufacturing Facility, as well as the Oxford University Hospitals NHS Foundation Trust and Oxford Health NHS Foundation Trust and the trial sites (appendix pp 46?48). We are grateful for the input of the protein production team at the Jenner Institute and the team at the Pirbright Institute. Publisher Copyright: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
PY - 2020/8/15
Y1 - 2020/8/15
N2 - 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 (R2=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.
AB - 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 (R2=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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U2 - 10.1016/S0140-6736(20)31604-4
DO - 10.1016/S0140-6736(20)31604-4
M3 - Article
C2 - 32702298
AN - SCOPUS:85088146774
VL - 396
SP - 467
EP - 478
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10249
ER -