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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.
Lancet. 2020 08 15; 396(10249):467-478.Lct

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 Gieβen-Marburg-Langen.

Authors+Show Affiliations

The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Institute of Virology, Philipps University of Marburg, Marburg, Germany.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK.School of Population Health Sciences, University of Bristol, Bristol, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.National Infection Service, Public Health England, Salisbury, UK.Vaccine Institute, St George's University, London, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Department of Microbiology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR Imperial Clinical Research Facility, Imperial College London, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.The Jenner Institute, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address: andrew.pollard@paediatrics.ox.ac.uk.No affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32702298

Citation

Folegatti, Pedro M., et al. "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." Lancet (London, England), vol. 396, no. 10249, 2020, pp. 467-478.
Folegatti PM, Ewer KJ, Aley PK, et al. 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. Lancet. 2020;396(10249):467-478.
Folegatti, P. M., Ewer, K. J., Aley, P. K., Angus, B., Becker, S., Belij-Rammerstorfer, S., Bellamy, D., Bibi, S., Bittaye, M., Clutterbuck, E. A., Dold, C., Faust, S. N., Finn, A., Flaxman, A. L., Hallis, B., Heath, P., Jenkin, D., Lazarus, R., Makinson, R., ... Pollard, A. J. (2020). 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. Lancet (London, England), 396(10249), 467-478. https://doi.org/10.1016/S0140-6736(20)31604-4
Folegatti PM, et al. 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. Lancet. 2020 08 15;396(10249):467-478. PubMed PMID: 32702298.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. 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 - ,, Y1 - 2020/07/20/ PY - 2020/07/08/received PY - 2020/07/14/revised PY - 2020/07/14/accepted PY - 2020/7/24/pubmed PY - 2020/8/25/medline PY - 2020/7/24/entrez SP - 467 EP - 478 JF - Lancet (London, England) JO - Lancet VL - 396 IS - 10249 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 Gieβen-Marburg-Langen. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/32702298/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(20)31604-4 DB - PRIME DP - Unbound Medicine ER -