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.
Bibliographical noteFunding 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.
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.
Open Access: This is an Open Access article under the CC BY-NC-ND 4.0 license.
Publisher Copyright: © 2020 The Author(s). Published by Elsevier Ltd.
Citation: Pedro M Folegatti 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, The Lancet, Volume 396, Issue 10249,
2020, Pages 467-478, ISSN 0140-6736, https://doi.org/10.1016/S0140-6736(20)31604-4.