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
Pedro M Folegatti, Katie J Ewer, Parvinder K Aley, Brian Angus, Stephan Becker, Sandra Belij-Rammerstorfer, Duncan Bellamy, Sagida Bibi, Mustapha Bittaye, Elizabeth A Clutterbuck, Christina Dold, Saul N Faust, Adam Finn, Amy L Flaxman, Bassam Hallis, Paul Heath, Daniel Jenkin, Rajeka Lazarus, Rebecca Makinson, Angela M Minassian, Katrina M Pollock, Maheshi Ramasamy, Hannah Robinson, Matthew Snape, Richard Tarrant, Merryn Voysey, Catherine Green, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Andrew J Pollard, Oxford COVID Vaccine Trial Group
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.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Figures
References
- WHO . World Health Organization; Geneva: 2020. Coronavirus disease (COVID-19) situation report—181.
- WHO Draft Landscape of COVID-19 candidate vaccines. July 14, 2020.
- Fidler S, Stöhr W, Pace M. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet. 2020;395:888–898.
- Hanke T. Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials. Expert Rev Vaccines. 2019;18:1029–1041.
- Mothe B, Manzardo C, Sanchez-Bernabeu A. Therapeutic vaccination refocuses T-cell responses towards conserved regions of HIV-1 in early treated individuals (BCN 01 study) EClinicalMedicine. 2019;11:65–80.
- Coughlan L, Sridhar S, Payne R. Heterologous two-dose vaccination with simian adenovirus and poxvirus vectors elicits long-lasting cellular immunity to influenza virus A in healthy adults. EBioMedicine. 2018;29:146–154.
- van Doremalen N, Haddock E, Feldmann F. A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques. Sci Adv. 2020;6
- Folegatti PM, Bittaye M, Flaxman A. Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial. Lancet Infect Dis. 2020;20:816–826.
- van Doremalen N. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. BioRxiv. 2020 doi: 10.1101/2020.05.13.093195. published online May 13. (preprint)
- Dicks MD, Spencer AJ, Edwards NJ. A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity. PLoS One. 2012;7
- Morris SJ, Turner AV, Green N, Warimwe GM. Laboratory-scale production of replication-deficient adenovirus vectored vaccines. Methods Mol Biol. 2016;1349:121–135.
- Bliss CM, Bowyer G, Anagnostou NA. Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP. Sci Rep. 2018;8
- Folegatti PM, Bellamy D, Roberts R. Safety and immunogenicity of a novel recombinant simian adenovirus ChAdOx2 as a vectored vaccine. Vaccines (Basel) 2019;7:40.
- Ewer K, Rampling T, Venkatraman N. A monovalent chimpanzee adenovirus ebola vaccine boosted with MVA. N Engl J Med. 2016;374:1635–1646.
- Hesse EM, Shimabukuro TT, Su JR. Postlicensure safety surveillance of recombinant zoster vaccine (Shingrix)—United States, October 2017–June 2018. MMWR Morb Mortal Wkly Rep. 2019;68:91–94.
- Yu J, Tostanoski LH, Peter L. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science. 2020 doi: 10.1126/science.abc6284. published online May 20.
- Robbiani DF, Gaebler C, Muecksch F. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. 2020 doi: 10.1038/s41586-020-2456-9. published online June 18.
- Wang X, Guo X, Xin Q. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa721ciaa721. published online June 4.
- Deng W, Bao L, Liu J. Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science. 2020 doi: 10.1126/science.abc5343. published online July 2.
- Grifoni A, Weiskopf D, Ramirez SI. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020;181:1489. 501.e15.
- Sekine T, Perez-Potti A, Rivera-Ballesteros O. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. bioRxiv. 2020 doi: 10.1101/2020.06.29.174888. published online June 29. (preprint)
- Weiskopf D, Schmitz KS, Raadsen MP. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol. 2020;5
- Bolles M, Deming D, Long K. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011;85:12201–12215.
- Liu L, Wei Q, Lin Q. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4
- Weingartl H, Czub M, Czub S. Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets. J Virol. 2004;78:12672–12676.
Source: PubMed