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

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.

Figure 1

Solicited local (A) and systemic (B) adverse reactions in first 7 days after vaccination as recorded in participant symptom electronic diaries Day 0 is the day of vaccination. P=60-min post-vaccination observation period in the clinic. MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine. *Mild: 38·0°C to <38·5°C; moderate: 38·5°C to <39·0°C; severe: ≥39·0°C. †Self-reported feeling of feverishness.

Figure 1

Solicited local (A) and systemic (B) adverse reactions in first 7 days after vaccination as recorded in participant symptom electronic diaries Day 0 is the day of vaccination. P=60-min post-vaccination observation period in the clinic. MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine. *Mild: 38·0°C to <38·5°C; moderate: 38·5°C to <39·0°C; severe: ≥39·0°C. †Self-reported feeling of feverishness.

Figure 2

Solicited local (A) and systemic (B) adverse reactions in first 7 days after priming and booster doses of ChAdOx1 nCoV-19 in the non-randomised subset of ten participants Day 0 is the day of vaccination. P=60-min post-vaccination observation period in the clinic. *Mild: 38·0°C to <38·5°C; moderate: 38·5°C to <39·0°C; severe: ≥39·0°C. †Self-reported feeling of feverishness.

Figure 3

SARS-CoV-2 IgG response by standardised ELISA to spike protein in trial participants (A) and in 180 convalescent plasma samples from 172 patients with PCR-confirmed COVID-19 and eight asymptomatic health-care workers (B) Error bars show median (IQR). Participants in the prime boost group received their second dose at day 28. Lower limit of quantification is 1 ELISA unit. Red stars in panel B show five samples also tested on the Marburg VN assay (see figure 4). MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Figure 4

Live SARS-CoV-2 neutralisation assays (Marburg VN and PHE PRNT₅₀) and microneutralisation assays (PHE MNA) Panels A and B show live SARS-CoV-2 neutralisation (Marburg VN) in prime (A) and prime boost (B) trial participants (boosted at day 28) and convalescent plasma from patients with PCR-confirmed COVID-19 and asymptomatic health-care workers. Panels C, E, and F show the PHE MNA (at IC₅₀, IC₈₀, and IC₉₀, respectively) and panel D the PHE PRNT₅₀. The day 42 timepoint was only measured in participants who received a booster dose at day 28. Solid lines connect samples from the same participant. Boxes show median (IQR). Dotted lines show upper limits of detection. MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine. PHE=Public Health England. MNA=microneutralisation assay. PRNT=plaque reduction neutralisation test. VN=virus neutralisation. IC=inhibitory concentration. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. *ELISA results for these five convalescent plasma samples are shown in figure 3 as red stars.

Figure 5

PseudoNA results in trial participants and in convalescent plasma samples from 146 patients with PCR-confirmed COVID-19 and 24 asymptomatic health-care workers Solid lines connect samples from the same participant. Boxes show median (IQR). Results for days 35 and 42 are samples from participants who received a booster dose at day 28. IC=inhibitory concentration. MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine.

Figure 6

Interferon-γ ELISpot response to peptides spanning the SARS-CoV-2 spike vaccine insert Error bars show median (IQR). The lower limit of detection, indicated with the dotted line, is 48 spot-forming cells per million PBMCs. PBMC=peripheral blood mononuclear cell. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. ELISpot=enzyme linked immunospot. MenACWY=meningococcal group A, C, W-135, and Y conjugate vaccine.