Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

Abstract

Background: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older.

Methods: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 10¹⁰ virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 10¹⁰ virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA₈₀). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA₈₀ at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48).

Interpretation: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities.

Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Figure 1

Study profile for the low-dose (A) and standard-dose (B) cohorts *One participant excluded from immunogenicity analyses, due to mislabelling of laboratory sample. †Reasons for not receiving boost dose included that the participant moved away or was unavailable for visits, delay in receiving boost dose, or withdrawal of consent.

Figure 2

Solicited local adverse reactions in the 7 days after prime and boost doses of standard-dose vaccine, by age Day 0 is the day of vaccination. Participants shown are those randomly assigned to receive two doses, and data are only shown for participants who received both doses of vaccine.

Figure 3

Solicited systemic adverse reactions in the 7 days after prime and boost doses of standard-dose vaccine, by age Day 0 is the day of vaccination. Feverish is self-reported feeling of feverishness, whereas fever is an objective fever measurement (mild: 38·0 to <38·5°C, moderate: 38·5 to <39·0°C, severe: ≥39·0°C). Participants shown are those randomly assigned to receive two doses, and data are only shown for participants who received both doses of vaccine.

Figure 4

SARS-CoV-2 IgG response to the receptor binding domain in the standard-dose groups (A) and low-dose groups (C) and the spike protein in the standard-dose groups (B) and the low-dose groups (D), by age Datapoints are medians, with whiskers showing the IQRs. Solid lines show participants who were randomly assigned to and received two doses of vaccine and dashed lines indicate participants who were randomly assigned to receive one dose. The vertical black line indicates when participants who received two doses received their boost dose. Data for the control groups are shown in the appendix (p 12)). AU=arbitrary units. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Figure 5

Neutralising antibody titres measured using a live SARS-CoV-2 microneutralisation assay (MNA₈₀) after prime and boost doses of vaccine in standard-dose groups (A) and low-dose groups (B), by age Datapoints are medians, with whiskers showing the IQR. Solid lines show participants who were randomly assigned to and received two doses of vaccine and dashed lines indicate participants who were randomly assigned to receive one dose. Horizontal dotted lines show upper and lower limits of assay (values outside this range set to 640 beyond the upper limit and 5 beyond the lower limit). Data for the control groups are shown in the appendix (p 14)). To normalise data across assay runs, a reference sample was included in all assay runs and test samples normalised to this value by generating log₁₀ ratios. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Figure 6

IFN-γ ELISpot response to peptides spanning the SARS-CoV-2 spike insert after prime and boost doses of vaccine for all participants who were given two doses of vaccine, by age group and vaccine dose ELISpot data were unavailable for the 18–55 years low-dose group because PBMCs were not collected in this group. Datapoints are medians, with whiskers showing the IQR. The lower limit of detection is 48 SFCs per million PBMCs (horizontal dotted line). Day 42 samples are from participants who received the boost dose at day 28 (vertical dotted line). Data for both one-dose and two-dose groups, with numbers analysed at each timepoint, are in the appendix (p 15)). ELISpot=enzyme-linked immunospot. PBMC=peripheral blood mononuclear cells. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. SFC=spot-forming cells.

Figure 7

Anti-ChAdOx1 vector neutralising titres after prime and boost doses of vaccine, by age and vaccine dose, and the correlation between pre-boost dose anti-ChAdOx1 neutralising antibodies and 28 days after boost dose antibody and T-cell responses (A) Anti-ChAdOx1 neutralising antibody titres in participants who received ChAdOx1 nCoV-19 vaccine by age and dose: datapoints are medians, with whiskers showing the IQR. Values below the limit of detection were assigned a value of 1. (B) Anti-ChAdOx1 neutralising antibody titre immediately before boost dose of vaccine versus standardised IgG ELISA against SARS-CoV-2 spike 28 days after the boost dose of vaccine with linear regression of logged values (p=0·037). (C) Anti-ChAdOx1 neutralising antibody titres immediately before boost dose of vaccine versus SARS-CoV-2 spike specific T cells measured by IFN-γ ELISpot on day 14 after the boost dose of vaccine with linear regression of logged values (p=0·22). In B and C, each datapoint is one participant and the solid line shows the linear regression, with the shaded area showing the 95% CI from an unadjusted linear regression of anti-vector neutralisation titres against logged ELISA (in B) or ELISpot (in C) response. Data were unavailable at day 56 for the 56–69 years standard-dose group. ELISpot=enzyme-linked immunospot. PBMC=peripheral blood mononuclear cells. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. SFC=spot-forming cells.