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.2021 Mar 6;397(10277):881-891.
doi: 10.1016/S0140-6736(21)00432-3. Epub 2021 Feb 19.

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Merryn Voysey  1, Sue Ann Costa Clemens  2, Shabir A Madhi  3, Lily Y Weckx  4, Pedro M Folegatti  5, Parvinder K Aley  1, Brian Angus  5, Vicky L Baillie  3, Shaun L Barnabas  6, Qasim E Bhorat  7, Sagida Bibi  1, Carmen Briner  8, Paola Cicconi  5, Elizabeth A Clutterbuck  1, Andrea M Collins  9, Clare L Cutland  3, Thomas C Darton  10, Keertan Dheda  11, Christina Dold  1, Christopher J A Duncan  12, Katherine R W Emary  1, Katie J Ewer  5, Amy Flaxman  5, Lee Fairlie  13, Saul N Faust  14, Shuo Feng  1, Daniela M Ferreira  9, Adam Finn  15, Eva Galiza  16, Anna L Goodman  17, Catherine M Green  18, Christopher A Green  19, Melanie Greenland  1, Catherine Hill  3, Helen C Hill  9, Ian Hirsch  20, Alane Izu  3, Daniel Jenkin  5, Carina C D Joe  5, Simon Kerridge  1, Anthonet Koen  3, Gaurav Kwatra  3, Rajeka Lazarus  21, Vincenzo Libri  22, Patrick J Lillie  23, Natalie G Marchevsky  1, Richard P Marshall  20, Ana V A Mendes  24, Eveline P Milan  25, Angela M Minassian  5, Alastair McGregor  26, Yama F Mujadidi  1, Anusha Nana  8, Sherman D Padayachee  27, Daniel J Phillips  1, Ana Pittella  28, Emma Plested  1, Katrina M Pollock  29, Maheshi N Ramasamy  1, Adam J Ritchie  5, Hannah Robinson  1, Alexandre V Schwarzbold  30, Andrew Smith  31, Rinn Song  1, Matthew D Snape  1, Eduardo Sprinz  32, Rebecca K Sutherland  33, Emma C Thomson  34, M Estée Török  35, Mark Toshner  36, David P J Turner  37, Johan Vekemans  20, Tonya L Villafana  20, Thomas White  20, Christopher J Williams  38, Alexander D Douglas  5, Adrian V S Hill  5, Teresa Lambe  5, Sarah C Gilbert  5, Andrew J Pollard  39; Oxford COVID Vaccine Trial Group
Collaborators, Affiliations

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Merryn Voysey et al. Lancet..

Erratum in

  • Department of Error.
    [No authors listed][No authors listed]Lancet. 2021 Mar 6;397(10277):880. doi: 10.1016/S0140-6736(21)00515-8.Lancet. 2021.PMID:33676625Free PMC article.No abstract available.

Abstract

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.

Methods: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov,NCT04324606 (COV001),NCT04400838 (COV002), andNCT04444674 (COV005).

Findings: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]).

Interpretation: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.

Funding: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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Figures

Figure 1
Figure 1
Exploratory analysis of vaccine efficacy against primary symptomatic COVID-19 more than 14 days after a booster dose, by prime-boost interval (A) All participants who received two doses. (B) Participants who received two standard doses. (C) Participants who received a low dose plus standard dose. Each datapoint shows one estimate of vaccine efficacy calculated in a subset of participants who received two doses of vaccine with a prime-boost interval falling within a 20-day interval. The x-axis shows the midpoint of the interval such that the first datapoint, plotted at 36 days, includes data from participants who received vaccines between 26 and 46 days apart. Estimates are from unadjusted log-binomial models. Dotted lines show 95% CIs for each point estimate of vaccine efficacy. Bar charts below each plot show the number of events included in each efficacy analysis.
Figure 2
Figure 2
Exploratory analysis of vaccine efficacy over time from 22 days after a single standard dose ChAdOx1 nCoV-19 (A) and persistence of anti-SARS-CoV-2 spike IgG by standardised ELISA antibody after a single dose of either standard-dose or low-dose vaccine (B) (A) Each datapoint shows one estimate of vaccine efficacy calculated in a subset of participants who were followed up during a 21-day period after their first dose (n=18 548). Datapoints are plotted on the x-axis at the midpoint of the follow-up period. For each estimate of vaccine efficacy, cases were censored if they occurred before or after the 21-day period, such that the first datapoint, plotted at 33 days, shows vaccine efficacy in the 3 weeks from 22 days to 43 days after vaccination. Lines show 95% CIs for each point estimate of vaccine efficacy. The bar chart shows the number of participants with COVID-19 included in each model. Data are also in table 2. (B) Solid lines show estimates from a linear model with shaded areas showing SEs. Samples included are from participants given a single dose in study COV001 who had a blood sample taken at 6 months (n=44), and participants in COV002 who had a blood sample taken at the time of their booster dose (n=264). Timings for booster doses varied. All participants had blood taken at day 28. Because of laboratory capacity, samples from all participants in the trial have not all been processed on this assay.
Figure 3
Figure 3
Anti-SARS-CoV-2 spike IgG responses by multiplex immunoassay at 28 days after the second dose in participants receiving two standard doses or low dose plus standard dose, by prime-boost interval (n=3337) Participants who were NAAT positive before the blood sample taken at day 28 were not included in the analyses. About 15% of samples from participants were analysed using this assay. The midlines of the boxes show medians and the outer bounds of the boxes show IQRs. Error bars show 1·5 × the IQR above or below the 75th or 25th percentile. Data are also in the appendix (p 9).
Figure 4
Figure 4
Relationship between binding and neutralising antibody 28 days after second dose, and vaccine efficacy against primary symptomatic COVID-19 Vaccine efficacy with 95% CI against primary symptomatic COVID-19 in participants who received two standard doses and those who received a low dose plus standard dose combined are shown plotted against the GMT (95% CI) of anti-SARS-CoV-2 spike IgG from an immunoassay (A), and the GMT (95% CI) pseudovirus neutralisation (B), for each prime boost interval. GMT=geometric meant titre.
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