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Cited by 1,119SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesVaccine Coverage and Hesitancy

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

Open access
Voysey, Merryn, Costa Clemens, Sue Ann, Madhi, Shabir A, Weckx, Lily Y, Folegatti, Pedro M, Aley, Parvinder K, Angus, Brian, Baillie, Vicky L +758 more·2021·The Lancet
DOI 10.1016/s0140-6736(21)00432-3PMC PMC7894131
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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: 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), and NCT04444674 (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.

AI snapshot

Written from the paper’s full text.

TL;DR

In a pooled analysis of four randomised ChAdOx1 nCoV-19 trials, two doses had 66·7% efficacy against symptomatic COVID-19 more than 14 days after the second dose, and exploratory analyses found higher efficacy with a longer prime-boost interval. A single standard dose showed 76·0% efficacy from day 22 to day 90, with no evidence of waning protection in that period.

Key findings

  • 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 8597 ChAdOx1 nCoV-19 recipients versus 248 (2·9%) in 8581 controls; two standard doses had 63·1% efficacy (51·8–71·7) and low dose plus standard dose had 80·7% (62·1–90·2).
  • A single standard dose had 76·0% efficacy (95% CI 59·3–85·9) against primary symptomatic COVID-19 from day 22 to day 90, with no evidence of waning protection; anti-spike IgG declined by 34% by day 90 (GMR 0·66, 95% CI 0·59–0·74).
  • In exploratory analyses, two standard doses had higher efficacy with a longer prime-boost interval: 81·3% (60·3–91·2) at ≥12 weeks versus 55·1% (33·0–69·9) at <6 weeks; binding antibody responses were more than two-fold higher after ≥12 weeks than <6 weeks in participants aged 18–55 years (GMR 2·32, 95% CI 2·01–2·68).
  • Serious adverse events occurred in 108 (0·9%) of 12 282 ChAdOx1 nCoV-19 recipients and 127 (1·1%) of 11 962 controls; there were no hospital admissions for COVID-19 in the vaccine group after the initial 21-day exclusion period versus 15 in the control group, and seven deaths were considered unrelated to vaccination.

Methods

  • Pooled analysis of four randomised controlled trials: COV001 (UK phase 1/2), COV002 (UK phase 2/3), COV003 (Brazil phase 3), and COV005 (South Africa phase 1/2); participants were randomly assigned 1:1 to two standard doses of ChAdOx1 nCoV-19 (5 × 10¹⁰ viral particles) or control vaccine/saline, with a UK subset receiving a low first dose (2·2 × 10¹⁰ viral particles).
  • The primary outcome was virologically confirmed symptomatic COVID-19 more than 14 days after the second dose; secondary analyses included cases more than 21 days after the first dose, and exploratory outcomes included antibody responses and efficacy by prime-boost interval.
  • Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated; 17 178 were included in the primary analysis (8597 vaccine, 8581 control), with data cutoff Dec 7, 2020. Vaccine efficacy was calculated using robust Poisson regression adjusted for study and age group with an offset for time at risk; exploratory interval analyses used unadjusted log-binomial models.

Limitations

  • The paper states the studies were not designed to establish whether vaccine efficacy differed by dose interval; the interval analyses were post-hoc, exploratory, and not prespecified, with potential for multiple sources of bias.
  • The paper notes short follow-up after the second dose, and that single-dose analyses mix participants with events before booster and those who did not receive a booster, groups that differed in age, sex, health or social care worker status, dose, country, ethnicity, and follow-up time.
  • The paper states asymptomatic infections were measured only in the UK, no correlate of protection has been defined, and the interval comparisons have overlapping confidence intervals; the text also makes evident possible confounding by epidemic timing and country.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(21)00432-3

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 32 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose.

    “332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose.”
    Quote in the paperSubstantial claim
  • Findingown data

    Vaccine efficacy results varied by dose interval in exploratory analyses.

    “with results varying by dose interval in exploratory analyses.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The apparent trend of higher vaccine efficacy with a longer prime-boost interval is not due to measured or unmeasured confounding.
  • Findingown data

    Overall vaccine efficacy more than 14 days after the second dose was 66.7% (95% CI 57.4-74.0) in the primary analysis.

    “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.”
    • Also stated in: § Results · plain
      “There were 332 cases of primary symptomatic COVID-19 occurring more than 14 days after a booster dose, 84 (1·0%) in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group, with overall efficacy of 66·7% (95% CI 57·4–74·0; table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites table 1

      Not checked in the free run.

    • Rests on an assumption: The control products used in the trials do not protect against COVID-19.
  • Findingown data

    In participants who received two standard doses, vaccine efficacy against primary symptomatic COVID-19 more than 14 days after the second dose was 59.9% (95% CI 32.0 to 76.4) at a prime-boost interval of 6-8 weeks.

    “6–8 weeks | 64 | 20/1112 (1·8%) | 44/1009 (4·4%) | 59·9% (32·0 to 76·4)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites table 1

      Not checked in the free run.

    • Rests on an assumption: The control products used in the trials do not protect against COVID-19.
  • Findingown data

    In participants who received two standard doses, vaccine efficacy more than 14 days after the second dose was 63.1% (95% CI 51.8-71.7).

    “In the participants who received two standard doses, 74 (1·0%) cases occurred in the 7201 participants in the ChAdOx1 nCoV-19 group and 197 (2·7%) in the 7179 in the control group, with vaccine efficacy of 63·1% (51·8–71·7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites table 1

      Not checked in the free run.

    • Rests on an assumption: The control products used in the trials do not protect against COVID-19.
  • May combine two claims. 29
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    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 a control participant.

    “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.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    For low dose plus standard dose, vaccine efficacy against any NAAT-positive COVID-19 more than 14 days after the second dose was 67.6% (95% CI 50.8 to 78.7).

    “Low dose plus standard dose | 117 | 29/1396 (2·1%) | 88/1402 (6·3%) | 67·6% (50·8 to 78·7)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites table 1

      Not checked in the free run.

    • Rests on an assumption: The control products used in the trials do not protect against COVID-19.

  • May combine two claims.

    Findingown data

    These two cohorts differ in some key characteristics; participants who received a booster dose were slightly younger, a greater proportion were men, and a smaller proportion were white compared with those who did not receive a booster dose.

    “These two cohorts differ in some key characteristics; participants who received a booster dose were slightly younger, a greater proportion were men, and a smaller proportion were white compared with those who did not receive a booster dose.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An exploratory analysis modelling the change in vaccine efficacy against primary symptomatic COVID-19 (from 14 days after the second dose) showed that efficacy was high after a 2-month prime-boost interval and continued to increase with longer dose intervals.

    “An exploratory analysis modelling the change in vaccine efficacy against primary symptomatic COVID-19 (from 14 days after the second dose) showed that efficacy was high after a 2-month prime-boost interval and continued to increase with longer dose intervals (figure 1A, B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Efficacy against asymptomatic infections in the UK showed a similar pattern, with efficacy estimates increasing as the interval between doses increased; however, the number of cases available for each analysis was small within each dose interval bracket and CIs were wide.

    “Efficacy against asymptomatic infections in the UK showed a similar pattern, with efficacy estimates increasing as the interval between doses increased; however, the number of cases available for each analysis was small within each dose interval bracket and CIs were wide (table 1, appendix p 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plotting anti-SARS-CoV-2 spike IgG against vaccine efficacy for each dose interval showed evidence of a potential relationship between binding antibody and vaccine protection, as well as between neutralisation antibody and vaccine efficacy.

    “Plotting anti-SARS-CoV-2 spike IgG against vaccine efficacy for each dose interval showed evidence of a potential relationship between binding antibody and vaccine protection, as well as between neutralisation antibody and vaccine efficacy, suggesting potential correlates of protection (figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the cohort receiving a low dose plus standard dose, there were 47 cases of asymptomatic infection and vaccine efficacy was 49.3% (7.4 to 72.2; 16 cases vs 31 cases).

    “In the cohort receiving a low dose plus standard dose, there were 47 cases and vaccine efficacy was 49·3% (7·4 to 72·2; 16 cases vs 31 cases).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was less variation in the prime-boost interval for the low dose plus standard dose cohort, with most data accruing in those who had about 3 months between first and second doses, and efficacy remained high during this period.

    “There was less variation in the prime-boost interval for the low dose plus standard dose cohort, with most data accruing in those who had about 3 months between first and second doses, and efficacy remained high during this period (figure 1C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The slightly lower vaccine efficacy against symptomatic COVID-19 of 66.7% after a booster dose appears counterintuitive compared with the 76% efficacy after a single dose, although these differences are non-significant.

    “The slightly lower vaccine efficacy against symptomatic COVID-19 of 66·7% after a booster dose appears counterintuitive compared with the 76% efficacy after a single dose, although these differences are non-significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Kaplan-Meier cumulative incidence of primary symptomatic COVID-19 showed clear differentiation between ChAdOx1 nCoV-19 and control groups, with non-overlapping confidence intervals, in line with efficacy estimates.

    “Kaplan-Meier cumulative incidence of primary symptomatic COVID-19 showed clear differentiation between ChAdOx1 nCoV-19 and control groups, with non-overlapping confidence intervals, in line with efficacy estimates (appendix pp 12–13).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Vaccine efficacy after two standard doses was 55.1% (95% CI 33.0-69.9) with an interval of less than 6 weeks and 81.3% (60.3-91.2) when more than 12 weeks apart.

    “Vaccine efficacy after two standard doses was 55·1% (95% CI 33·0–69·9) with an interval of less than 6 weeks and 81·3% (60·3–91·2) when more than 12 weeks apart (table 1).”
    • Also stated in: § Discussion · plain
      “In our study, vaccine efficacy after the second dose was higher in those with a longer prime-boost interval, reaching 81·3% in those with a dosing interval of 12 weeks or more versus 55·1% in those with an interval of less than 6 weeks.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A smaller proportion of UK COV002 participants who received a booster dose received a low-dose prime vaccination (33.4% vs 40.9%).

    “A smaller proportion of UK COV002 participants who received a booster dose received a low-dose prime vaccination (2894 [33·4%] of 8676 participants) than in those who did not receive a booster (480 [40·9%] of 1173).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Participants receiving a booster dose were older (median age 40 years [IQR 30-52] vs 36 years [28-48]), with a higher proportion of men (44.2% vs 39.0%) and non-white participants (24.1% vs 20.8%), and a smaller proportion of health or social care workers (60.1% vs 65.7%) compared with those who did not receive a booster dose.

    “Participants receiving a booster dose were older (median age 40 years [IQR 30–52] in those who received a booster dose vs 36 years [28–48] for those who did not), with a higher proportion of men (8471 [44·2%] of 19 150 vs 1072 [39·0%] of 2752) and non-white participants (4615 [24·1%] of 19 150 vs 571 [20·8%] of 2751), and a smaller proportion of health or social care workers (11 518 [60·1%] of 19”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The primary analysis supports the findings reported in the interim analysis that the vaccine is efficacious and safe.

    “The primary analysis supports the findings reported in the interim analysis that the vaccine is efficacious and safe.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The control products used in the trials do not protect against COVID-19.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The linear and non-linear models for antibody decay gave similar outputs.

    “Both models gave similar outputs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The additional exploratory analyses of single-dose efficacy were not prespecified and are considered supportive analyses to the previously published interim efficacy analysis.

    “These are considered as supportive analyses to the previously published interim efficacy analysis and were not prespecified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Safety data were reviewed on an ongoing basis by the independent data monitoring safety board.

    “Safety data were reviewed on an ongoing basis by the independent data monitoring safety board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ChAdOx1 nCoV-19 was authorised for emergency use in the UK on Dec 30, 2020, based on a regimen of two standard doses administered 4-12 weeks apart for adults aged 18 years and older.

    “ChAdOx1 nCoV-19 was authorised for emergency use in the UK on Dec 30, 2020,14 on the basis of the interim analysis data,4 based on a regimen of two standard doses administered 4–12 weeks apart for adults aged 18 years and older”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Medicines and Healthcare products Regulatory Agency Regulatory approval of COVID-19 Vaccine AstraZeneca https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca Jan 28, 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [4] Voysey M Costa Clemens SA Madhi SA Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 397 2021 99 111 33306989 PMC7723445 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All other funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

    “All other funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All endpoints were adjudicated for inclusion in the analysis by an independent masked endpoint review committee.

    “All endpoints were adjudicated for inclusion in the analysis by an independent masked endpoint review committee.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Participants were not randomly assigned to their dosing interval, and the exploratory analyses should be interpreted with caution because it is not possible to exclude the possibility that any apparent trend is due to measured or unmeasured confounding factors.

    “Participants were not randomly assigned to their dosing interval and these exploratory analyses should be interpreted with caution because it is not possible to exclude the possibility that any apparent trend is due to measured or unmeasured confounding factors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Duration of follow-up varied by prime-boost interval.

    “Duration of follow-up varied by prime-boost interval (appendix p 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The interim analysis was statistically significant and subsequent efficacy results are considered supportive of that analysis, with no further adjustment of α.

    “This analysis was statistically significant and subsequent efficacy results are considered supportive of that analysis, with no further adjustment of α.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    AstraZeneca reviewed the data from the study and the final manuscript before submission, but the academic authors retained editorial control.

    “AstraZeneca reviewed the data from the study and the final manuscript before submission, but the academic authors retained editorial control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In our data, the length of follow-up after the second dose was short and follow-up tends to be longer in those who were boosted early and thus have shorter prime-boost intervals.

    “In our data, the length of follow-up after the second dose was short and follow-up tends to be longer in those who were boosted early and thus have shorter prime-boost intervals.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    If there was no effect of a vaccine on asymptomatic infection (about a third of infections), it would be expected that an efficacious vaccine would simply convert severe cases to mild cases and mild cases to asymptomatic, with overall NAAT positivity unchanged.

    “If there was no effect of a vaccine on asymptomatic infection (about a third of infections), it would be expected that an efficacious vaccine would simply convert severe cases to mild cases and mild cases to asymptomatic, with overall NAAT positivity unchanged.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Asymptomatic infections constitute about a third of infections.

  • May combine two claims.

    Interpretationown data

    It is not clear what effect each of these individual sources of variation in the data have on vaccine efficacy estimates. However, the same trend seen with efficacy is also seen in the immunological data, suggesting an underlying biological mechanism.

    “It is not clear what effect each of these individual sources of variation in the data have on vaccine efficacy estimates. However, the same trend seen with efficacy is also seen in the immunological data, suggesting an underlying biological mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Vaccine efficacy against any NAAT-positive infection after a second dose appears lower than single-dose efficacy, probably because of the larger proportion of UK cases in the analysis and therefore the larger number of asymptomatic infections included, for which efficacy is lower.

    “Vaccine efficacy against any NAAT-positive infection after a second dose appears lower than single-dose efficacy, probably because of the larger proportion of UK cases in the analysis and therefore the larger number of asymptomatic infections included, for which efficacy is lower.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The studies were not designed to establish whether vaccine efficacy differed by dose interval and the presence of data of varying intervals arose because of the logistics of running large-scale clinical trials in a pandemic setting. These are therefore post-hoc exploratory analyses only with potential for multiple sources of bias, and were not prespecified.

    “The studies were not designed to establish whether vaccine efficacy differed by dose interval and the presence of data of varying intervals arose because of the logistics of running large-scale clinical trials in a pandemic setting. These are therefore post-hoc exploratory analyses only with potential for multiple sources of bias, and were not prespecified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    High protective efficacy recorded early after a single dose of vaccine in this study, and also seen with other vaccines from different manufacturers, suggests other immunological mechanisms might be at play early after the first dose, because lower levels of neutralising antibody are detected after a single dose.

    “By contrast, high protective efficacy recorded early after a single dose of vaccine in this study, and also seen with other vaccines from different manufacturers,3 suggests other immunological mechanisms might be at play early after the first dose, because lower levels of neutralising antibody are detected after a single dose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Polack FP Thomas SJ Kitchin N Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine N Engl J Med 383 2020 2603 2615 33301246 PMC7745181 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Greater protective efficacy associated with stronger immune responses after a wider prime-boost interval have been seen with other vaccines such as those for influenza, Ebola virus disease, and malaria.

    “Greater protective efficacy associated with stronger immune responses after a wider prime-boost interval have been seen with other vaccines such as those for influenza, Ebola virus disease, and malaria.16, 17, 18”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Ewer K Rampling T Venkatraman N A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA N Engl J Med 374 2016 1635 1646 25629663 PMC5798586

      Not checked in the free run.

    • cites [17] Fernandez-Arias C Arias CF Zhang M Herrero MA Acosta FJ Tsuji M Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines PLoS One 13 2018 e0190940 PMC5766151 29329308

      Not checked in the free run.

    • cites [18] Ledgerwood JE Zephir K Hu Z Prime-boost interval matters: a randomized phase 1 study to identify the minimum interval necessary to observe the H5 DNA influenza vaccine priming effect J Infect Dis 208 2013 418 422 23633407 PMC3699006

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cases included in single-dose estimates occurred earlier in the year than those included in post-second-dose analyses, and the intensity of the epidemics varied in the different countries, making single-dose and two-dose estimates difficult to directly compare with each other.

    “Cases included in single-dose estimates occurred earlier in the year than those included in post-second-dose analyses, and the intensity of the epidemics varied in the different countries, making single-dose and two-dose estimates difficult to directly compare with each other.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In our interim analysis, we identified a higher efficacy in a subgroup analysis of those who received the low dose plus standard dose regimen. This finding is supported by the results of this analysis, although these findings are exploratory.

    “In our interim analysis, we identified a higher efficacy in a subgroup analysis of those who received the low dose plus standard dose regimen.4 This finding is supported by the results of this analysis, although these findings are exploratory.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Voysey M Costa Clemens SA Madhi SA Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 397 2021 99 111 33306989 PMC7723445

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    With further data available, we show that the enhanced immunogenicity and efficacy with the low dose plus standard dose regimen might be partly driven by the longer dosing interval that was a feature of this subgroup, further supporting the observation of a relationship between dose interval and efficacy in those who received two standard doses.

    “With further data available, we show that the enhanced immunogenicity and efficacy with this regimen might be partly driven by the longer dosing interval that was a feature of this subgroup, further supporting the observation of a relationship between dose interval and efficacy in those who received two standard doses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Although transmission studies were not included in the analysis, swabs were obtained from volunteers every week in the UK study, regardless of symptoms, to allow assessment of the overall effect of the vaccine on risk of infection, and thus a surrogate for potential onward transmission.

    “Although transmission studies were not included in the analysis, swabs were obtained from volunteers every week in the UK study, regardless of symptoms, to allow assessment of the overall effect of the vaccine on risk of infection, and thus a surrogate for potential onward transmission.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The findings presented here for the ChAdOx1 nCoV-19 vaccine are consistent with policy recommendations in different countries to use dose intervals of 4-12 weeks for this vaccine.

    “The findings presented here for the ChAdOx1 nCoV-19 vaccine are consistent with policy recommendations in different countries to use dose intervals of 4–12 weeks for this vaccine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent modelling of delayed boosting suggests that even in the presence of substantial waning of first-dose efficacy, programmes that delay a second dose to vaccinate a larger proportion of the population result in greater immediate overall population protection.

    “Recent modelling of delayed boosting suggests that even in the presence of substantial waning of first-dose efficacy, programmes that delay a second dose to vaccinate a larger proportion of the population result in greater immediate overall population protection.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Jurgens G Modelling decay of population immunity with proposed second dose deferral strategy medRxiv 2021 published online Jan 6. 10.1101/2021.01.05.21249293 (preprint).

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Exploratory analyses show protection with dosing intervals from less than 6 weeks to 12 weeks or more and that a longer interval provides better protection after a booster dose without compromising protection in a 3-month period before the second dose is administered.

    “Exploratory analyses are presented in this report that show protection with dosing intervals from less than 6 weeks to 12 weeks or more and that a longer interval provides better protection after a booster dose without compromising protection in a 3-month period before the second dose is administered.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    These results confirm those seen in the interim analysis of the trials.

    “These results confirm those seen in the interim analysis of the trials.”
    Quote in the paperNot a substantial claim
41 of 41

  • The paper relies on this without support.

    The control products used in the trials do not protect against COVID-19.

    “receive either ChAdOx1 nCoV-19 vaccine or a control product (MenACWY in the UK, MenACWY prime and saline boost in Brazil, and saline only in South Africa).”

  • The paper relies on this without support.

    Antibody responses are a valid proxy for protection against COVID-19.

    “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]).”

  • The paper relies on this without support.

    The apparent trend of higher vaccine efficacy with a longer prime-boost interval is not due to measured or unmeasured confounding.

    “Participants were not randomly assigned to their dosing interval and these exploratory analyses should be interpreted with caution because it is not possible to exclude the possibility that any apparent trend is due to measured or unmeasured confounding factors.”

  • The paper relies on this without support.

    Participants who received only a single dose are comparable to those who received two doses for the purpose of estimating single-dose efficacy.

    “After initially providing consent to participate in a single-dose study, some participants chose not to receive the second dose, providing a self-selected cohort of single-dose recipients.”

  • The paper relies on this without support.

    Delays in administering the second dose are unrelated to participants' risk of COVID-19.

    “Additionally, because of the time required to manufacture the second dose, there were delays in administration of the second dose for a large number of trial participants who received the two-dose schedule.”

  • The paper relies on this without support.

    The four trials are similar enough in design and population to be pooled for the primary efficacy analysis.

    “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) are included in this primary analysis because all four trials now meet the required criteria for inclusion of having at least five primary outcome cases.”

  • The paper relies on this without support.

    The planned UK roll-out will involve vaccinating people in high-risk categories with their first dose immediately and delivering the second dose 12 weeks later.

    “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.”

  • The authors state this as an assumption.

    There is a relationship between the humoral immune response and efficacy.

    “assuming there is a relationship between the humoral immune response and efficacy”

  • The paper relies on this without support.

    Asymptomatic infections constitute about a third of infections.

    “about a third of infections”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A single dose of adenovirus-vectored vaccines induces polyfunctional antibodies that neutralize virus and mediate other antibody-dependent effector functions, plus strong T cell responses.

    “After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses.”

    From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [88]

  • Increasing the interval between ChAdOx1 nCoV-19 doses was associated with increased immunogenicity and efficacy.

    “Increased immunogenicity and efficacy was observed with increasing interval between doses for the ChAdOx1 nCoV-19 vaccine88, and this strategy may therefore result in better protection after two doses and could be considered for other vaccines.”

    From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [88]

  • A second dose provides additional benefit for Gam-COVID-Vac, with efficacy around 90%.

    “Additional benefit of a second dose is evident for Gam-COVID-Vac, when efficacy is ~90%87–90 (Table 1; see Supplementary Figure 1).”

    From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [88]

  • ChAdOx-1 nCoV-19 had about 70% efficacy against symptomatic COVID-19 after one or two doses.

    “There was ~70% efficacy for ChAdOx-1 nCoV-19 (after one or two doses)87,88 and Ad26.COV2.S (after one dose)89 (Table 1).”

    From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [88]

  • A pooled analysis of ChAdOx1 nCoV-19 efficacy in the United Kingdom, Brazil, and South Africa before emergence of B.1.351 and P.1 reported overall vaccine efficacy of 66.7% (95.8% CI, 57.4 to 74.0).

    “A pooled analysis of the efficacy of the ChAdOx1 nCoV-19 vaccine in the United Kingdom, Brazil, and South Africa, performed before the emergence of the B.1.351 and P.1 variants, reported an overall vaccine efficacy of 66.7% (95.8% confidence interval [CI], 57.4 to 74.0).24”

    From Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant (2021) · cites this paper as [24]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion reverses the age difference between booster groups

    Minor

    The discussion says booster recipients were younger, but the results report a higher median age for booster recipients: 40 years versus 36 years.

1 of 1

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References 15 · Cited by 1,119

Authors
Voysey, M., Costa Clemens, S. A., Madhi, S. A., Weckx, L. Y., Folegatti, P. M., Aley, P. K., Angus, B., Baillie, V. L., Barnabas, S. L., Bhorat, Q. E., Bibi, S., Briner, C., Cicconi, P., Clutterbuck, E. A., Collins, A. M., Cutland, C. L., Darton, T. C., Dheda, K., Dold, C., Duncan, C. J. A., Emary, K. R. W., Ewer, K. J., Flaxman, A., Fairlie, L., Faust, S. N., Feng, S., Ferreira, D. M., Finn, A., Galiza, E., Goodman, A. L., Green, C. M., Green, C. A., Greenland, M., Hill, C., Hill, H. C., Hirsch, I., Izu, A., Jenkin, D., Joe, C. C. D., Kerridge, S., Koen, A., Kwatra, G., Lazarus, R., Libri, V., Lillie, P. J., Marchevsky, N. G., Marshall, R. P., Mendes, A. V. A., Milan, E. P., Minassian, A. M., McGregor, A., Mujadidi, Y. F., Nana, A., Padayachee, S. D., Phillips, D. J., Pittella, A., Plested, E., Pollock, K. M., Ramasamy, M. N., Ritchie, A. J., Robinson, H., Schwarzbold, A. V., Smith, A., Song, R., Snape, M. D., Sprinz, E., Sutherland, R. K., Thomson, E. C., Török, M. 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J., Owen, L., Owens, D., Owino, N., Pacurar, M., Paiva, B. V. B., Palhares, E. M. F., Palmer, S., Parracho, H. M. R. T., Parsons, K., Patel, D., Patel, B., Patel, F., Patrick-Smith, M., Payne, R. O., Peng, Y., Penn, E. J., Pennington, A., Peralta Alvarez, M. P., Pereira Stuchi, B. P., Perez, A. L., Perinpanathan, T., Perring, J., Perumal, R., Petkar, S. Y., Philip, T., Phillips, J., Phohu, M. K., Pickup, L., Pieterse, S., Pinheiro, J. M., Piper, J., Pipini, D., Plank, M., Plant, S., Pollard, S., Pooley, J., Pooran, A., Poulton, I., Powers, C., Presa, F. B., Price, D. A., Price, V., Primeira, M. R., Proud, P. C., Provstgaard-Morys, S., Pueschel, S., Pulido, D., Quaid, S., Rabara, R., Radia, K., Rajapaska, D., Rajeswaran, T., Ramos, L., Ramos, A. S. F., Ramos Lopez, F., Rampling, T., Rand, J., Ratcliffe, H., Rawlinson, T., Rea, D., Rees, B., Resuello-Dauti, M., Reyes Pabon, E., Rhead, S., Riaz, T., Ricamara, M., Richards, A., Richter, A., Ritchie, N., Ritchie, A. J., Robbins, A. J., Roberts, H., Robinson, R. E., Roche, S., Rollier, C., Rose, L., Ross Russell, A. L., Rossouw, L., Royal, S., Rudiansyah, I., Ryalls, K., Sabine, C., Saich, S., Sale, J. C., Salman, A. M., Salvador, N., Salvador, S., Sampaio, M. D., Samson, A. D., Sanchez-Gonzalez, A., Sanders, H., Sanders, K., Santos, E., Santos Guerra, M. F. S., Satti, I., Saunders, J. E., Saunders, C., Sayed, A. B. A., Schim van der Loeff, I., Schmid, A. B., Schofield, E., Screaton, G. R., Seddiqi, S., Segireddy, R. R., Senger, R., Serrano, S., Shaik, I., Sharpe, H. R., Sharrocks, K., Shaw, R., Shea, A., Sheehan, E., Shepherd, A., Shiham, F., Silk, S. E., Silva-Reyes, L., Silveira, L. B. T. D., Silveira, M. B. V., Singh, N., Sinha, J., Skelly, D. T., Smith, D. C., Smith, N., Smith, H. E., Smith, D. J., Smith, C. C., Soares, A. S., Solórzano, C., Sorio, G. L., Sorley, K., Sosa-Rodriguez, T., Souza, C. M. C. D. L., Souza, B. S. D. F., Souza, A. R., Souza Lopez, T., Sowole, L., Spencer, A. J., Spoors, L., Stafford, L., Stamford, I., Stein, R., Stockdale, L., Stockwell, L. V., Strickland, L. H., Stuart, A., Sturdy, A., Sutton, N., Szigeti, A., Tahiri-Alaoui, A., Tanner, R., Taoushanis, C., Tarr, A. W., Tarrant, R., Taylor, K., Taylor, U., Taylor, I. J., Taylor, J., te Water Naude, R., Templeton, K., Themistocleous, Y., Themistocleous, A., Thomas, M., Thomas, K., Thomas, T. M., Thombrayil, A., Thompson, J., Thompson, F., Thompson, A., Thompson, A., Thompson, K., Thornton-Jones, V., Thotusi, L. H. S., Tighe, P. J., Tinoco, L. A., Tiongson, G. F., Tladinyane, B., Tomasicchio, M., Tomic, A., Tonks, S., Towner, J., Tran, N., Tree, J. A., Trillana, G., Trinham, C., Trivett, R., Truby, A., Tsheko, B. L., Tubb, P., Turabi, A., Turner, R., Turner, C., Turner, N., Tyagi, B., Ulaszewska, M., Underwood, B. R., van Eck, S., Varughese, R., Verbart, D., Verheul, M. K., Vichos, I., Vieira, T. A., Walker, G., Walker, L., Wand, M. E., Wardell, T., Warimwe, G. M., Warren, S. C., Watkins, B., Watson, M. E. E., Watson, E., Webb, S., Webster, A., Welch, J., Wellbelove, Z., Wells, J. H., West, A. J., White, B., White, C., White, R., Williams, P., Williams, R. L., Willingham, S., Winslow, R., Woods, D., Woodyer, M., Worth, A. T., Wright, D., Wroblewska, M., Yao, A., Yim, Y. T. N., Zambrano, M. B., Zimmer, R. L., Zizi, D., & Zuidewind, P.
Affiliations
  • University of Oxford (GB)
  • South African Medical Research Council (ZA)
  • Universidade Federal de São Paulo (BR)
  • Stellenbosch University (ZA)
  • Soweto CTC (ZA)
  • University of the Witwatersrand (ZA)
  • Liverpool School of Tropical Medicine (GB)
  • Sheffield Teaching Hospitals NHS Foundation Trust (GB)
  • University of Cape Town (ZA)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • University Hospital Southampton NHS Foundation Trust (GB)
  • University of Bristol (GB)
  • St George's, University of London (GB)
  • St Thomas' Hospital (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
  • AstraZeneca (United Kingdom) (GB)
  • North Bristol NHS Trust (GB)
  • UCL Biomedical Research Centre (GB)
  • University of Hull (GB)
  • Escola Bahiana de Medicina e Saúde Pública (BR)
  • Universidade Federal do Rio Grande do Norte (BR)
  • London North West Healthcare NHS Trust (GB)
  • Setshaba Research Centre (ZA)
  • NIHR Imperial Biomedical Research Centre (GB)
  • Universidade Federal de Santa Maria (BR)
  • Universidade Federal do Rio Grande do Sul (BR)
  • Western General Hospital (GB)
  • MRC University of Glasgow Centre for Virus Research (GB)
  • University of Cambridge (GB)
  • Nottingham University Hospitals NHS Trust (GB)
  • Aneurin Bevan University Health Board (GB)
Corresponding author
Pollard, Andrew J
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2021-03
Volume
397
Issue
10277
Pages
881-891
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(21)00432-3
PMC
PMC7894131
OpenAlex
W3131762051
Cited by
1,119
References
15
Citations by year
2026: 20 · 2025: 42 · 2024: 93 · 2023: 163 · 2022: 373 · 2021: 424 · 2020: 3
FWCI
83.38
Type
journal article
Language
en
Update notices
erratum (2021-03-06)
Open access
Licence
Locations
  • The Lancet (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • LSTM Online Archive (Liverpool School of Tropical Medicine) (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
  • Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
  • ePrints Soton (University of Southampton) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Bill and Melinda Gates Foundation
  • NIHR
  • UKRI
  • CEPI
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Social Sciences › Health › Vaccine Coverage and Hesitancy
Keywords
AZD1222, COVID-19 vaccines, single-dose administration, booster dose timing, immunogenicity, vaccine efficacy, SARS-CoV-2, antibody response, vaccine safety, pooled analysis of trials
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, ChAdOx1 nCoV-19, Adolescent, Adult, Aged, Antibody Formation, Humans, Immunization Schedule, Immunization, Secondary, Middle Aged, Randomized Controlled Trials as Topic, Young Adult, Asymptomatic Infections

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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