Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "Central randomisation
was implemented in this study. Participants were
randomly assigned to one of two vaccination groups:
active vaccine versus placebo. This was based on a
computer-generated randomisation schedule prepared
before the study by, or under the supervision of, the
sponsor. "
Comment: Allocation sequence random. Allocation sequence probably concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: “Participants and sites were blinded to assignment until the unblinding visit”
Comment: Blinded study (participants and personnel/carers). SAFETY Per-protocol analysis was performed on the outcomes. Reasons for exclusion: a subset was analysed (unclear if it was pre-planned); for efficacy participants who received 2 doses of vaccine/placebo in the double-blind phase, were SARS-CoV-2 seronegative at day 1 and day 71 and had no major protocol violations possibly impacting efficacy were analysed. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was probably no substantial impact of failure to analyze participants according to their randomized assignment due to similar proportions between groups in the per protocol analyses. Risk assessed to be some concerns for the outcomes: Local adverse events. Systemic adverse events. Adverse events. EFFICACY Per-protocol analysis was performed on the outcomes. Reasons for exclusion: Only participants who received 2 doses of vaccine/placebo in the double-blind phase, were SARS-CoV-2 seronegative at day 1 and day 71 and had no major protocol violations possibly impacting efficacy were analysed. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was probably no substantial impact of failure to analyze participants according to their randomized assignment due to similar proportions between groups in the per protocol analyses. Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. |
| Missing outcome data |
Some concerns |
Comment: 31,835 participants randomized; 11,639 analyzed for efficacy; 2984 participants analyzed for reactogenicity and AEs.
SAFETY Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: in addition to those excluded from the per-protocol analysis (assessed in domain 2), there seem to be no further missing data for reactogenicity and adverse events. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. EFFICACY Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: in addition to those excluded from the per-protocol analysis (assessed in domain 2), for efficacy 11,639 of 14,492 (80%) were analysed. Reasons for missing data from per-protocol analysis were not reported. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome because proportions of missing data were similar between groups (20%). Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry was available (Date November 4, 2020).
MORTALITY, CONFIRMED COVID, CONFIRMED SYMPTOMATIC COVID, LOCAL, SYSTEMIC and ADVERSE EVENTS Outcomes pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. CONFIRMED SEVERE COVID Confirmed severe COVID was not pre-specified in the registry. No information on whether the result was selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Confirmed severe COVID. |
| Overall risk of bias |
Some concerns |