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: “Using an interactive Web-based response system, we randomly assigned the participants”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quotes: "All the participants and site personnel were unaware of the trial-group assignments, except for staff members who prepared, dispensed, or administered the injections." "In anticipation of recommendations by regulatory authorities that booster doses be made available, we revised the protocol to allow for the unblinding of the trial-group assignments before the 2-month cutoff."
Comment: Early unblinding was allowed in double-blind trial. Deviations from intended intervention arising because of the study context: One participant crossed over from vaccine to placebo. Among over 10,000 participants, we judged cross-over of one participant to be negligible, hence, deviations did probably not arise because of the trial context. All randomized participants who receive at least one dose of the study intervention were analyzed for safety. As we are assessing the effect of assignment to intervention, the analysis method performed on these safety outcomes, was considered appropriate. Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Serious adverse events. Per-protocol analysis was performed on the efficacy outcomes. Reasons for exclusion: early unblinding, protocol deviations. 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 ethical reason for unblinding, which underlies the imbalance in exclusions. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
| Missing outcome data |
Low |
Comment: 10,136 participants randomized; 10,075 participants analyzed for safety; 9366 participants analyzed for efficacy.
Safety data available for nearly all participants randomized. Efficacy data not available for all or nearly all participants randomized. Reasons: protocol deviations such as early unblinding was accounted for in domain 2 and constituted most of the missing data. There were few missing data due to losses to follow-up and withdrawals. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. The trial was unblinded early, but most cases would have been unaffected since unblinding starded on 24th September and data cut off was 5th October. No cases of local and systemic adverse events would have been affected since duration of follow-up was 30 days and enrollment ended on August 10th. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol (dated prospectively in May 2021), statistical analysis plan, and registry (dated a few days after the study started enrollment) were available.
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 symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |