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: From protocol, "Central randomization will be implemented in this study... Randomization will be based on a computer-generated randomization schedule prepared before the study by, or under the supervision of, the sponsor. The randomization will be balanced by using randomly permuted blocks. The interactive web response system (IWRS) will assign a unique intervention code, which will dictate the intervention assignment and matching study intervention kit for the participant."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind" trial.
Comment: Blinded study (participants and personnel/carers). MORTALITY, ADVERSE EVENTS, AND SERIOUS ADVERSE EVENTS Safety analysis on those who received at least one dose of the intervention. 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. Adverse events. Serious adverse events. NEUTRALIZING ANTIBODY GMT, NEUTRALIZING SEROCONVERSION RATE Per-protocol analysis was performed on the outcomes. Reasons for exclusion: 0 vs 2 vs 1 participants did not receive the intervention; and 19 vs 24 vs 28 did not comply with the protocol (i.e., did not have post-baseline immunogenicity data without major protocol deviations and were SARS-COV-2 seronegative at baseline). 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 arms. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT. Neutralizing seroconversion rate. |
| Missing outcome data |
Low |
Comment: 777 participants randomized; 774 participants analyzed for safety; 688 (89%) analyzed for immunogenicity.
MORTALITY, ADVERSE EVENTS, AND SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality. Adverse events. Serious adverse events. NEUTRALIZING ANTIBODY GMT, NEUTRALIZING SEROCONVERSION RATE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: Most accounted for in domain 2; plus 1 vs 3 vs 0 loss to follow-up; 2 vs 3 vs 3 withdrawals; and 1 vs 1 vs 1 Other. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Neutralizing antibody seroconversion rate. |
| 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: Mortality, Neutralizing antibody GMT, Neutralizing antibody seroconversion rate, Adverse events, and Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and registry were available (dated August 10, 2021).
Outcome 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: Mortality. Neutralizing antibody GMT. Neutralizing antibody seroconversion rate. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |