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: "computer randomisation was conducted using RedCAP, stratified by site, age group (18–60 years or 61 years and older), and day of randomisation, with a block size of 42"
Comment: Allocation sequence random random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "Participants were masked to the vaccine that they had received until the second visit, 28 days after vaccination... Study staff were aware of vaccine allocations"
Comment: Single blinded study (participants blinded and personnel unblinded) Deviations from intended intervention arising because of the study context: One participant crossed over; considered negligible among sample size of 1240. Hence, no important deviations arose because of the trial context. SPECIFIC ANTIBODY GMT, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Intention-to-treat analysis was carried out for safety and specific antibody titre outcomes. As we are assessing the effect of assignment to intervention, the analysis method performed on these outcomes was considered appropriate. Risk assessed to be low for the outcomes: Specific antibody GMT. Local adverse events. Systemic adverse events. Serious adverse events. NEUTRALIZING ANTIBODY GMT OMICRON Per-protocol analysis was performed on the neutralization antibody titre outcomes. A pre-planned subsample was 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 the analysis being pre-planned and balance in proportions not analysed between groups. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT Omicron. |
| Missing outcome data |
Low |
Comment: 1240 participants randomized; 1239 participants analyzed for safety; 1204 participants analyzed for specific antibody titers; 80 participants analyzed for neutralizing antibody titers.
SPECIFIC ANTIBODY GMT, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Safety and specific antibody data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Specific antibody GMT. Local adverse events. Systemic adverse events. Serious adverse events. NEUTRALIZING ANTIBODY GMT OMICRON Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Outcome assessed in a random subset of 80 participants, subsequent risk of bias already taken into account in domain 2. Risk assessed to be low for the outcome Neutralizing antibody GMT Omicron |
| 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 for outcome assessment: participants self-reporting adverse events were blinded; laboratory staff were blinded. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT Omicron. Local adverse events. Systemic adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and prospective trial registry were available (dated 30 July 2021).
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: Specific antibody GMT. Neutralizing antibody GMT Omicron. Local adverse events. Systemic adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |