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 |
Some concerns |
Quote: "Eligible participants were stratified by age (18-64 and ≥ 65 years) and history of confirmed SARS-CoV-2 infection, and randomly assigned in 1:1:1:1:1:1 ratio to one of six regimens."
Comment: Allocation sequence probably random. No information on allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “Open-label.”
Comment: Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: No participant cross-over. Hence, deviations did not arise because of the trial context. NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT OMICRON, SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON Immunogenicity was assessed in a per-protocol population. Reasons for exclusion: 1/202, 2/101, 3/100, 3/100 and 2/99 were excluded because of COVID infections before day 15 blood-draws. 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 small proportions. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT. Neutralizing antibody GMT Omicron. Seroconversion neutralizing antibody Omicron. LOCAL and SYSTEMIC ADVERSE EVENTS Safety was assessed in all participants who received vaccination. 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: Local adverse events. Systemic adverse events. |
| Missing outcome data |
Low |
Comment: 602 participants randomized; 597 participants analyzed for safety; 586 participants analyzed for immunogenicity.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Neutralizing antibody GMT Omicron. Seroconversion neutralizing antibody Omicron. Local adverse events. Systemic adverse events. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor) NEUTRALIZING ANTIBODY GMT. NEUTRALIZING ANTIBODY GMT OMICRON. Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Neutralizing antibody GMT Omicron. Seroconversion neutralizing antibody Omicron LOCAL and SYSTEMIC ADVERSE EVENTS The authors reported on adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Local adverse events. Systemic adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (Date March 21, 2022)
Immunogenicity and safety outcomes pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified for immunogenicity and safety. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Neutralizing antibody GMT Omicron. Seroconversion neutralizing antibody Omicron. Local adverse events. Systemic adverse events. |
| Overall risk of bias |
Some concerns |