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: “Participants were assigned to study groups in a 1:1:1:1 fashion; randomization was stratified by study site after obtaining written informed consent.”
Comment: Allocation sequence probably random. No information on allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. Risk assessed as some concerns |
| Deviations from intervention |
Some concerns |
Quote: “single-(participant)-blinded Participants were unblinded for the booster vaccination by e-mail eight days after injection, after completing the reactogenicity questionnaires.”
Comment: Blinded study (participants) Deviations from intended intervention arising because of the study context: No participant cross-over. SPECIFIC ANTIBODY GMT. SPECIFIC ANTIBODY GMT (>90D).LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. SERIOUS ADVERSE EVENTS Per-protocol analysis was performed on the outcomes. Reasons for exclusion: baseline positive (2.6%, 1.7%, 0.9%, 1.7%), positive between baseline and follow up (1.8%, 0.9%, 0.0%, 0,0%). 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 balance between groups. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Specific antibody GMT (>90D). Local adverse events. Systemic adverse events. Serious adverse events. NEUTRALIZING ANTIBODY GMT. NEUTRALIZING ANTIBODY GMT (>90D) Per-protocol analysis was performed on the outcomes. Quote: "In 2 randomly drawn subsamples, we analyzed neutralizing antibodies in 35 participants (Ad26.COV2.S: n = 12, mRNA-1273: n = 11, BNT162b2: n = 12)." 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 balance between groups. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT. Neutralizing antibody GMT (>90D). |
| Missing outcome data |
Some concerns |
Comment: 461 participants randomized; 433 participants analyzed for reactogenicity and serious adverse events specific antibody GMT; 279 participants analyzed for specific antibody GMT (>90D); 35 participants analyzed for neutralizing antibody GMT and neutralizing antibody GMT (>90D).
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. SPECIFIC ANTIBODY GMT, LOCAL ADVERSE EVENTS,SYSTEMIC ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Reasons for missigness for the outcomes reactogenicity and specific antibody GMT are related to protocol deviation and this bias was addressed in domain 2. Risk assessed to be low for the outcomes: Specific antibody GMT. Local adverse events. Systemic adverse events. Serious adverse events SPECIFIC ANTIBODY GMT (>90D), NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT (>90D) Reasons (specific antibody GMT (>90D), neutralizing antibody GMT and neutralizing antibody GMT (>90D)): Only measured in a subset of participants. Risk of bias assessed in domain 2 Risk assessed to be some concerns for the outcomes: Specific antibody GMT (>90D). Neutralizing antibody GMT. Neutralizing antibody GMT (>90D). |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. SPECIFIC ANTIBODY GMT,SPECIFIC ANTIBODY GMT (>90D), NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT (>90D) Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Specific antibody GMT. Specific antibody GMT (>90D). Neutralizing antibody GMT. Neutralizing antibody GMT (>90D). LOCAL, SYSTEMIC, and SERIOUS ADVERSE EVENTS Blinded study (patient who is the outcome assessor). Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, supplementary materials and registry (dated June 16, 2021) 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 outcome: Specific antibody GMT. Specific antibody GMT (>90D). Neutralizing antibody GMT. Neutralizing antibody GMT (>90D). Local adverse events. Systemic adverse events. Serious adverse events |
| Overall risk of bias |
Some concerns |