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 |
Quotes: "computerised random number generator" "The site received the product in such blocks, in masked vials in order to prevent their identification, labelled with each subject´s number. Therefore, the decision to accept or reject a participant was made, and informed consent was obtained from the participant, in ignorance of the assignment in the sequence."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "All participants (investigators, subjects, and monitors) were kept blinded during all the study performance and data management"
Comment: Blinded study (participants and personnel/carers). Specific antibody and safety outcomes were not reported as 'per protocol' and no participants were reported to be excluded due to protocol violations. As we are assessing the effect of assignment to intervention, the analysis method was considered appropriate. Risk assessed to be low for the outcomes: Specific antibody GMT. Adverse events. Serious adverse events. Only those with 30% or more inhibition of RBD-ACE-2 binding were analysed for neutralizing antibody outcomes. 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. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: 726 participants randomized; 726 participants analysed for safety; 719 participants analyzed for specific antibody GMTs; among intervention arms, 211/484 participants analyzed for neutralizing antibody GMTs.
Safety and specific antibody GMT data were available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Specific antibody GMT. Adverse events. Serious adverse events. Neutralizing antibody GMT data not available for all or nearly all participants randomized. Reasons: "We also measured neutralizing antibody titers against live-SARS-CoV-2 in serum samples of participants with ≥30% of inhibition of RBD-ACE-2 binding", this was accounted for in domain 2. Risk assessed to be low for the outcome: Neutralizing antibody GMT. |
| 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: Specific antibody GMT. Neutralizing antibody GMT. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry was available.
Adverse events and Specific antibody GMT outcomes were 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. Adverse events. Serious adverse events. Neutralizing antibody GMT outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMTs. |
| Overall risk of bias |
Some concerns |