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: "Randomisation codes were generated by the randomisation statistician by means of block randomisation using SAS software version 9.4. The randomisation code was allocated to each participant in sequence in the order of enrolment, and then the participants received the investigational products labelled with the same code. Concealed random group allocations and blinding codes were kept in signed envelopes. Investigators, participants, and laboratory staff were masked to group allocation."
Comment: Allocation sequence random Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "Double-blinded. Concealed random group allocations and blinding codes were kept in signed envelopes. Investigators, participants, and laboratory staff were masked to group allocation."
Comment: Blinded study (participants and personnel/carers) SERIOUS ADVERSE EVENTS Safety population included all participants who received a third dose. 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: Serious adverse events. NEUTRALIZING ANTIBODY ASSAY GMT. SEROCONVERSION OMICRON. NEUTRALIZING ANTIBODY ASSAY GMT OMICRON Per-protocol analysis was performed on the inmunogenicity outcomes. Reasons for exclusion: didn't have a blood sample taken 28 days after the third dose (1 vs 0 vs 1 vs 5) and received another licensed inactivated COVID-19 vaccin (0 vs 0 vs 1 vs 1). Withdrew 10 vs 10 vs 9 vs 8. 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 number of participants excluded. Risk assessed to be some concerns for the outcomes: Neutralizing antibody assay GMT, Seroconversion Omicron, Neutralizing antibody assay GMT Omicron |
| Missing outcome data |
Low |
Comment: 384 participants randomized; 346 participants analyzed for safety, 337 participants analyzed for inmunogenicity.
SERIOUS ADVERSE EVENTS Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 10 (1.5mcg group 10M) vs 10 (3.0mcg group 10M) vs 9 (1.5mcg group 12M) vs 8 (3.0mcg group 12M) withdrew. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome based on same proportions between arms. Risk assessed to be some concerns for the outcome: Serious adverse events. NEUTRALIZING ANTIBODY ASSAY GMT. SEROCONVERSION OMICRON. NEUTRALIZING ANTIBODY ASSAY GMT OMICRON Data not available for all or nearly all participants randomized. Risk of bias already assessed on domain 2. Risk assessed to be low for the outcomes: Neutralizing antibody assay GMT, Seroconversion Omicron, Neutralizing antibody assay 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 (outcome assessor). Risk assessed to be low for the outcomes: Neutralizing antibody assay GMT, Seroconversion Omicron, Neutralizing antibody assay GMT Omicron Serious adverse events |
| Selection of the reported results |
Low |
Comment: The registry was available (dated Sept 16, 2020).
If data analyzed and presented as pre-specified
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 outcome:Neutralizing antibody assay GMT, Seroconversion Omicron, Neutralizing antibody assay GMT Omicron Serious adverse events. |
| Overall risk of bias |
Some concerns |