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: “Participants were randomised 1:1 to receive either a third (booster) dose of vaccine or placebo. Using a block size of four, randomisation was done by the unblinded contract research organisation (CRO) managing the study using a master randomisation code uploaded to an Interactive Web Response System.”
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: “Double-blind. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to the treatment group allocation.”
Comment: Blinded study (participants and personnel/carers) Available case analysis for most outcomes; only those lost to follow-up were not included in the analysis. 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: Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Small subsample (15/184) analysed for cellular response. Reasons for exclusion: samples for cellular response assays were collected for a small subset of randomly selected participants. 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 because participants were selected randomly for the subsample. Risk assessed to be some concerns for the outcome: Cellular response. |
| Missing outcome data |
Some concerns |
Comment: 184 participants randomized; 167 participants analyzed for immunogenicity and safety; 15 analyzed for cell response.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 11 vs. 6 lost to follow-up; reasons were accounted for in domain 2 for cellular response. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to blinding. Risk assessed to be some concerns for the outcomes: Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Risk assessed to be low for the outcome: Cellular response. |
| 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: Confirmed symptomatic COVID. Mortality. Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry was available.
Neutralizing antibody and safety outcomes pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified for these outcomes. Risk assessed to be low for the outcomes: Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Specific antibody response, cellular response outcomes were 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 for these outcomes. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Cellular response. |
| Overall risk of bias |
Some concerns |