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) MORTALITY. LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS. ITT analysis was performed for this outcome. 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: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. SPECIFIC ANTIBODY GMT. SEROCONVERSION NEUTRALIZING ANTIBODY. NEUTRALIZING ANTIBODY GMT Per-protocol analysis was performed on the outcomes. Reasons for exclusion:lost to follow up (11 vs 6) 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 los number of exclusions. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Neutralizing seroconversion rate. SEROCONVERSION NEUTRALIZING ANTIBODY (>90D). NEUTRALIZING ANTIBODY GMT (>90D). SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON (>90D). NEUTRALIZING ANTIBODY GMT OMICRON (>90D). Per-protocol analysis was performed on the outcomes. Reasons for exclusion:lost to follow up (11 vs 6) 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 arms. Risk assessed to be some concerns for the outcomes: Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron (>90D). Neutralizing antibody Omicron (>90d). |
| Missing outcome data |
Some concerns |
Comment: 184 participants randomized; 184 participants analyzed for mortality and safety; 167 participants analysed for Specific antibody GMT, Neutralizing antibody GMT and Neutralizing seroconversion rate. 68 participants analyzed for
Neutralizing antibody GMT (>90d), Seroconversion neutralizing antibody Omicron (>90D). Neutralizing antibody Omicron (>90d). 52 participants analysed for Seroconversion neutralizing antibody (>90d).
MORTALITY. LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. SPECIFIC ANTIBODY GMT. SEROCONVERSION NEUTRALIZING ANTIBODY. NEUTRALIZING ANTIBODY GMT 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. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Neutralizing seroconversion rate. SEROCONVERSION NEUTRALIZING ANTIBODY (>90D). NEUTRALIZING ANTIBODY GMT (>90D). SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON (>90D). NEUTRALIZING ANTIBODY GMT OMICRON (>90D). Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missigness in the data not reported. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to balance between arms. Risk assessed to be some concerns for the outcomes: Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron (>90D). Neutralizing antibody Omicron (>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. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Specific antibody GMT. Seroconversion neutralizing antibody. Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT. Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron (>90d). Neutralizing antibody GMT Omicron (>90d). |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry (Date July 15th, 2020) was available.
LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS.SEROCONVERSION NEUTRALIZING ANTIBODY. NEUTRALIZING ANTIBODY GMT. SEROCONVERSION NEUTRALIZING ANTIBODY (>90D). NEUTRALIZING ANTIBODY GMT (>90D). SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON (>90D). NEUTRALIZING ANTIBODY GMT OMICRON (>90D). 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:Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Neutralizing antibody GMT. Neutralizing seroconversion rate. Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron (>90D). Neutralizing antibody Omicron (>90d). MORTALITY. 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 Risk assessed to be low for the outcome: Mortality SPECIFIC ANTIBODY GMT. Specific antibody response was 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 this outcome. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. |
| Overall risk of bias |
Some concerns |