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: “The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four, and randomisation was done with the electronic data capture system REDCap (version 10.6.13) by trained site staff.”
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: Double-blind. “Participants, laboratory staff, and the clinical study team not delivering the vaccines, including those assessing adverse events, were masked to treatment allocation. Data analysts were not masked to treatment allocation. Participant masking was maintained by concealing randomisation pages, preparing vaccines out of sight, and applying masking tape to vaccine syringes to conceal dose, volume, and appearance.”
Comment: Blinded study (participants and personnel/carers). Those who received at least one dose of the intervention (all participants) were analyzed for safety. As we are assessing the effect of assignment to intervention, the analysis method performed on these safety outcomes, was considered appropriate. Per-protocol analysis was performed on the immunogenicity outcomes. Reasons for exclusion: 2/44, 6/44, 7/39 and 4/39 self-reported SARS-CoV-2 infection before fourth dose; 5/44, 3/44, 0/39 and 2/39 seropositive before fourth dose by anti-nucleocapsi assay; 2/44, 1/44, 1/39 and 0/39 did not attend day 14 visit and blood draw. Due to logistical reasons, only 50% of study sites collected cellular immunology samples (proximity to external laboratory). 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 relative balance between arms and blinding. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. Risk assessed to be some concerns for the outcomes: Cellular response. |
| Missing outcome data |
Low |
Comment: 166 participants randomized; 166 participants analyzed for safety; 40 analyzed for cellular response.
Data available for all or nearly all participants randomized for safety. Data not available for all or nearly all participants randomized for immunogenicity. No evidence that the result is not biased. Reasons: 2/44, 6/44, 7/39 and 4/39 self-reported SARS-CoV-2 infection before fourth dose; 5/44, 3/44, 0/39 and 2/39 seropositive before fourth dose by anti-nucleocapsi assay; 2/44, 1/44, 1/39 and 0/39 did not attend day 14 visit and blood draw. Due to logistical reasons, only 50% of study sites collected cellular immunology samples (proximity to external laboratory). This potential source of bias has been taken into account in domain 2. Risk assessed to be low for the outcomes: Cellular response. Adverse events. Serious adverse events. |
| 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: Cellular response. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective protocol, statistical analysis plan and registry 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 outcomes: Cellular response. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |