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 in each cohort were randomly assigned using block randomization with a block size of five, developed with SAS software (version 9.4). Concealed random grouping allocations and blinding codes were kept in signed and sealed envelopes and were blinded to investigators, participants, and laboratory staff."
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Some concerns |
Quote: “blinded to investigators, participants, and laboratory staff”
Comment: Blinded study (participants and personnel/carers). Analysis for reactogenicity included all participants who received the booster dose, analysis for safety included all who received at least one dose. 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: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. Per-protocol analysis was performed on the immunogenicity outcomes; 7 [12%] vs 12 [20%] vs 5 [17%] participants were excluded. Reasons for exclusion from per-protocol analysis were not clearly reported. 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 relatively small and balanced number of excluded participants. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT. |
| Missing outcome data |
Some concerns |
Comment: 150 participants randomized; 150 participants analyzed for safety; 130 participants analyzed for reactogenicity; 126 participants analyzed for immunogenicity.
Safety data available for all participants randomized. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. Immunogenicity and reactogenicity data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: 2/4/1 withdrew, 2/5/2 informed dissent; 1/1/1 ineligible for dose 3; 1/2/1 reason not reported (immunogenicity only). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome as balanced between arms. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT. Local adverse events. Systemic 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: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol is available but, according to the report, was updated in June 2020. The updated version of the protocol was not available. The registry was available and the third dose interventions were added retrospectively in July 2021.
No information on whether the booster dose results were selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT d14. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |