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: "a randomization
list was created by the stratified blocked randomization method using the SAS
software (version 9.4)... A vaccine randomization list was also generated using SAS software with a
randomization block size of 10. Then, participant and vaccine randomization lists
were inputted into the interactive web response system (IWRS), and participants
were vaccinated according to the randomization number and vaccine number
obtained from IWRS. The randomization and blinding were conducted by independent
personnel who were not involved in the study."
Comment: Allocation sequence random. Allocation sequence probably concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind" trial.
Comment: Blinded study (participants and personnel/carers). Mortality Safety analysis on those who received at least one dose of the intervention. 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 outcome: Mortality. Neutralizing antibody GMT, Neutralizing seroconversion rate Per-protocol analysis was performed on the outcomes. Reasons for exclusion: 14 vs 12 vs 27 vs 33 vs 14 vs 22 participants due to protocol deviations. 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 similar proportions between groups. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT. Neutralizing seroconversion rate. Neutralizing antibody GMT omicron. Per-protocol analysis was performed on the outcomes. Reasons for exclusion: only a subset of 200 participants with sequential enrollment numbers in the 7–9-month group were used in the cross-neutralizing activity tests. 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 outcome: Neutralizing antibody GMT omicron. |
| Missing outcome data |
Low |
Comment: 1833 participants randomized; 1800 participants analyzed for safety; 1678 analyzed for Neutralizing antibody GMT; 200 analyzed for nAb against Omicron.
Mortality Data available for nearly all participants randomized. Risk assessed to be low for the outcome: Mortality. Neutralizing antibody GMT, Neutralizing seroconversion rate, Neutralizing antibody GMT Omicron Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for nAb GMT: 33 (2%) participants withdrew; while most of the exclusions were accounted for in Domain 2. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Neutralizing seroconversion rate. Neutralizing antibody 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: Mortality. Neutralizing antibody GMT. Neutralizing seroconversion rate. Neutralizing antibody GMT Omicron. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and registry were available (dated October 6, 2021).
Mortality, Neutralizing seroconversion rate, and Neutralizing antibody GMT 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 outcomes: Mortality. Neutralizing seroconversion rate. Neutralizing antibody GMT. Neutralizing antibody GMT Omicron Outcome 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. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT Omicron. |
| Overall risk of bias |
Some concerns |