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: "Randomisation codes for each vaccination schedule cohort were generated individually and randomly assigned using block randomisation developed with SAS version 9.4. Adults aged 18–59 years were assigned with a block size of five and adults aged 60 years and older were assigned with a block size of 14. Concealed random group allocations and blinding codes were kept in signed and sealed envelopes.
Investigators, participants, and laboratory staff were masked to group assignment. The randomisation code
was assigned to each participant in sequence in the order of enrolment by investigators, who were involved in the rest of the trial."
Comment: Allocation sequence random Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote:"Double blind. Investigators, participants, and laboratory staff were masked to group assignment."
Comment: blinded study SAFETY ITT analysis was used. 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 some concerns for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Per-protocol analysis was performed on the outcomes. Reasons for exclusion: "protocol violations". As per protocol only participants who received their assigned third doses and had available antibody results on day 14 after the third dose were inlcuded in the analysis. 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 of exclusions between arms. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: 510 participants randomized; 510 participants analyzed for safety.
Immunogenicity outcomes: 180 particpants randomized; 162 particpants analyzed. SAFETY Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: protocol deviations (risk assessed in domain 2) Risk assessed to be low for the outcome: Neutralizing antibody GMT. |
| 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 |
Low |
Comment: The protocol, statistical analysis plan, and two prospective registries were available (date April 20, 2020).
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 outcome: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |