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 |
Some concerns |
Quote: “participants were randomly assigned in a blinded manner to one of five vaccine groups … according to pre-generated randomization schedules with two-factor, two-level stratification employed”
Comment: Allocation sequence probably random No information on allocation concealment Risk assessed to be some concerns |
| Deviations from intervention |
Some concerns |
Quote: “Participants and trial site personnel managing the conduct of the trial remained blinded to vaccine assignment.” (report) "Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (registry)
Comment: Blinded study (participants and study personnel) SAFETY Analysis performed on participants who received at least one dose of the intervention. As we are assessing the effect of assignment to intervention, the intention-to-treat 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 IMMUNOGENICITY Quote: "This Set included all participants who received at least 1 dose of study vaccine or placebo. Immunogenicity Analysis Sets are described in the protocol and statistical analysis plan. Any participant who tested SARS-CoV-2 positive by qualitative PCR testing from screening and prior to the immunogenicity assessment for a particular time point were excluded from the Per-Protocol Analysis Set for that time point as were participants who had major protocol deviations that might affect their immune responses" As we are assessing the effect of assignment to intervention, the intention-to-treat analysis method performed on these outcomes, was considered inappropriate. There was probably no substantial impact of failure to analyze participants according to their randomized assignment Risk assessed to be some concerns for the outcomes: Specific antibody GMT. |
| Missing outcome data |
Low |
Comment: 1288 participants randomized; 1283 participants analyzed for safety; 1198 participants analyzed for immunogenicity
SAFETY Data available for 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: likely protocol deviations (accounted for in domain 2) Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Specific 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: Specific antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective trial registry was available (April 30th).
SPECIFIC AB GMT, LOCAL AE, SYSTEMIC AE 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: Specific antibody GMT. Local adverse events. Systemic adverse events. ADVERSE EVENTS Different timepoint in the registry (pre-specified at 28 days and reported at 35 days after first dose) 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 outcomes: Adverse events. SERIOUS ADVERSE EVENTS 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 outcomes: Serious adverse events |
| Overall risk of bias |
Some concerns |