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: “Block randomization into study arms and placebo was done at a 1:1:1 ratio stratified by site and by a priori defined risk strata: 19–64 years without risk of severe COVID-19, 19–64
years with risk of severe disease, and ≥65 years. ”
Comment: Allocation sequence random. No information on allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Comment: Blinded study (participants and personnel/carers). CONFIRMED SYMPTOMATIC COVID, CONFIRMED SEVERE COVID. MORTALITY Per-protocol analysis was performed on the outcomes. Reasons for exclusion: did not receive dose 2 (232 vs 275), protocol deviation (30 vs 50), Occurrence of Exclusion criteria (49 vs 49), SARS-Cov-2 diagnosis PCR+ (199 vs 221), IgG+ or IgM+ before first dose (43 vs 43), Physician decision (25 vs 26), Other (10 vs 11) 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 groups. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Severe COVID.Mortality. LOCAL, SYSTEMIC, ADVERSE and SERIOUS ADVERSE EVENTS ITT analysis. As we are assessing the effect of assignment to intervention, the analysis method performed on these safety outcomes, was considered appropriate. br/>Risk assessed to be low/for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. [ |
| Missing outcome data |
Some concerns |
Comment: 29354 participants randomized; 29354 participants analyzed for safety; 28674 particpants analyzed for mortality; 28675 participants analyzzed for Confirmed COVID and Severe COVID
MORTALITY, LOCAL, SYSTEMIC, ADVERSE and SERIOUS ADVERSE EVENTS 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. CONFIRMED COVID, SEVERE COVID Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: deviatios from protocol (taking into account in domain 2) lost to follow up (1702 vs 1324). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to balance between arms. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
| 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: Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was 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: Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |