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 statistician generated a random allocation sequence. The allocation of the randomization code was concealed by use of the unmasked pharmacist who prepared the vaccine in a location not accessible to other study staff.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “The appearance of the vaccine and placebo were identical, and the participants, investigators, and laboratory staff were blinded to the allocation.”
Comment: Blinded study (participants and personnel/carers). MORTALITY, LOCAL and SYSTEMIC 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. Risk assessed to be low for the outcomes: Mortality, Local adverse events, and Systemic adverse events. CONFIRMED SYMPTOMATIC COVID and CONFIRMED SEVERE COVID Per-protocol analysis was performed on the outcomes. Reasons for exclusion: 2412 vs 905 excluded from analysis, mostly since seropositive at baseline, became unblinded/received other approved COVID-19 vaccine, and PCR positive before 14 days after 2nd dose. 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 balanced proportions between arms. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID and Confirmed severe COVID. |
| Missing outcome data |
Low |
Comment: 16,876 participants randomized; 16,876 participants analyzed for safety outcomes; 15,363 (91%) analyzed for symptomatic COVID-19; 13,067 (77%) analyzed for severe COVID-19.
MORTALITY, LOCAL and SYSTEMIC ADVERSE EVENTS Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality, Local adverse events, and Systemic adverse events. CONFIRMED SYMPTOMATIC COVID and CONFIRMED SEVERE COVID Data not available for nearly all participants randomized. No evidence that the result is not biased. Reasons: most exclusions accounted for in domain 2 due to protocol violations. Other reasons included 10 vs 3 withdrew consent. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID and 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. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (dated August 3, 2021).
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: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. |
| Overall risk of bias |
Some concerns |