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: “Central randomization will be implemented in this study. This will be based on a computer-generated randomization schedule prepared before the study by or under the supervision of the sponsor. The IWRS will assign a unique intervention code, which will dictate the intervention assignment for the participant.” Comment: Allocation sequence random. Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance. Risk assessed to be low. |
| Deviations from intervention |
Some concerns |
Quote: “Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)” Comment: Blinded study (participants and personnel/carers) Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol). Reasons for exclusion: Positive SARS-CoV-2 status at time of vaccination based on serology and/or PCR; Major protocol deviation evaluated to possibly impact efficacy (In/exclusion criteria ; Received wrong treatment or incorrect dose; Received a disallowed concomitant medication; Other) As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was no substantial impact of failure to analyze participants according to their randomized assignment Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID-19 (variant) |
| Missing outcome data |
Some concerns |
Comment: 44325 patients randomized; 39321 patients analyzed for efficacy. Data not available for all or nearly participants for efficacy (89%). No evidence that the result is biased. Patients were excluded because they violated the protocol or positive SARS-CoV-2 status at time of vaccination and the bias had been taken into account in domain 2. Hence missingness was considered unrelated to the true value of the outcome. Variant classification: 171 cases identified /91 cases sequenced and classified 53.21% of cases analyzed for variants. No evidence that the result is not biased. No reasons for missing data reported Missingness could depend on the true value of the outcome Not likely that missingness depended on the true value of the outcome Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID-19 (variant) |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups.>br/>Blinded study (outcome assessor). It is not clear if cases were unblinded at the moment of the identification of the variant however, we consider these results can't be affected by the knowledge of the intervention allocation. Risk assessed to be low for the outcome: Confirmed symptomatic COVID-19 (variant) |
| Selection of the reported results |
Low |
Comment: The prospective protocol, statistical analysis plan and registry were available (22 July 2020) Outcome pre-specified "Development of SARS-CoV-2 variants" reported as exploratory endpoint in the protocol. 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: Confirmed symptomatic COVID-19 (variant) |
| Overall risk of bias |
Some concerns |