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. |
| Deviations from intervention |
Some concerns |
Quote: “Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)”
Comment: Blinded study (participants and personnel/carers) EFFICACY 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 due to the small number. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID-19 after first dose. Confirmed symptomatic against Beta variant Severe or critical COVID-19. SAFETY Safety outcomes such as serious adverse events, withdrawals due to adverse events and all-cause mortality were analyzed on the full analysis set (all participants who received vaccine or placebo). As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed appropriately. Risk assessed to be low for the outcomes: Serious adverse events. Withdrawals due to adverse events. All-cause mortality. Adverse events (solicited and unsolicited) were monitored in a safety subset of volunteers in centers (as planned in the trial protocol). Reasons: centers selected based on rapid start-up capacity and projected incidence rates for COVID-19 that would allow for rapid efficacy signal detection 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: - The safety subset was prespecified and the researchers are transparent about any differences between the safety subset and the overall population. - Furthermore, it was used as a way to gather detailed data on solicited local/systemic adverse events for the 7 days after each injection. All participants were trained in assessing and reporting events by study staff. All data was transferred automatically to the centers using e-diaries. As a result, the participants were all at a subset of centers that had sufficient research capacity, which we considered a reasonable logistical decision. Risk assessed to be some concerns for the outcomes: Local adverse events. Systemic adverse events. Adverse events (unsolicited). |
| Missing outcome data |
Some concerns |
Comment: 44325 patients randomized; 43783 patients analyzed for safety; 39321 patients analyzed for efficacy.
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. Risk assessed to be low for outcomes: Confirmed symptomatic COVID-19 after first dose. Severe or critical COVID-19. EFFICACY AGAINST VARIANTS Variant sequence: 171 cases identified /91 cases sequenced and classified 53.21% of cases analyzed for variants. Data not available for all or nearly all participants randomized. Reasons for missing data: not reported Missingness could not depend on the true value of the outcome. Risk assessed to be some concerns for the outcome: Confirmed symptomatic against Beta variant. SAFETY Data available for all or nearly participants for serious adverse events, withdrawals due to adverse events and mortality outcomes (<95%). Risk assessed to be low for outcomes: All-cause mortality. Serious adverse events. Withdrawals due to adverse events. Data not available for all or nearly participants for the other safety outcomes. No evidence that the result is biased. Patients were excluded because this was a subgroup of volunteers from centers selected based on rapid start-up capacity and projected incidence rates for COVID-19 that would allow for rapid efficacy signal detection and the bias had been taken into account in domain 2. Hence missingness was considered unrelated to the true value of the outcome. Risk assessed to be low for outcomes: Local adverse events. Systemic adverse events. Adverse events (unsolicited). |
| 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-19 after first dose. Severe or critical COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events (Unsolicited). Serious adverse events. Withdrawals due to adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and registry were available.
Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. EFFICACY ON VARIANTS 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 outcomes: Confirmed symptomatic COVID-19 after first dose. Confirmed symptomatic against Beta variant. Confirmed hospital admissions or death. Severe or critical COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events (unsolicited). Serious adverse events. Withdrawals due to adverse events. |
| Overall risk of bias |
Some concerns |