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: "Through the use of an interactive Web-based system, participants were randomly assigned"
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
Deviations from intervention |
Some concerns |
Quote: "all participants and study personnel, with the exception of those preparing or administering the injections, were unaware of group assignments"
Comment: Blinded study (participants and personnel/carers). Safety analysis was carried out on participants who received at least one dose of the intervention. 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. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. Per-protocol analysis was performed on efficacy and immunogenicity outcomes. Reasons for exclusion: 14 [0.9%] vs. 10 [1.3%] did not receive 2 doses; 64 [4.2%] vs. 11 [1.5%] had important protocol deviations as determined by the investigator or did not complete 1 month follow-up after the second dose. For immunogenicity, a subset of 394/2285 (117.2%) was analysed as planned in the protocol. 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 small number of excluded participants for efficacy and to the pre-planned method of analysis for immunogenicity. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Neutralizing antibody GMT. |
Missing outcome data |
Low |
Comment: 2285 participants randomized; 2268 to 2260 participants analyzed for safety; 2186 participants analysed for efficacy; 394 participants analysed for immunogenicity.
Safety and efficacy data available for nearly all participants randomized. Immunogenicity data not available for all or nearly all participants randomized. Reasons for missing immunogenicity data were accounted for in risk of bias domain 2 (per-protocol analysis of a small subset of participants). Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. |
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. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. |
Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry were available (dated 25 March 2021).
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. Confirmed severe COVID. Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. |
Overall risk of bias |
Some concerns |