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: "Randomization was stratified on center and age group (18–64 years or ≥ 65 years). A web-based
randomization system was used (CleanWeb e-CRF, Telemedecine Technologies, S.A.S), with a
centralized block randomization list with blocks of size 4 (not communicated to the
investigating team). The randomization list was generated by an independent statistician from
the trial clinical research unit (URC-EST). Participants were randomized by the investigator.
Vaccines were administered intramuscularly into the deltoid muscle on day 0 by trained
personnel. The health care professional administering the vaccine was aware of the treatment
group because of differences in the preparation of the vaccines. The injection was therefore
performed by a person not involved in the study and the investigating physician did not know
which vaccine the volunteer had received."
Comment: Allocation sequence random. Allocation sequence probably concealed. |
| Deviations from intervention |
Some concerns |
Quote: "single-blinded".
Comment: Unblinded study (participants unblinded and personnel/carers blinded). Deviations from intended intervention arising because of the study context: No participant cross-over. Hence, deviations did not arise because of the trial context. MORTALITY, LOCAL, SYSTEMIC, 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. Risk assessed to be low for the outcomes: Mortality, Local adverse events, Systemic adverse events, and Serious adverse events. SPECIFIC ANTIBODY GMT and NEUTRALIZING ANTIBODY GMT Per-protocol analysis was performed on the outcomes. Reasons for exclusion: 8 vs 8 vs 5 due to COVID infection or positive serology; 2 insufficient volume for blood draw; 1 wrongly included. 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 similar proportions across groups. Risk assessed to be some concerns for the outcomes: Specific antibody GMT and Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: 247 participants randomized; 247 participants analyzed for safety outcomes & COVID; 223 (90%) analyzed for immunogenicity.
MORTALITY, LOCAL, SYSTEMIC, and SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality, Local adverse events, Systemic adverse events, and Serious adverse events. SPECIFIC ANTIBODY GMT and NEUTRALIZING ANTIBODY GMT Data not available for nearly all participants randomized. No evidence that the result is not biased. Reasons: all 24 were protocol violations accounted for in domain 2. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Specific antibody GMT and Neutralizing antibody GMT. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor re: participants; blinded investigating physician and lab personnel). MORTALITY, SPECIFIC ANTIBODY GMT, and NEUTRALIZING ANTIBODY GMT Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality, Specific antibody GMT, and Neutralizing antibody GMT. LOCAL, SYSTEMIC, and SERIOUS ADVERSE EVENTS The authors reported on adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Local adverse events, Systemic adverse events, and Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and registry were available (dated November 17, 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: Mortality, Specific antibody GMT, Neutralizing antibody GMT, Local adverse events, Systemic adverse events, and Serious adverse events. |
| Overall risk of bias |
Some concerns |