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|
|Quote: "Participants were randomly assigned, using an interactive response technology system"
Comment: Allocation sequence random.
Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
|Deviations from intervention||
|Quote: "This study had a modified double-blind design, such that all participants and outcome assessors were masked to group assignments and unblinded study staff involved in vaccine preparation were not involved in safety outcome assessments"
Comment: Partially blinded study (blinded participants, unblinded personnel).
Deviations from intended intervention arising because of the study context:
Cross-over: One participant randomized to the high-dose group received medium antigen dose vaccine formulation on D0 and received a high-dose formulation as planned on D22.
We do not consider cross-over of one participant as having any important impact on the results.
Safety outcome and mortality were analysed for those who received at least one dose of the intervention, according to the vaccine actually received. Since only one participant crossed over, we do not consider this having any important impact on the results.
As we are assessing the effect of assignment to intervention, this analysis method was considered appropriate.
Risk assessed to be low for the outcomes: Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Per-protocol analysis was performed in the immunogenicity outcomes.
Reasons: deviations from 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 balance number of exclusions between arms.
Risk assessed to be some concern for the outcome: neutralizing antibody GMT
|Missing outcome data||
|Comment: 722 participants randomized; 721 participants analyzed for mortality and adverse events; 714 participants analyzed for solicited local and systemic reactions/496 participants analyzed for neutralizing antibodies GMT
Data were available for nearly all participants randomized for safety outcomes and mortality.
Data were not available for all or nearly all participants randomized for neutralizing antibody GMT, however the missignes was due to deviations in the protocol and the bias is already assessed in domain 2.
Risk assessed to be low for the outcomes: Mortality. Neutralizing antibody GMT Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
|Measurement of the outcome||
|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: Mortality. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
|Selection of the reported results||
|Comment: The prospective trial registry was available (dated 21 February, 2021).
Outcomes were 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: neutralizing antibody GMT. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
|Overall risk of bias||