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: "The randomisation codes for phases 1 and 2 were generated by the randomisation statistician, using block randomisation and SAS software (version 9.4). The randomisation code was assigned to each participant in sequence in order of enrolment, and participants received the study vaccine or placebo labelled with the same code." (report) "All trial vaccines and placebos will be pasted with blind labels" (protocol) "Personnel who conduct blinding are forbidden to participate in other relevant work of this clinical trial, and should not disclose the blinding code to any person participating in this clinical trial." (protocol) 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: “The vaccine and placebo were completely identical in appearance, and all participants, investigators, and laboratory staff were masked to group allocation.”
Comment: Blinded study (patients and investigators). SAFETY All randomized participants were included in the 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: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Per-protocol analysis was performed on the outcomes. Reasons for exclusion: two participants in the 1·5 μg group were excluded from the per-protocol analysis (one did not have a blood sample taken 28 days after the second dose, and one was found not to meet the eligibility criteria after enrolment. One participant in the 3 μg group was excluded from the per-protocol analysis because the second dose was given outside of the specified time window and one was given placebo. In the placebo group one participants was given 3mcg dose. 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 exclusions. Risk assessed to be some concerns for the outcome: Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: Data from interim analysis Comment: 422 participants randomized in phase 1 and 2; 421 participants analyzed for safety outcomes. 350 participants randomized in phase 2/340 participants . Data available for all or nearly all participants Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. 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. Quote:” After unblinding, the investigators responsible for the observation and evaluation of the subjects and the CRAs responsible for the source data verification should be kept blind until the database is finally locked.” (Protocol) Comment: Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The prospective registry was available (May 12, 2020).
The outcomes Neutralizing antibody GMT, Adverse events and Serious adverse events 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, Adverse events and Serious adverse events The outcomes Local adverse events and Systemic adverse events were not pre-specified No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Local adverse events. Systemic adverse events. |
| Overall risk of bias |
Some concerns |