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 |
Some concerns |
Quote: "no specific randomisation was used when allocating participants to the vaccinations schedule cohorts" "The randomisation codes for each vaccination schedule cohort were generated individually, using block randomisation with a block size of six in phase 1 and a block size of five in phase 2, using SAS software (version 9.4). The randomisation code was assigned to each participant in sequence in the order of enrolment, and then the participants received the investigational products labelled with the same code" Comment: No specific randomisation between schedule cohorts. The allocation sequence between vaccine groups and placebo was generated adequately. Unclear allocation concealment. Risk assessed as some concerns |
| Deviations from intervention |
Some concerns |
Quote: "The vaccine and the placebo are identical in appearance. All participants, investigators, and laboratory staff were masked to treatment allocation." (publication) "Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (trial registry) Comment: Blinded study (patients, care providers, and investigators). SAFETY All randomized participants who received at least one dose were analysed for safety outcomes. 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 outcomes: Local adverse events. Systemic adverse events. Adverse events. IMMUNOGENICITY Per-protocol analysis was performed on the outcomes. Reasos fro exclusion: "A participant in the 6 μg group was mistakenly given placebo rather than vaccine at the second dose; therefore, this participant was included in the 6 μg group dataset in the overall safety evaluation but not in the immunogenicity analysis. Two participants (in the 3mcg group) did not have available antibody results, and so were not included in the immunogenicity analysis. One participant (in the placebo group) did not have available antibody results, and so was not included in the immunogenicity analysis. 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 outcomes: Specific antibody GMT. Neutralizing antibody GMT. |
| Missing outcome data |
Low |
Comment: 600 participants randomized; 600 participants analyzed for adverse evens outcomes; 590 participants analyzed for neutralizing antibody outcomes; 582 participants analyzed for specific antibody outcomes. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Total 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: Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were not available at the time of data extraction. The prospective trial registry was available (April 20, 2020)
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: Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. |
| Overall risk of bias |
Some concerns |