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." (original phase 1/2 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 |
Low |
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). Per-protocol analysis was performed on the outcomes. In the original phase 1-2 trial population two participants (0.5%) crossed over to a different group due to mistakenly receiving an intervention they were not assigned to. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately, however, the proportion moved to another group was negligible. Risk assessed to be low for the outcomes: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 350 participants randomized; 349 participants analyzed for serious adverse events; 303 participants analyzed for other adverse events; 144 participants analyzed for immunogenicity.
SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized for this outcome. Risl assessed to be low for the outcome: Serious adverse events NEUTRALIZING ANTIBODY GMT. LOCAL ADVERSE EVENTS. SYSTEMIC ADVERSE EVENTS. ADVERSE EVENTS Data not available for all or nearly all participants randomized for this outcomes No evidence that the result is not biased. Reasons: 14%, 10%, 17% and 2% withdrew; 1%, 0%, 2% and 4% did not receive at least one dose. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcomes: Neutraizing antibody GMT. Local adverse events. Systemic adverse events. 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: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan and registry for the original 2-dose phase 1-2 trial were available.
Outcomes for the booster dose trial not pre-specified. No information on whether the results were selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Solicited adverse events. Adverse events. |
| Overall risk of bias |
Some concerns |