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: "The phase 2 study participants were randomly assigned (1:1:1) to receive either the 3AU (low), 7AU (medium) or 35AU (high dose) of VLA2001. The randomisation code was generated by the study statistician and allocation was performed within a secure web platform."
Comment: In Phase 1, 15 participants received low, medium and high doses sequentially and unblinded to assess safety, before start of Phase 2. Phase 1 and Phase 2 participants combined for this analysis. Allocation sequence random for the majority of participants. Allocation sequence concealed for the majority of participants. |
| Deviations from intervention |
Low |
Quote: "The investigational medicinal product (IMP) was provided to study sites in packaging that was identical for all strengths of the vaccine. IMP allocation was based on an identifier linked to the randomisation, therefore as there was no visual difference between the doses, study staff and participants remained blinded to dose allocation."
Comment: Blinded study (participants and personnel/carers) apart from 15 participants in Phase 1. This possible source of bias taken into account in Domain 1. Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Mortality. Specific antibody GMTs. Neutralizing antibody GMTs. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 153 participants randomized; 144 to 153 participants analyzed.
Data available for all or nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality. Specific antibody GMTs. Neutralizing antibody GMTs. 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. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality. Specific antibody GMTs. Neutralizing antibody GMTs. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective trial registry was available.
Adverse events and immunologic outcomes 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 GMTs. Local adverse events.Specific antibody GMTs. Systemic adverse events. Adverse events. Serious adverse events. Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified |
| Overall risk of bias |
Some concerns |