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 randomization scheme was generated using SAS software (version 9.4 or higher). For the age group ≥30 years, an overall randomization ratio of 2:1 was achieved as follows: Participants were evaluated for their COVID-19 serostatus at screening (rapid antibody test). Seronegative participants were randomized 1:1 to receive either VLA2001 or AZD1222, until a total of 1,200 participants had been randomized in the immunogenicity subgroup. Remaining seronegative participants, as well as seropositive participants, were randomized 7:2 to VLA2001 or AZD1222. The block sizes for randomization type were block type with a size: multiple of 2 (1:1 ratio) and 9 (7:2 ratio); and the randomization number scheme consisted of 5 digits. Designated personnel involved in obtaining randomization codes and preparing the vaccines were not masked.”
Comment: Allocation sequence random. Unclear allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “In the observer blinded study arms, vaccine group allocation was concealed from the study personnel involved in the outcome assessments. Designated personnel involved in obtaining randomization codes and preparing the vaccines were not masked. All other laboratory/medical personnel and participants were masked.”
Comment: Blinded study (participants and personnel/carers). SAFETY Safety analysis was conducted on all participants who received at least one dose. 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 immunogenicity outcomes in pre-specified randomly sampled subgroups. Reasons for exclusion: positive COVID-19 MNA at screening (14·0% vs. 13.2%), COVID infection (2.2% vs. 1.8%), missing sample (1.8% vs. 1.7%). 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 between groups. Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. |
| Missing outcome data |
Low |
Comment: 2975 participants randomized; 2972 participants analyzed for safety, 148-985 participants analyzed for immunogenicity.
SAFETY Data available for all or nearly all participants randomized for safety. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Data not available for all or nearly all participants randomized for immunogenicity, but this potential risk of bias has been taken into account in domain 2. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. |
| 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. Cellular response. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (Date April 24, 2021).
Safety and immunogenicity 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: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |