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: "Unblinded statisticians (Cytespace Research and Octalsoft) were involved in designing the randomisation plan and theinteractive web response system(IWRS) system for the study. Therandomisation plan,stratified for thepresence or absence of chronic conditions,was used to generate treatment allocation. The master randomisation list, containing the randomisation number and intended treatment allocation, as well as the kit code, was sent to the IWRSand kits were despatched to the sites according to the IWRSby an unblinded statistician from the CROtasked with labelling of vaccine vials and the generation of the master randomisation code.Participants were assigned a computer-generated randomisation code and each vial was labelled with a unique code that ensured appropriate masking. The IWRS system assigned the same treatment group for the second visit.
Allocation sequence random. allocation sequence concealed. Risk assessed to be low. |
| Deviations from intervention |
Some concerns |
Quote: “Study staff and the participants were masked to group assignment.”
Comment: Blinded study (participants and personnel/carers) Per-protocol analysis was performed on the efficacy outcomes where 8841 [58.6%] vs. 8978 [59.5%] participants were excluded. Reasons for exclusion: did not receive any injection, baseline seropositive, missing baseline serology, not scheduled to receive a second dose, positive on RT-PCR for COVID-19 before day 14 after the second dose, received other COVID-19 vaccine, randomisation code broken, inclusion criteria deviations, randomisation errors, did not comply with schedule, deviations from pharmacy manual. 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 due to similar proportions and reasons for exclusion in the pre-planned per protocol analysis. Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID against Delta variant. |
| Missing outcome data |
Some concerns |
Comment: Data from interim analysis. Comment: 30174 participants randomized (1601 in the embedded Phase 2 reactogenicity set); 30128 participants analyzed for safety; 1589 participants analyzed for reactogenicity (Phase 2 reactogenicity set); 12,355 participants analyzed for efficacy. Data not available for all or nearly all participants randomized for efficacy, but this possible risk of bias was taken into account in domain 2. Variant classification: 207 cases identified /146 cases sequenced and classified 70.53% of cases analyzed for variants. Risk assessed to be some concerns for the outcome: Confirmed symptomatic against Delta variant. |
| 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: Confirmed symptomatic COVID against Delta variant. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available. 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: Confirmed symptomatic COVID against Delta variant. |
| Overall risk of bias |
Some concerns |