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: "Computer-generated randomisation lists were prepared by the study statistician" "Clinical research nurses who were not involved in safety endpoint evaluation performed the randomisation using REDCapTM (the electronic data capture system)"
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 |
Some concerns |
Quote: "Clinical research nurses who were not involved in safety endpoint evaluation ... prepared and administered vaccine" (report) "Staff involved in study delivery will be aware of which vaccine the participant is receiving (arm allocation); the participant themselves will remain blinded to their vaccine allocation" (protocol) "Participants and laboratory staff processing the immunogenicity endpoints were blinded to vaccines received" (report) "Participant blinding to vaccines was maintained by concealing randomisation pages, preparing vaccines out of sight and applying masking tape to vaccine syringes to conceal dose volume and appearance" (report)
Comment: Single blind study (participants blinded, personnel not blinded). Deviations from intended intervention arising because of the study context: No participant cross-over. Co-interventions of interest (PPE, use of painkillers/NSAIDs, other vaccines) were not described, we assume they were not used or that they were balanced between groups. Hence, deviations did probably not arise because of the trial context. SAFETY Data for safety outcomes 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 outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Per-protocol analysis was performed on the immunogenicity outcomes (as planned in the trial protocol where they are called modified intention to treat analyses). Reasons for exclusions: Positive baseline SARS-CoV-2 status (n=20), COVID-19 positive in days 0-14 post prime (n=2), Withdrew from trial before D56 (n=1), Failed bleed at day 56 (n=8). 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 reasons for exclusions being balanced between treatment groups (10 [8.7%] vs 6 [5.3%] vs 9 [7.6%] vs 6 [5.2%]). Risk assessed to be some concerns for outcomes: Cellular response. |
| Missing outcome data |
Some concerns |
Comment: 463 participants randomized; 463 participants analyzed for Adverse events and Serious adverse events; 353 participants analyzed for local and systemic adverse events; 408 to 432 participants analyzed for immunogenicity.
ADVERSE EVENTS. SERIOUS ADVERSE EVENTS Data available for all participants randomized for safety. Risk assessed to be low for outcomes: Adverse events. Serious adverse events. LOCAL ADVERSE EVENTS.SYSTEMIC ADVERSE EVENTS Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons unclear. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome due to balance between arms. Risk assessed to be some concerns for the outcomes: Local adverse events. Systemic adverse events. IMMUNOGENICITY Data not available for all or nearly all participants randomized for immunogenicity. No evidence that the result is not biased. The bias is accounted for in domain 2. Risk assessed to be low for outcomes: Cellular response. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Quote: "Laboratory staff will also be blinded to the vaccine schedule received." (protocol) "The clinical team assessing the safety endpoints were not blinded" (report) Comment: Outcome assessment was blinded for immunogenicity outcomes and unblinded for safety outcomes; CELLULAR RESPONSE Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Cellular response. LOCAL, SYSTEMIC, ADVERSE and SERIOUS ADVERSE EVENTS These outcomes may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective protocol, statistical analysis plan, and registries were available (10-Feb-2021).
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: Cellular response. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |