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: "Using an interactive web response system, participants were randomised by centre in a 1:1 ratio to either the Ad5-nCoV group or the placebo control group. A subset of 3000 participants, proportionally balanced between countries of enrolment, comprised an extended safety and or immunogenicity cohort for additional monitoring. Participants were assigned a treatment identification number to ensure adequate blinding."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “Participants and study staff remained blinded to the participant’s assigned group.”
Comment: Blinded study (participants and personnel/carers). All participants that received intervention in immunogenicity and safety sub-cohorts were analysed, except ten participants in the safety cohort. 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: Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. Per-protocol analysis was performed on the efficacy outcomes. Reasons for exclusion: vaccinated twice (6 vs. 2); missing data (235 vs. 220), enrolled on cut-off date (243 vs. 236), PCR positive with covid symptoms on date of injection (3 vs. 5), remaining reasons were not reported but likely to be because 14 days post vaccination had not been reached. 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 balanced reasons between groups. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. |
| Missing outcome data |
Low |
Comment: 36,982 participants randomized; 36,717 participants analyzed for SAEs; 29,177 participants analyzed for efficacy; 3154/3159 participants analyzed for reactogenicity and AE; 508 participants analyzed for immunogenicity.
Data available for all or nearly all participants randomized for SAEs. Data not available for all or nearly all participants randomized for efficacy, reactogenicity, AEs and immunogenicity. No evidence that the result is not biased. Reasons: Efficacy analysis was triggered by a predefined incidence of the primary efficacy outcome (confirmed disease), at which point not all participants had completed ≥14 days of follow up. Subcohorts (the extended safety cohort, which collected detailed solicited and unsolicited adverse events following immunisation; the immunogenicity cohort, a subset of the extended safety cohort in which antibody responses prevaccination and postvaccination were measured) were pre-defined. The size of the subcohorts was based on regulatory guidance of size of the safety and immunogenicity database recommended for emergency use authorisation. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome because the cohorts were predefined. These potential sources of risk of bias have been taken into account in domain 2. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to 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: Confirmed symptomatic COVID. Confirmed severe COVID. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry were available.
Outcome 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. Confirmed severe COVID. Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |