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|
|Quote: "Randomisation lists were prepared by the study statistician (MV) using block randomisation, stratified by study site and study group, and uploaded into to the secure web platform used for the study electronic case report form (REDCap version 9.5.22) for COV001, COV002, and COV003. In COV005, the randomisation list was held by the unmasked study pharmacist who prepared the vaccines for administration, with all other trial staff masked to group allocation."
Comment: Allocation sequence random. Allocation sequence concealed.
|Deviations from intervention||
|Quote: "three single-blind randomised controlled trials in the UK (COV001/COV002), Brazil (COV003), and one double-blind study in South Africa (COV005)"
Comment: Blinded studies (patients in 3 trials, patients and physicians in 1 trial).
No participant cross-over.
Intention to treat analysis was performed on the outcomes: All cause mortality.Severe or critical COVID. Adverse events. Serious adverse events.As we are assessing the effect of assignment to intervention, this analysis method was considered appropriate.
Risk assessed to be low for the outcome:All cause mortality. Severe or critical COVID. Adverse events. Serious adverse events.
Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol).
Reasons for exclusions: In non-randomised open-label group; In HIV cohorts; Not enrolled in an efficacy cohort; Not in SD/SD or LD/SD vaccine group; Baseline seropositivity results unavailable; Baseline seropositivity results positive; Vaccine administration errors; Less than 15 days of follow up accrued post second dose; PCR+ test ? 14 days post-second dose
As we are assessing the effect of assignment to intervention (intent-to-treat effect), this domain was evaluated as some concerns for efficacy outcomes.
Risk assessed to be some concerns for outcomes: Confirmed COVID. Confirmed symptomatic COVID.Hospital admissions or death due to confirmed COVID.
|Missing outcome data||
|Comment: Data from interim analysis.
24,422 participants randomized; 24,422 participants analyzed for safety; 17,117 participants analyzed for efficacy.
Data available for all participants for safety, 70% of participants for efficacy.
Reasons for missingness are unrelated to the outcome (exclusion of ineligible participants, administrator error, interruptions due to interim analysis etc.) and were already accounted for in ROB domain 2 of bias due to deviation of intervention.
Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Severe or critical COVID. Hospital admissions or death due to confirmed COVID.All casue mortality.Adverse events. Serious adverse events.
|Measurement of the outcome||
|Quote: "All endpoints were adjudicated for inclusion in the analysis by an independent blinded endpoint review committee"
Comment: Blinded outcome assessors.
Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID.Severe or critical COVID. Hospital admissions or death due to confirmed COVID. All cause mortality. Adverse events. Serious adverse events.
|Selection of the reported results||
|Quote: "This report provides updated primary efficacy and safety results after a
further month of data collection"
Comment: The protocols, statistical analysis plan, and registries were available for each of the four included trials.
The updated efficacy results reported were not analyzed as pre-specified in terms of endpoints and subgroups.
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 COVID. Confirmed symptomatic COVID. Severe or critical COVID. Hospital admissions or death due to confirmed COVID. All cause mortality. Adverse events. Serious adverse events.
|Overall risk of bias||