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: "Participants were randomly assigned in a blinded manner using the centralized Interactive Response Technology according to pre-generated randomization schedules"
Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. Risk assessed to be low |
| Deviations from intervention |
Some concerns |
Quote: "To maintain the blind, placebo vaccination via the intramuscular route was included, and unblinded site personnel managed vaccine logistics, preparation, and administration (if necessary) so as to maintain the blind from the remainder of the site personnel and participants."
Comment: Not fully blinded study (participants and some personnel were blinded). Two participants crossed over from placebo to vaccine group. This deviation was considered negligible among 968 participants analysed for safety outcomes and 2684 participants analysed for efficacy outcomes. SAFETY The two participants randomized to the placebo group that crossed over were analyzed "as-treated" in the intervention group. Nevertheless, due to the small proportion crossing over, we considered the safety analyses to be probably appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for outcomes: Local adverse events. Systemic adverse events. Unsolicited adverse events. Serious adverse events. IMMUNOGENICTY Per-protocol analysis was performed on the immunogenicity outcomes evaluated in this cohort (as planned in the trial protocol) Reasons for exclusion: did not received both doses (71 vs 77), positive baseline hepatitis B status (38 vs 19), important protocol deviations (27 vs 32), missing at least a baseline and on serum sample result after vaccination (17 vs 14), positiva baseline hepatitis C status (14 vs 20). Risk assessed to be some concerns for the outcomes:Specific antibody GMT. Neutralizing antibody GMT. EFFICACY Per-protocol analysis was performed on the efficacy outcomes evaluated in this cohort (as planned in the trial protocol). Reasons for exclusion: Seropositivity at baseline (849 vS 873), SARS-CoV-2 positivity before day 28 (97 vS 78), Did not received both doses (24 vs 31), had important protocol deviations (4 vS 7), Lost to follow-up (6 vs 9), was withdrawn by physicians (1 vs 0), became pregnant (2 vs 3), Withdrew with no reason reported (10 vs 15), Had adverse event, not related to vaccine (1 vs 0). Risk assessed to be some concerns for the outcomes: Confirmed symptomatic. Confirmed symptomatic against Beta variant. Confirmed COVID19 severe or critical |
| Missing outcome data |
Low |
Comment:
4419 participants randomized; 2684 participants analyzed for efficacy,3947 participants analyzed for immunogenicity, 4408 participants analysed for safety. SAFETY Data available for all or nearly all participants. Risk assessed to be low for outcomes:Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. IMMUNOGENICITY Data available for 89% of population for immunogenicity. Most patients were excluded because the planned analysis was a per-protocol analysis and the bias had been taken into account in domain 2. Risk assessed to be low for the outcomes:Specific antibody GMT. Neutralizing antibody GMT. EFFICACY Data available for 61% of population for efficacy. For efficay outcomes pariticpants were excluded because they had not received the intervention (9 vs. 10), discontinued (24 vs. 31), or were excluded due to seropositive status at baseline (500 vs. 514). Most patients were excluded because the planned analysis was a per-protocol analysis and the bias had been taken into account in domain 2. Risk assessed to be low for the outcomes: Confirmed symptomatic.Confirmed severe or critical EFFICACY AGAINST VARIANTS Variant sequence: 44 cases identified /41 cases sequenced and classified 93.18% of cases analyzed for variants. Data not available for all or nearly all cases. Reasons for missing data: "Of these participants, 41 (93%) had samples that were adequate for whole-genome sequencing; samples from 3 participants in the placebo group could not be sequenced." Missingness could not depend on the true value of the outcome. Risk assessed to be some concerns for the outcomes:Confirmed symptomatic against Beta 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. Confirmed symptomatic aginst Beta variant. Confirmed severe or critical.Specific antibody GMT. Neutralizing antibody GMT. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, SAP and prospective registry were available. (23 June 2020).
SAFETY, EFFICACY, IMMUNOGENICITY Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified for these outcomes. Risk assessed to be low for the outcomes:Confirmed symptomatic. Confirmed severe or critical Specific antibody GMT. Neutralizing antibody GMT; Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. EFFICACY AGAINST VARIANTS Confirmed symptomatic against Beta variant was not prespecified in the registry. Post-hoc anlysis No information on whether the result was selected from multiple outcome measurements or analyses of the data. Risk assessed to be some concerns for the outcome: Confirmed symptomatic against Beta variant. |
| Overall risk of bias |
Some concerns |