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 1:1 ratio via block randomization to receive two doses of NVX-CoV2373 or placebo (normal saline), 21 days apart, using a centralized Interactive Response Technology system according to pre-generated randomization schedules" 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: "This was an observer-blinded study. Only unblinded site personnel managed study vaccine logistics and preparation and they were not involved in study-related assessments or had participant contact for data collection following vaccine administration" (report) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor" (NCT04583995 registry) "Double blind" (EudraCT 2020-004123-16 registry) Comment: Blinded study (participants, personnel, investigators). Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol). Reasons for exclusions were balanced between treatment groups (549 [7.2%] vs 551 [7.3%]), with the majority of those excluded due to seropositivity before 7 days after dose 2 (399 vs 402). Other reasons: Received only 1 dose (102 vs 107); Had major protocol deviation, missed dose, or censoring event (48 vs 42). As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was no substantial impact of failure to analyze participants according to their randomized assignment Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID-19 (variant) |
| Missing outcome data |
Some concerns |
Comment: 15,187 participants randomized; 14,039 participants analyzed for efficacy. Most of the missing efficacy data were due to protocol violations that were accounted for in domain 2. Variant classification: 106 cases identified /95 cases sequenced and classified 89.62% of cases analyzed for variants No evidence that the result is not biased. No reasons for missing data reported Missingness could depend on the true value of the outcome Not likely that missingness depended on the true value of the outcome Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID-19 (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.>br/>Blinded study (outcome assessor). It is not clear if cases were unblinded at the moment of the identification of the variant however, we consider these results can't be affected by the knowledge of the intervention allocation. Risk assessed to be low for the outcome: Confirmed symptomatic COVID-19 (variant) |
| Selection of the reported results |
Some concerns |
Comment: The protocol, SAP and prospective registry were available.(24 August 2020). The outcome Confirmed symptomatic B.1.117 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. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Confirmed symptomatic COVID-19 (variants) |
| Overall risk of bias |
Some concerns |