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). SAFETY All randomized participants who received at least one dose were analysed for safety outcomes. 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: Adverse events. Serious adverse events. EFFICACY 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. Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Confirmed symptomatic against Alpha variant. All-cause mortality. IMMUNOGENICITY Per-protocol analysis was performed on the immunogenicity outcomes (as planned in the trial protocol). From protocol: "Immune measurements (ELISA) will be conducted on serum (IgG) for SARS-CoV-2 anti-S protein serology in approximately 900 participants in the Anti-S Protein Serology Subset"; "Additional immunogenicity assessments specific to SARS-CoV-2 (or related variants) will include a neutralising antibody assay, which will be performed in approximately 900 participants in a Neutralisation Assay Subset"; "Cell-mediated immune responses, as assessed by ELISpot ± intracellular cytokine staining, will be performed in approximately 450 participants in the Cell-mediated Assay Subset." Number of particpants analyzed were balanced between treatment groups. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. Risk assessed to be some concerns for the outcomes:Specific antibody GMT. Neutralizing antibody GMT. Cellular response |
| Missing outcome data |
Low |
Comment: 15,185 participants randomized; 15,139 participants analyzed for safety; 13,989 participants analyzed for efficacy; between 950 and 831 participants analyzed for immunogenicity outcomes.
SAFETY Safety data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. EFFICACY 8% missing data. Data not available for all or nearly all cases. No evidence that the result is not biased. Protocol deviations (accounted for in domain 2) Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. All-cause mortality. EFFICACY AGAINST VARIANTS 106 cases identified /95 cases sequenced and classified 89.62% of cases analyzed for identification of variants. Data not available for all or nearly all cases. No evidence that the result is not biased. Reasons for missing data: "Unknown samples were those where the PCR tests were performed with a non-DHSC PCR test (e.g., at a local hospital laboratory) where variant determination was not performed." Missingness could not depend on the true value of the outcome. Risk assessed to be some concerns for the outcome: Confirmed symptomatic against Alpha variant. IMMUNOGENICITY Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Outcomes analyzed in a sub-set of paerticipants according to protocol (accounted for in domain 2). Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. Cellular response. |
| 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 COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Confirmed symptomatic against Alpha variant. All-cause mortality. Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective protocol, statistical analysis plan were available(24 August 2020).
SAFETY, EFFICACY, IMMUNOGENICITY 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. Confirmed severe COVID. All-cause mortality. Specific antibody GMT. Neutralizing antibody GMT. Cellular response. Adverse events. Serious adverse events. EFFICACY AGAINST VARIANTS The outcome Confirmed symptomatic against Alpha 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 Alpha variant. |
| Overall risk of bias |
Some concerns |