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: "Randomization was performed with the use of a centralized interactive response technology system."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. Risk assessed as low. |
| Deviations from intervention |
Some concerns |
Quote: "The investigators and trial staff, participants, site monitors, and sponsor personnel (or its designees) were unaware of the trial vaccine administered until unblinding of the trial data as specified in the protocol; however, pharmacists and vaccine administrators who were involved in injection preparation and administration and who had no other role in trial conduct were aware of these assignments."
Comment: Blinded study (participants and personnel/carers). SAFETY Data for the safety outcomes were analyzed in the full analysis set with data. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. EFFICACY Data for the outcome Mortality were analyzed in the full analysis set with data. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcome: Mortality. Data for the efficacy outcomes were analyzed using modified intention-to-treat or per protocol analysis. 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. Reasons for exclusion: mITT - did not receive at least one dose, had serologic or virologic evidence of previous SARS-CoV-2 infection before the first injection, received wrong injection; Per protocol - did not receive planned injections of mRNA-1273 or placebo, did not comply with the timing of the second injection, had immunologic or virologic evidence of previous Covid-19 at baseline, and major protocol deviations. Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. |
| Missing outcome data |
Low |
Comment: 3732 participants randomized; 3726 participants analyzed for safety; 3138 to 3236 participants analyzed for efficacy outcomes.
SAFETY Safety data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. EFFICACY Data for the outcome Mortality were available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality. Data for the outcomes Confirmed COVID and Confirmed symptomatic COVID. not available for all or nearly all participants randomized. The reason for missigness f data has been taken into account in domain 2. Risk assessed to be low for the outcomes: Mortality. 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 COVID-19. Confirmed symptomatic COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and prospective registry were available (dated 2 December 2020).
Outcomes were 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 COVID. Confirmed symptomatic COVID. Mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |