| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "The randomization will be in a blinded manner using a centralized Interactive Response Technology (IRT), in accordance with pregenerated randomization schedules" (protocol) Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "The investigator, study staff, study participants, site monitors, and Sponsor personnel (or its designees) will be blinded to the IP administered until study end" (protocol) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor" (registry) Comment: Blinded study (participants, personnel, investigators). 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 outcomes: Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. Per-protocol analysis was performed on the efficacy outcomes (as planned in the trial protocol). Reasons for exclusions were balanced between treatment groups (1274 [8.4%] vs 1327 [8.7%]), with the majority of those excluded due to positive or unknown baseline SARS-CoV-2 status (868 vs 800). Other reasons: Randomized but received no investigational product (IP) (28 vs 40), Received IP other than what the participant was randomized to (5 vs 7), Discontinued study or study vaccine without receiveing second dose (136 vs 203), Did not receive second dose of IP (144 vs 155), Received vaccine out of window (81 vs 98), Major protocol deviation (12 vs 24). As we are assessing the effect of assignment to intervention (intent-to-treat effect), this domain was evaluated as some concerns for the efficacy outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Authors refer to three patients in the vaccine group who had cross over and recieved at lease one dose of placebo. We decided not to downgrade for risk of bias since the percentage is low. Quote:"Among participants who received an incorrect injection, three participants in the mRNA-1273 group received at least one dose of placebo and no dose of mRNA-1273 and were included in the placebo safety population, and three received one dose of placebo and one dose of mRNA-1273 and were included in the mRNA-1273 safety population; in the placebo group all seven received mRNA-1273 and were included in the mRNA-1273 safety population." |
| Missing outcome data |
Low |
Comment: Data from interim analysis. 30,418 participants randomized; 29,235 to 30,351 participants analyzed for safety outcomes; 28,207 participants analysed for efficacy outcomes. Data available for >95% of population for safety outcomes. Data were available for 93% of efficacy population where 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 outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Quote: “Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor” (registry) "COVID-19 Cases were adjudicated by a blinded committee" Comment: Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and registry were available. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed appropriately for an interim analysis. Risk assessed to be low for the outcomes: Confirmed symptomatic COVID. Confirmed severe COVID. Mortality. Local adverse events. Systemic adverse events. Unsolicited adverse events. Withdrawals due to adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |