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 |
Quotes: "Random assignment" (report) "All participants will be centrally assigned to randomized study intervention using an IRT [Interactive Response Technology]." (protocol) "The IRT will provide the investigator(s) or pharmacists a dose tracking number to be allocated to the participant at the dispensing visit." (protocol)
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 |
Quotes: "double-blind"
Comment: Blinded study (participants and personnel/carers). ADVERSE EVENTS; SERIOUS ADVERSE EVENTS Data for the outcomes adverse events and serious adverse events were analyzed using modified intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. LOCAL REACTOGENICITY EVENTS; SYSTEMIC REACTOGENICITY EVENTS Data for the outcomes local reactogenicity and systemic reactogenicity were assessed in a subgroup of participants (pre-specified in the protocol). Quote: "The first participants randomized in each age group in the United States of America participated in a substudy to assess immunogenicity and reactogenicity". 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 since the subset was prespecified and the researchers are transparent about any differences between the safety subset and the overall population. Risk assessed to be some concerns for the outcomes: Local reactogenicity events. Systemic reactogenicity events. IMMUNOGENICITY Data for the outcomes specific antybody GMTs and neutralazing antibody GMTs were assessed in a subgroup of participants (pre-specified in the protocol). Quote: "The first participants randomized in each age group in the United States of America participated in a substudy to assess immunogenicity and reactogenicity". 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 since the subset was prespecified and the researchers are transparent about any differences between the safety subset and the overall population. Risk assessed to be some concerns for the outcomes: Specific antybody GMTs. Neutralazing antibody GMTs. EFFICACY Data for the outcome mortality were analyzed using modified intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Mortality. Per-protocol analysis was performed for the outcomes Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Reasons for exclusion: did not receive first dose: 51 (0.2%) vs. 19 (0.2%), Had a positive, missing, or indeterminate serostatus at baseline: 1046 (4.8%) vs. 516 (4.8%); Were followed for <15 days after second dose: 2206 (10.2%) vs. 920 (8.5%); Had confirmed SARS-CoV-2 RT-PCR–positive Covid-19 infection <15 days after second dose: 73 (0.3%) vs. 69 (0.6%). 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 due to similar levels of and reasons for exclusion in either arm. Risk assessed to be some concerns for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. |
| Missing outcome data |
Some concerns |
Comment: 32451 participants randomized;32448 participnats analyzed for the oucome all cause mortality; 32380 participants analyzed for adverse events and serious adverse events; 2750 participants analyzed for the outcome local reactogenicity events; 2766 participants analyzed for the outcome systemic reactogenicity events; 2831 participants analyzed for the outcome specific antibody GMTs; 1840 participants analyzed for the outcome neutralizing antibody GMTs; 27410 participants analyzed for infection after second dose and severe disease, 26145 participants analyzed for disease after second dose
ADVERSE EVENTS.SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized for the outcomes adverse events and serious adverse events.. Risk assessed to be low for the outcomes: Adverse events. Serious adverse events. LOCAL REACTOGENICITY EVENTS. SYSTEMIC REACTOGENICITY EVENTS Data not available for all or nearly all participants for the outcomes local reactogenicity events and systemic reactogenicity events. No evidence that the result is not biased. No reasons for the missingess reported Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (missigness balanced between arms) Risk assessed to be some concerns for the outcomes: Local reactogenicity events. Systemic reactogenicity events. IMMUNOGENICITY OUTCOMES Data not available for all or nearly all participants for the outcomes specific and neutralizing antibody GMTs. No evidence that the result is not biased. No reasons for the missingess reported Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (missigness balanced between arms) Risk assessed to be some concerns for the outcomes: Specific antibody GMT. Neutralizing antibody GMT. EFFICACY Data available for nearly all participants randomized for the outcome mortality. Risk assessed to be low for the outcomes: Mortality. Data no available for all participants for the outcomes:Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. Reasons: 1.3% in the vaccine arm and 2.2% in the placebo arm discontinued before second dose (deaths, losses to follow up and withdrawals); 1.1% and 2.4% discontinued after the second dose (deaths, losses to follow up, physician and participant withdrawals and other reasons); others were excluded from analysis - 4.8% and 4.8% had a positive, missing, or indeterminate serostatus at baseline, 10.2% and 8.5% were followed for <15 days after second dose, 0.3% and 0.6% had confirmed SARS-CoV-2 RT-PCR–positive Covid-19 infection <15 days after second dose. Efficacy data not available for all or nearly all participants randomized, but this bias has been taken into account in domain 2. Risk assessed to be low for the outcomes: Confirmed COVID. Confirmed symptomatic COVID. Confirmed severe COVID. |
| 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-19. Severe or critical COVID-19. Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local reactogenicity events. Systemic reactogenicity events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and prospective registry were available (dated 18 August 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-19. Severe or critical COVID-19. Mortality. Specific antibody GMT. Neutralizing antibody GMT. Local reactogenicity events. Systemic reactogenicity events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |