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 |
Some concerns |
Quote: "Computer generated randomization list with block sizes of four was used for randomization."
Comment: Allocation sequence random. No information on allocation concealment. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "Participants were blinded to boost vaccine until 180 days postvaccination. Laboratory staff processing immunological samples were blinded to vaccine allocation. Clinical nurses and research staff accessing adverse events were unblinded."
Comment: Unblinded study (participants blinded; personnel/carers unblinded). Deviations from intended intervention arising because of the study context: No participant cross-over. Hence, deviations did not arise because of the trial context. MORTALITY, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, SPECIFIC ANTIBODY GMT Per-protocol analysis was performed on the outcomes. Reasons for exclusion: 2 participants in the BNT162b2 arm were excluded post-vaccination due to not meeting inclusion criteria (previous SARS-CoV-2 infection). 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 the small number in one arm. Risk assessed to be some concerns for the outcomes: Mortality, Specific antibody GMT, Local adverse events, and Systemic adverse events. NEUTRALIZING ANTIBODY GMT OMICRON Quote: "A random subset of 120 participants (30 in each group) was tested for live virus neutralization with wild-type, alpha, delta and omicron BA.1 variants of SARS-CoV" 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 balance between arms. Risk assessed to be some concerns for the outcomes: Neutralizing antibodies GMT Omicron |
| Missing outcome data |
Low |
Comment: 340 participants randomized; 338 participants analyzed for mortality, cellular response, local adverse events and systemic adverse events/120 participants analyzed for Neutralizing antibody GMTs
MORTALITY, SPECIFIC ANTIBODY GMT, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality, Specific antibody GMT, Local adverse events, and Systemic adverse events. NEUTRALIZING ANTIBODY GMT OMICRON Data not available for all participants randomized. The outcome was tested on a subset of participants ramdomly selected. Subsequente bias was assessed in domain 2. Risk assessed to be low for the outcomes: Neutralizing antibody GMT Omicron |
| Measurement of the outcome |
Some concerns |
Quote: "Participants were blinded to boost vaccine until 180 days postvaccination. Laboratory staff processing immunological samples were blinded to vaccine allocation. Clinical nurses and research staff accessing adverse events were unblinded."
NEUTRALIZING ANTIBODY GMT OMICRON, SPECIFIC ANTIBODY GMT 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: Neutralizing antibody GMT Omicron, and Specific antibody GMT. MORTALITY Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor). Observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Mortality. LOCAL and SYSTEMIC ADVERSE EVENTS Comment: Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor). The authors reported on adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Local adverse events and Systemic adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (dated November 24, 2021).
NEUTRALIZING ANTIBODY GMT OMICRON, SPECIFIC ANTIBODY GMT, SYSTEMIC ADVERSE EVENTS and LOCAL ADVERSE EVENTS Outcome 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: Neutralizing antibody GMT Omicron, and Specific antibody GMT, Systemic adverse events and Local adverse events. MORTALITY Mortality outcome was pre-specified in the registry but up to a different timepoint, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if at a shorter timepoint. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Mortality. |
| Overall risk of bias |
Some concerns |