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 1:1 via computer-
generated randomly permuted blocks of size 4 to receive
either two vaccine doses (referred to as a primary dose
plus a homologous booster dose of Ad26.COV2.S) as part
of the vaccine group or two doses of saline placebo
(placebo group) 56 days apart. Central randomisation
was implemented in this study. Participants were
randomly assigned to one of two vaccination groups:
active vaccine versus placebo. This was based on a
computer-generated randomisation schedule prepared
before the study by, or under the supervision of, the
sponsor. "
Comment: Allocation sequence random. Allocation sequence probably concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Some concerns |
Quote: "Participants and sites were blinded to assignment until the unblinding visit"
Comment: Blinded study (participants and personnel/carers). Per-protocol analysis was performed on the outcomes. Reasons for exclusion: for reactogenicity and unsolicited AEs a subset was analysed (unclear if it was pre-planned); for efficacy participants who received 1 dose of vaccine/placebo in the double-blind phase, were SARS-CoV-2 seronegative at day 1 and had no major protocol violations possibly impacting efficacy were analysed. 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 proportions between groups in the per protocol analyses. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic. Confirmed severe COVID. Local adverse events. Systemic adverse events. Adverse events. |
| Missing outcome data |
Low |
Comment: 31,835 participants randomized; 27,200 analyzed for efficacy; 6067 participants analyzed for reactogenicity and unsolicited adverse events.
SAFETY Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: missing data is related to the use of a sub-set of participants in the analysis (assessed in domain 2). Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events. EFFICACY For the efficacy outcomes, in addition to those excluded for protocol deviations (assessed in domain 2) there were also participants excluded due to "participant withdrawal" (468 VS 1273), "lost to follow up" (170 VS 219), "death" (6 VS 13), etc. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome Risk assessed to be some concerns for the outcomes: Confirmed symptomatic. 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 symptomatic. Confirmed severe COVID. Local adverse events. Systemic adverse events. Adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available.
CONFIRMED SYMPTOMATIC COVID, LOCAL and SYSTEMIC ADVERSE REACTIONS, and ADVERSE EVENTS Outcomes 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 symptomatic. Local adverse events. Systemic adverse events. Adverse events. CONFIRMED SEVERE COVID Confirmed severe COVID was not pre-specified in the registry. No information on whether the result was selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Confirmed severe COVID. |
| Overall risk of bias |
Some concerns |