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: “Randomisation, stratified by country and age group (18 – 60 and ≥61 years old), was performed centrally using an interactive web response system.”
Comment: Allocation sequence random random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. Risk assessed to be low. |
| Deviations from intervention |
Some concerns |
Quote: "Due to the difference in appearance and presentation between the CVnCoV vaccine candidate and placebo, site personnel involved in preparing and administering the vaccine were not involved in the further conduct of the trial, and investigators, site personnel, and others directly involved in the conduct of the trial were blinded to participant treatment for the duration of the trial."
Comment: Blinded study (participants and personnel/carers). SAFETY Data for safety outcomes were analyzed using 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: Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. EFFICACY Data for the outcome Mortality were analyzed using 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 on the outcomes: Confirmed symptomatic COVID-19. Severe confirmed COVID-19. Analyses were carried out on participants who received both doses of CVnCoV or placebo according to their treatment allocation, who had not developed virologically confirmed COVID-19 before Day 43 (15 days after the second dose), and who were SARS-CoV-2 naïve at baseline and Day 43. 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 these being standard reasons from exclusion from per-protocol analyses. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID-19. Severe confirmed COVID-19. |
| Missing outcome data |
Low |
Comment: 39,680 participants randomized; 3982 to 39,529 participants analyzed (depending on outcome).
SAFETY Data on serious adverse events were available for nearly all participants randomized. Risk assessed to be low for the outcome: Serious adverse events Data on local-, systemic-, and adverse events were not available for all or nearly all participants randomized. As planned according to the prospective registry, these outcomes were asessed only on participants in the phase 2b part of the trial; Phase 3 participants were not analysed for these outcomes. Risk assessed to be low for the outcomes: Local adverse events. Systemic adverse events. Adverse events; EFFICACY Data on mortality were available for nearly all participants randomized. Risk assessed to be low for the outcome: Mortality Data for the outcomes Confirmed symptomatic COVID and Confirmed severe COVID were not available for all or nearly all participants randomized. Most of the reasons for missing data were related to per-protocol analyses were accounted for in domain 2 (participants with protocol violations were excluded). Risk assessed to be low for the outcomes: 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 symptomatic COVID-19. Severe COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The trial registries were available (prospectively registered on 3 December 2020).
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: Confirmed symptomatic COVID-19. Severe COVID-19. All-cause mortality. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |