Trial EudraCT, 2022-000063-51; NCT05249829
Publication Lee l, medRxiv, 2023
Primary outcome on the report: 1) Geometric mean concentration (GMC) of mRNA-1273.214 and mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 2) Ratio of GMC_mRNA-1273.214/GMC_mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 3) Geometric mean concentration (GMC) of mRNA-1273.214 and mRNA-1273 against the prototype strain at Day 29 or Month 3 after study vaccine administration; 4) Ratio of GMC_mRNA-1273.214/GMC_mRNA-1273 against the prototype strain at Day 29 or Month 3 after study vaccine administration; 5) GMC of mRNA-1273.529 and mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 6) Ratio of GMC_mRNA-1273.529/GMC_mRNA-1273 against the BA.1 strain at Day 29 or Month 3 after study vaccine administration; 7) Solicited local and systemic reactogenicity ARs during a 7-day follow up period after vaccination; 8) Unsolicited AEs during the 28-day follow-up period after vaccination; 9) SAEs, medically attended AEs (MAAEs), AEs leading to withdrawal, and AEs of special interest (AESIs) from Day 1 to end of study.

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: "Randomization during both parts was performed using an interactive response technology... Enrollment was observer-blinded to treatment assignment because the study vaccines differed in appearance. Dose preparation, administration, and accountability was performed by designated site personnel who did not participate in any clinical study evaluations. The unblinded site personnel prepared the dose out of view of the participant as well as blinded site personnel, and did not reveal the identity of the study vaccine except in case of emergency."
Comment: Allocation sequence random.
Allocation sequence probably concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: "observer-blinded" trial.
Comment: Blinded study (participants and personnel/carers).

MORTALITY. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS
ITT analysis.
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 the outcomes: Mortality, Adverse events and Serious adverse events.

CONFIRMED SYMPTOMATIC COVID, NEUTRALIZING ANTIBODY SEROCONVERSION OMICRON
Per-protocol analysis was performed on the outcomes.
Reasons for exclusion: 320 vs 358 participants excluded due to baseline SARS-CoV-2 positivity, and 7 vs 22 major protocol deviations; and additionally for immunogenicity 65 vs 69 excluded due to 28-day SARS-CoV-2 positivity.
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.
Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID, and Neutralizing antibody Seroconversion Omicron.
Missing outcome data
Some concerns 		Comment: 2824 participants randomized; 2824 participants analyzed for safety; 1934 analyzed for Covid outcomes; 1871 analyzed for immunogenicity.

MORTALITY. ADVERSE EVENTS. SERIOUS ADVERSE EVENTS
Data available for all or nearly all participants randomized.
Risk assessed to be low for the outcomes: Mortality, Adverse events and Serious adverse events.

CONFIRMED SYMPTOMATIC COVID
Data not available for nearly all participants randomized.
No evidence that the result is not biased.
Reasons: Most exclusions accounted for in domain 2. Plus: for Covid outcomes 176 (6%) missing baseline serology data.
Missingness could depend on the true value of the outcome.
Not likely that missingness depended on the true value of the outcome since similar proportions of missing data between arms.
Risk assessed to be some concerns for the outcomes: Confirmed symptomatic COVID.

NEUTRALIZING ANTIBODY SEROCONVERSION OMICRON
Data not available for nearly all participants randomized.
No evidence that the result is not biased.
Reasons: Most exclusions accounted for in domain 2. Plus: for immunogenicity 139 (4.9%) either missing baseline or valid day 28 data.
Missingness could not depend on the true value of the outcome.
Risk assessed to be low for the outcome: Neutralizing antibody Seroconversion Omicron.
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, Mortality, Neutralizing antibody Seroconversion Omicron, Adverse events and Serious adverse events.
Selection of the reported results
Low 		Comment: The NCT registry was available (dated February 22, 2022).
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: Mortality, Confirmed symptomatic COVID, Neutralizing antibody Seroconversion Omicron, Adverse events and Serious adverse events.
Overall risk of bias
Some concerns