Trial NCT05216601
Publication Lien C, SSRN, 2022
Primary outcome on the report: 1. incidence of adverse events (AEs) within 28 days of the booster administration: incidences of solicited AEs for up to seven days after each vaccination and unsolicited AEs for up to 28 days after each vaccination. Other AEs, such as serious adverse events (SAEs) and adverse events of special interest (AESI), were recorded within the study period. 2. levels of neutralising antibody titres at Visit 5 (4 weeks after the booster dose): assessed by neutralising assay with the original (WT) SARS-CoV-2 and Beta variant in terms of geometric mean titre (GMT) and GMT ratio. 3. levels of anti-spike immunoglobulin G (IgG) antibody titres at Visits 4 (2 weeks after the booster dose) and 5: assessed by IgG titres in terms of geometric mean titre (GMT) and GMT ratio.

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: "The randomisation of each group was stratified based on site to three treatment arms, 15 mcg of MVC-COV1901, or 15 mcg or 25 mcg of MVC-COV1901-Beta in a 1:1:1 ratio."
Comment: Allocation sequence probably random.
No information on allocation concealment.
Deviations from intervention
Some concerns 		Quote: "open-label" trial.
Comment: Unblinded study (participants and personnel/carers).
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, ADVERSE EVENTS, AND SERIOUS ADVERSE EVENTS
ITT analysis (with N randomized denominators).
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.

SPECIFIC ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT OMICRON
Per-protocol analysis was performed on the outcomes.
Reasons for exclusion: 3 vs 2 vs 2 participants had COVID-19 or tested positive for anti-N during the trial.
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 arms.
Risk assessed to be some concerns for the outcomes: Specific antibody GMT, Neutralizing antibody GMT.Neutralizing antibody GMT Omicron
Missing outcome data
Low 		Comment: 62 participants randomized; 62 participants analyzed for Covid and safety; 55 analyzed for immunogenicity.

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

SPECIFIC ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT OMICRON
Data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 7 protocol violations that were accounted for in domain 2.
Missingness could not depend on the true value of the outcome.
Risk assessed to be low for the outcomes: Specific antibody GMT, Neutralizing antibody GMT. Neutralizing antibody GMT Omicron
Measurement of the outcome
Some concerns 		Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups.
Unblinded study (outcome assessor).

MORTALITY, SPECIFIC ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT, NEUTRALIZING ANTIBODY GMT OMICRON
Observer-reported outcome not involving judgement.
Risk assessed to be low for the outcomes: Mortality. Specific antibody GMT. Neutralizing antibody GMT. Neutralizing antibody GMT Omicron

ADVERSE and SERIOUS ADVERSE EVENTS
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: Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The prospective registry was available (dated January 31, 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, Specific antibody GMT, Neutralizing antibody GMT, Neutralizing antibody GMT Omicron, Adverse events, and Serious adverse events.
Overall risk of bias
Some concerns