Trial ChiCTR2200057758
Publication Zhang Y, Nature, 2023
Primary outcome on the report: The geometric mean titres (GMTs) of neutralising antibodies against the wild-type, delta and omicron variants of live SARS-CoV-2 at day 0 (pre-vaccination), 7, 14, and 28 after boosting vaccination ; the occurrence of adverse events within 14 days after the booster vaccination.

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: “An unblinded statistician created the computer-generated randomisation list. Participants were block-randomised (block size ten; ratio of 1:1:1:1:1) to receive ChAdTS-S, RQ3013, ZR202-CoV, CoronaVac or placebo. Participants, laboratory staff, and the research per-sonnel, including those undertaking adverse event assessments or delivering the vaccines, were masked to treatment allocation. The analysing statisticians remained masked until the statistical analysis plan was signed off. Concealed random group allocations and blinding codes were kept in signed and sealed envelopes.”
Comment: Allocation sequence random.
Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance.
Deviations from intervention
Some concerns 		Quote: “Participants, laboratory staff, and the research personnel, including those undertaking adverse event assessments or delivering the vaccines, were masked to treatment allocation.”
Comment: Blinded study (participants and personnel/carers).

MORTALITY, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS
Safety analysis conducted on those who received at least one dose of the intervention.
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. Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.

SEROCONVERSION NEUTRALIZING ANTIBODY. SEROCONVERSION NEUTRALIZING ANTIBODY (>90D). NEUTRALIZING ANTIBODY GMT. NEUTRALIZING ANTIBODY GMT (>90D). SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON. SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON (>90D). NEUTRALIZING ANTIBODY GMT OMICRON. NEUTRALIZING ANTIBODY GMT OMICRON (>90D).
Per-protocol analysis was performed on the immunogenicity outcomes.
Reasons for exclusion: 2% vs 2% vs 4% vs 6% vs 4% had morbidity preventing vaccination; 2% vs 4% vs 2% vs 2% vs 2% not vaccinated for other reasons; 0% vs 2% vs 0% vs 2% vs 0% were incorrectly vaccinated; 0% vs 1% vs 0% vs 0% vs 0% failed bleed at day 14; 0% vs 0% vs 0% vs 0% vs 2% withdrew at day 1.
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 blinded groups.
Risk assessed to be some concerns for the outcomes: Seroconversion neutralizing antibody. Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT. Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron. Seroconversion neutralizing antibody Omicron (>90d). Neutralizing antibody GMT Omicron. Neutralizing antibody GMT Omicron (>90d).
Missing outcome data
Some concerns 		Comment: 250 participants randomized; 235 participants analyzed for safety; 233 participants analyzed for immunogenicity.
Data not available for all or nearly all participants randomized.
No evidence that the result is not biased.
Reasons: 2% vs 2% vs 4% vs 6% vs 4% had morbidity preventing vaccination; 2% vs 4% vs 2% vs 2% vs 2% not vaccinated for other reasons; 0% vs 2% vs 0% vs 2% vs 0% were incorrectly vaccinated; 0% vs 1% vs 0% vs 0% vs 0% failed bleed at day 14; 0% vs 0% vs 0% vs 0% vs 2% withdrew at day 1.
Missingness could depend on the true value of the outcome.

MORTALITY, LOCAL ADVERSE EVENTS, SYSTEMIC ADVERSE EVENTS, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS
Not likely that missingness depended on the true value of the outcome due to balance between arms.
Risk assessed to be some concerns for the outcomes: Mortality.Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.

SEROCONVERSION NEUTRALIZING ANTIBODY . SEROCONVERSION NEUTRALIZING ANTIBODY (>90D). NEUTRALIZING ANTIBODY GMT. NEUTRALIZING ANTIBODY GMT (>90D). SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON. SEROCONVERSION NEUTRALIZING ANTIBODY OMICRON (>90D). NEUTRALIZING ANTIBODY GMT OMICRON. NEUTRALIZING ANTIBODY GMT OMICRON (>90D).
This potential source of bias has been taken into account in domain 2.
Risk assessed to be low for the outcomes:Seroconversion neutralizing antibody . Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT. Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron. Seroconversion neutralizing antibody Omicron (>90d). Neutralizing antibody GMT Omicron. Neutralizing antibody GMT Omicron (>90d).
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: Mortality. Seroconversion neutralizing antibody . Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT. Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron. Seroconversion neutralizing antibody Omicron (>90d). Neutralizing antibody GMT Omicron. Neutralizing antibody GMT Omicron (>90d). Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Selection of the reported results
Low 		Comment: The prospective protocol (dated December 2021), statistical analysis plan and retrospective registry were available.
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: Mortality. Seroconversion neutralizing antibody . Seroconversion neutralizing antibody (>90d). Neutralizing antibody GMT. Neutralizing antibody GMT (>90d). Seroconversion neutralizing antibody Omicron. Seroconversion neutralizing antibody Omicron (>90d). Neutralizing antibody GMT Omicron. Neutralizing antibody GMT Omicron (>90d). Local adverse events. Systemic adverse events. Adverse events. Serious adverse events.
Overall risk of bias
Some concerns