Methods
Criteria for considering studies for this systematic review
Types of studies
We include parallel or cluster-randomized controlled trials (RCTs) evaluating the efficacy, immunogenicity and safety of COVID-19 vaccines in humans.
Single-arm studies, non-randomized studies and modelling studies of interventions for COVID-19 are not included in the review.
We have no restriction on language.
Types of participants
Children or adults with no restriction on age and comorbidities
Types of interventions
Eligible interventions include any COVID-19 vaccines particularly:
Live attenuated virus vaccine
Inactivated virus vaccine
Protein subunit vaccine
Virus-Like particle (VLP) vaccine
Non-replicating viral vector (e.g., recombinant adenovirus) vaccine
Replicating viral vector vaccine
DNA based vaccine
RNA based vaccine
Type of comparator
Placebo (placebo could consist of saline placebo, injecting only the vaccine adjuvant or injecting vaccine protecting for other diseases such as meningococcal conjugate vaccine), no vaccine or another COVID-19 vaccine.
List of outcomes:
Critical outcomes:
- Incidence of participants with positive test for SARS-CoV-2 infection by RT-PCR OR Nucleic acid amplification testing (NAAT) or other validated test (symptomatic or asymptomatic)
- Incidence of symptomatic COVID-19 confirmed with positive test for SARS-CoV-2 infection by RT-PCR OR NAAT
- Severe or critical disease defined according to the WHO definition or as reported by trialists
- All-cause mortality
- Incidence of systemic adverse events (D14)
- Incidence of any adverse events
- Incidence of serious adverse events (SAEs)
Important outcomes:
- The geometric mean titres (GMT) of specific antibody against SARS-CoV-2 (2 weeks after the first dose, D28)
- The GMT of neutralizing antibody against SARS-CoV-2 (2 weeks after second doseD28)
- Cellular immune responses (D28 i.e., IFN-γ enzyme-linked immunospot - ELISpot)
- Incidence of local adverse events (D7)
- Incidence of withdrawal due to adverse events
- Incidence of specific safety outcomes:
- cardio-embolic events (Pulmonary embolism, stroke, venous thrombosis, cavernous sinus thrombosis, pericarditis)
- haematological events (thrombocytopenia, hemorrhage, bruising, neutropenia, anaemia, lymphadenopathy)
- neurological events (stroke, headache, delirium, paresthesia)
Assessment of risk of bias in the included studies
Each study is assessed with the Cochrane 'Risk of Bias 2' (RoB 2) tool for randomized controlled trials.We record judgments and justification per domain for all collected outcomes.
The Cochrane RoB 2 tool is structured into five domains: 1) risk of bias arising from the randomization process, 2) risk of bias due to deviations from intended interventions, 3) risk of bias due to missing outcome data, 4) risk of bias in the measurement of the outcome, 5) risk of bias in the selection of the reported result.
The risk of bias judgement 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.
We are considering the “effect of assignment to intervention” which might not be the analysis planned and reported by investigators. Consequently, when investigators planned to assess and report the “per-protocol” effect, the risk of bias for domain 2 may be evaluated as “some concerns”. We contact investigators to obtain the results of the intent-to-treat analysis.