STRENGTHS AND LIMITATIONS OF THIS STUDY

A comprehensive search strategy was developed by a librarian.

The possible heterogeneity among the included studies and comparisons between different types of vaccines can be challenging.

The risk of bias will be evaluated using a validated tool.

The protocol employed by pairs of independent researchers for the selection of studies increases the reliability of the results.

No language restrictions will be adopted.

Introduction

With more than 6 million deaths reported worldwide due to the COVID-19 pandemic, there is an urgency to expand immunisation.1 According to the Centers for Disease Control and Prevention, unlike the adult population, paediatric patients, who represent a quarter of the world’s population, have a higher number of critical or severe cases (>5 years).2 WHO defines paediatric patients as persons aged >2 to <19 years at the time of their diagnosis or treatment.3

Vaccines against COVID-19 have been developed and used in a relatively short period compared with other vaccines. Therefore, their efficacy, safety and side effects require continuous and extensive surveillance and research. Since then, randomised controlled trials have been conducted to confirm the efficacy of the existing vaccines against new variants.4 5

The primary hurdle in accepting the COVID-19 vaccine has been the lack of confidence in the safety of newly discovered vaccines. The most common reactions observed in adult patients are local pain, erythema, swelling and lymphadenopathy at the injection site. The most common systemic side effects associated with the COVID-19 vaccines are headache, fatigue, myalgia and nausea.6 7

Currently, with the efforts of regulatory agencies, the scientific community and government, the vaccinations for younger age groups have advanced, in addition to the administration of existing vaccines and emergence of others with different mechanisms of action.8–10

The benefits and security of vaccines in the paediatric population are yet to be widely publicised. Furthermore, this population has particular characteristics, and the behaviours adopted by parents or guardians directly affect childhood vaccination.11 12

Objective

This systematic review protocol aims to evaluate the safety of COVID-19 vaccines in paediatric patients and identify the correlation between the number of doses and side effects.

Materials and methods

This systematic review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIDMA) Protocol.13 This review was registered in PROSPERO (No: CRD42023390077).

Inclusion criteria

Randomised and quasi-randomised clinical trials that evaluated COVID-19 vaccine side effects in paediatric patients and were published from January 2020 in any language will be included in the study.

Exclusion criteria

Articles that are not peer-reviewed and that are observational studies, review articles, reports and case series will be excluded. Additionally, studies that did not have paediatric patients as a population will be excluded.

Patients, intervention, comparison, outcome strategy and types of studies

Patients: children and adolescents (0–17 years) who were healthy and previously SARS-CoV-2 infection-free.

Intervention: COVID-19 vaccine or a combination of vaccines against COVID-19.

Comparator/control: placebo or no vaccination.

Outcome: Side effects, safety and tolerability of the COVID-19 vaccine or the combination of vaccines against COVID-19.

Types of studies: Clinical trials.

Primary outcome

Side effects, safety and tolerability of the COVID-19 vaccine or the combination of COVID-19 vaccines.

Secondary outcomes

Correlation between the number of vaccine doses and side effects, and death caused by adverse events of vaccination.

Patient and public involvement

None

Search strategy

The following databases will be searched: PubMed, ClinicalTrials.gov, Web of Science, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). In addition, the reference lists of the retrieved articles will be manually searched to identify eligible studies. No language restrictions will be imposed.

Our search keywords will be based on Medical Subject Headings (MeSH) in the following combinations: “Pediatrics”, “Infant”, “Child”, “Adolescents” “vaccines”, “vaccination”, “vaccine COVID-19”, “SARS-CoV-2 vaccine”, “toxicity”, “side effects”, “adverse events”, “clinical trial”, “controlled clinical trial”. The search strategy to be used in PubMed is presented in table 1. The search strategy for all databases is available in online supplemental file.

Table 1

Search strategy for PubMed

Data collection and analysisStudy selection

Three researchers (CLF, ACAS and KSM) will independently select the studies of interest. Initially, the Rayyan (Mourad Ouzzani, University of Oxford, UK) will be used to identify duplicates. Subsequently, the titles and abstracts of the selected articles will be analysed to identify relevant papers. The same authors will analyse the whole texts according to the inclusion criteria. Discrepancies will be resolved by a fourth author (AKG). The study selection process is summarised in the PRISMA flow chart (figure 1).

Figure 1

PRISMA flow diagram for systematic review and meta-analysis. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers).**If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Data extraction

The authors developed and tested a data collection form. Data from each included study will be extracted independently by two authors (CLF and ACAS), and any subsequent discrepancies will be resolved through discussion with a third author (AKG). The extracted data will include authors, year of publication, study site, study type, main objectives, mean age of the population, vaccination schedule, follow-up of participants and side effects.

Missing data

For studies with incomplete or missing data, the authors will contact the article authors by telephone or email. In case of no response, the data will be excluded from the analysis and discussed in the discussion section.

Data synthesis

Data will be entered and analysed using Review Manager (RevMan, V.5.4, The Cochrane Collaboration, 2020). We will evaluate the heterogeneity between studies using the I2 statistic (<25%, low heterogeneity; 25%–50%, moderate heterogeneity and >50%, high heterogeneity). Fixed-effects models will be used, except when significant heterogeneity exists in the included studies (I2>50%). ORs with 95% CI will be estimated to determine the corresponding risk. Dichotomous data from each eligible study will be combined for meta-analysis using the Mantel/Haenszel model.

A sensitivity analysis will be performed to verify the possible sources of heterogeneity, removing one study at a time and verifying whether there is a considerable change in the 95% CI. Studies with high risks of bias will be excluded.

Quality assessment

KSM, ACAS and CLF will independently assess the risk of bias in eligible studies using the Cochrane risk-of-bias tool.14 Bias will be assessed as high, low or unclear for individual elements from five domains (selection, performance, attrition, reporting and others). Publication bias will be assessed by inspecting the funnel plot and asymmetry of the funnel plot will be tested using Egger’s test.

Assessing certainty in the findings

The quality of the evidence will be assessed based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). The GRADE tool classifies studies as low, moderate or high quality.15

Ethics and dissemination

The result of this systematic review will be disseminated through publication in an open-access peer-reviewed journal, scientific publications and reports. Ethical review is not required because we will only search and evaluate against publicly available literature.

Discussion

The decision to vaccinate paediatric patients raises several questions even though the rigour of vaccine production and release is constantly being disclosed.16 According to the WHO emergency list, 13 vaccines have been approved, and more than 90 are still under development and exploration.17 Even with the approval and clearance by regulatory health agencies, legal guardians or parents of children still have doubts about the safety and possible adverse reactions.18 19

In a systematic review of the safety and efficacy of vaccinations against COVID-19 in children and adolescents, local reactions had a low occurrence, with some reports of myocarditis and pericarditis.20 However, this review only evaluated English-language publications and did not include children younger than 1 year.

Currently, vaccinations continue to develop for younger age groups (from the age of 6 months), as new cases and virus variants continue to emerge every day.21

It is not possible to measure all the effects of the SARS-CoV-2 pandemic on the paediatric population. The suspension of face-to-face classes and social distancing has damaged cognitive and social development. In addition, the WHO warns of a reduction in childhood vaccination coverage; in 2021, about of 25 million children were not vaccinated.22 Non-adherence to the schedule of other vaccines may affect susceptibility to other diseases. During the pandemic outbreak, some children developed multisystem inflammatory syndrome after contact with the SARS-CoV-2 virus, which had symptoms similar to incomplete Kawasaki disease; it was reported in several countries23–25 with a mortality rate of approximately 1%–2%.16

Postmarketing pharmacovigilance, especially in the paediatric population, will help parents or guardians in decision-making. This protocol is designed to include large numbers of vaccinated paediatric patients across all age groups and different vaccines, to provide reliable results on childhood COVID-19 vaccination.

Ethics statementsPatient consent for publication

Not applicable.