Safety and efficacy of the COVID-19 vaccine in children and/or adolescents:A meta-analysis.

Dear editor,

Since 2019, the COVID-19 epidemic has raged worldwide, with children and adolescents accounting for a quarter of the world's population being greatly threatened. The safety and effectiveness of the COVID-19 vaccine for children have been examined. At present, clinical trials of COVID-19 vaccines for children are gradually increasing. The most common ones are attenuated and inactivated vaccines.The efficacy and safety of many randomized clinical trials (RCTs) and observational trials of the COVID-19 vaccine in children have been published through a systematic search of common databases between 2019, and November 8, 2021.

We read with great interest the report in this Journal by Chappell et al. who found that SARS-CoV-2 infections have occurred in immunocompromised children and young people with no increased risk of severe disease. Even without an increased risk of contracting COVID-19 in immunocompromised children and young adults. However, a meta-analysis of the safety and efficacy of COVID-19 vaccines in children and/or adolescents is still warranted. An extensive literature search was performed in PubMed, Web of Science, EMBASE, Elsevier ScienceDirect, and Cochrane Library to find all compliant articles published from January 1, 2020, to November 8, 2021. The following keywords were used on the search strategy: “COVID-19″, “2019-nCoV”, “SARS-CoV-2″, “2019 novel coronavirus”, “coronavirus disease 2019″, “severe acute respiratory syndrome coronavirus 2″, “children”, “child”, “adolescent”, and “teenager”. The reference lists, cited in the included studies and reviews, were eligible as exploratory targets to identify extensive articles. The inclusion criteria included: adult COVID-19 children/adolescents confirmed by reverse transcriptase-polymerase chain reaction (rt-PCR); peer-reviewed original articles in English; individual study populations being at least fifteen cases; the key available data tabulated data or effect (95% confidence interval (CI)), must be clearly stated. Case reports, repeated articles, review papers, and preprints were eliminated.

Single-group rates and corresponding 95% CIs were used to assess the association between children/adolescents and the COVID-19 vaccine in a whole random-effects meta-analysis model. The model includes effectiveness rates, adverse effects rates, and injection site pain rates in the COVID-19 group. The I statistic was used to quantify the heterogeneity of the effects among the included studies. A sensitivity analysis was perform to determine the robustness of the results. The "META" package of the R software (version 4.1.1) was applied. A significant association was not recognized until the two-tailed P < 0.05.

A total of 9 articles involving 264,674 patients were identified, including 7 RCTs and 2 observational studies. Table 1 describes the detailed characteristics of the effectiveness and safety studies.2, 3, 4, 5, 6, 7, 8, 9, 10 Seven studies have shown that the overall effectiveness of the COVID-19 vaccine is 96.09% (95% confidence interval [CI]:93.35–98.90, p < 0.01) (Fig. 1 A), of the attenuated vaccine is 95.05% (95% [CI]:90.21–100.16, p < 0.01) (Fig. 1A), and the inactivated vaccine 97.32% (95% [CI];95.17–99.52, p > 0.01) (Fig.1A). Safety is important for children. In 5 studies, we found that the adverse reaction was 0.59 (95% [CI]; 0.45–0.73, p < 0.01) (Fig.1B). The adverse reaction of the attenuated vaccine was 0.78 (95% [CI]: 0.62–0.94, p < 0.01) (Fig.1B), the adverse reaction of the inactivated vaccine was 0.47 (95% [CI]: 0.19–0.75, p < 0.01) (Fig.1B) The adverse reactions of inactivated vaccines are significantly less than that of attenuated vaccines. We also counted the pain at the injection site. In 7 studies, the pain at the injection site was 0.58 (95% [CI]: 0.43–0.72, p < 0.01) (Fig.1C), the injection pain of the attenuated vaccine was 0.78 (95% [CI]:0.60–0.95, p < 0.01) (Fig. 1C), the injection pain of the inactivated vaccine was 0.30(95% [CI]: 0.17–0.43, p < 0.01)(Fig. 1C), the injection of inactivated vaccine is less painful and more friendly to children and adolescents.

Table 1

The basic information of the included literature.

Study	Population	Study type	Country	Intervention	All person	controls	Vaccine efficacy(95%CI)	Injection-site pain	Adverse reactions
Walter et al.2	5–11years	Randomized controlled trial	United States	BNT162b2 mRNA	2268	750	90.7% (95% CI, 67.7–98.3)	1093	/
Frenck et al.3	12–15years	Randomized controlled trial	United States	BNT162b2 mRNA	2260	1129	100% (95% CI, 78.1 to 100)	939	/
Olson et al.4	12–18years	Randomized controlled trial	United States	Pfizer-BioNTech mRNA.2doses	464	285	93% (95% CI = 83–97%)	/	/
Hause et al.5	12–17years	observational study	United States	BNT162b2 mRNA	66,550	/	/	41,927	46,585
Freedman et al.6	12–15years	observational study	Israel	BNT162b2 mRNA	187,707	/	91.5% (95% CI 88.2–93.9%	/	/
Ali et al.7	12–17years	Randomized controlled trial	United States	mRNA-1273	3732	1243	98.8(95%CI= 97.0 to 99.7)	2290	2140
Han et al.8	3–17 years	Randomized controlled trial	China	CoronaVac	333	114	96•8% [95%CI= 93•1–98•8]	35	59
Zhu et al.9	6–17years	Randomized controlled trial	China	Recombinant Adenovirus Type-5–Vectored Coronavirus	150	50	98.0% (95%CI= 93.0–99.5)	50	82
Xia et al.10	3–17years	Randomized controlled trial	China	BBIBP-CorV	810	90	100%	53	229

Fig. 1

Forest plot of Vaccine efficacy (95%CI), njection-site pain, and adverse reactions.

In conclusion, our research shows that the current COVID-19 vaccine for children is effective and safe, and is more effective than the adult COVID-19 vaccine. There is a gap between the effectiveness of attenuated and inactivated vaccines, and the effectiveness of inactivated vaccines is the highest. We found that the inactivated vaccine is less painful at the injection site and is more friendly to children and adolescents. More carefully designed further studies based on risk factor adjusted estimates are necessary to confirm our findings.

Funding

This study was supported by fund (No. 20191203B96;No. 20191203B105;No. 20191231Y039); Youth Fund of Zhejiang Academy of Medical Sciences (No. 2019Y009); (No. 2020362651, No. 2021KY890); Clinical Research Fund of Zhejiang Medical Association (No. 2020ZYC-A13); Hangzhou Health and Family Planning Technology Plan Key Projects (No.2017ZD02); Hangzhou Medical and Health Technology Project (No. 0020290592). Zhejiang Traditional Chinese Medicine Scientific Research Fund Project (No.2022ZB280).

Data sharing statement

All the data and materials mentioned in the manuscript are available.

Ethics approval and consent to participate

This study was approved by the ethics committee of Affiliated Hospital of Hangzhou Normal University. This study was carried out according to the Declaration of Helsinki.

Declaration of Competing Interest

The authors declare no competing interests.