Introduction

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) is a respiratory infectious disease and is still in pandemic status [1]. According to the World Health Organization (WHO), there are 624,235,272 confirmed cases and 6,555,270 deaths worldwide as of October 24, 2022 [2]. Countries around the world have taken measures such as interventions and large-scale vaccinations in response to the COVID-19 pandemic. Previous meta-analyses and active surveillance studies have shown that the COVID-19 vaccine is a safe and effective way to prevent SARS-CoV-2 infection, symptomatic infection, severe cases, and death [3,4,5,6,7]. Currently, a total of 135 COVID-19 vaccines are in clinical trials worldwide, and 32 COVID-19 vaccines are in use [8]. By April 8, 2022, the WHO had assessed ten COVID-19 vaccines, including ChAdOx1-S/nCoV-19, Ad26.COV2.S, mRNA-1273, BNT162b2, BBIBP-CorV, CoronaVac, BBV152, NVX-CoV2373, and Ad5-nCoV to meet the necessary criteria for safety and efficacy [9]. A total of 5,392,424,039 people worldwide have received at least one dose of COVID-19 vaccines, and 4,951,178,365 people have been fully vaccinated as of October 18, 2022 [2].

Compared to adults, SARS-CoV-2 infection causes less severe illness and fewer deaths among children and adolescents [10]. However, there are still a considerable number of children and adolescents diagnosed with COVID-19. WHO surveillance data showed that from December 30, 2019, to September 13, 2021, the global numbers of COVID-19 cases < 5 years old and 5–14 years old were 1,695,265 and 6,020,084, respectively, accounting for 1.8% and 6.3% of the total number of cases [2, 10]. Children and adolescents infected with SARS-CoV-2 might also be underdiagnosed due to a less severe course of infection [10]. Furthermore, children and adolescents may develop severe COVID-19-related complications, such as multisystem inflammatory syndrome, which can lead to shock and multiple organ failure requiring intensive care [11]. The emergence of more transmissible Omicron variants has brought new challenges to the prevention and control of the pandemic. A study in 14 states in the United States found that the peak rate of COVID-19-related hospitalizations in children and adolescents aged 0–17 years during the Omicron-variant-dominant period was four times higher than that during the Delta-variant-dominant period [12].

The WHO recommends that countries consider vaccinating healthy children and adolescents over 5 years. The BNT162b2 vaccine is safe for children over 5 years, and the mRNA-1273 and BNT162b2 vaccines are approved for use in children over 12 years [13]. The effectiveness and safety of COVID-19 vaccines among children and adolescents are the focus of attention, with experimental studies [14,15,16] and observational studies [17,18,19,20,21,22,23,24] continuing to emerge. However, there is currently a lack of updated studies that systematically review the immunogenicity, effectiveness, and safety of COVID-19 vaccines among children and adolescents. Therefore, this study collected published studies and systematically evaluated the immunogenicity, effectiveness, and safety of COVID-19 vaccines among children and adolescents aged 2–18 years to provide scientific evidence and recommendations for the application of COVID-19 vaccines among children and adolescents.

Methods

This study was registered in the Prospective Register of Systematic Reviews (ID: CRD42022335219). The study process strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines [25].

Research strategies

We systematically searched MEDLINE (accessed through PubMed), Embase, and Web of Science from January 1, 2020, to October 8, 2022. The search terms consisted of following four parts: (1) SARS-CoV-2, COVID-19; (2) COVID-19 vaccine, SARS-CoV-2 vaccine; (3) infant, child, adolescent; and (4) immunogenicity, effectiveness, safety. The above four parts are logically connected using "AND". The detailed research strategy is shown in Supplementary Table 1.

Inclusion and exclusion process

Inclusion criteria were as follows: (1) research topic: studies that evaluated the immunogenicity, effectiveness or safety among children and adolescents (≤ 18 years old) after vaccination with COVID-19 vaccines; (2) study design: clinical trial, cohort study, case‒control study, and cross-sectional study were included; and (3) vaccine type: unlimited. Exclusion criteria are as follows: (1) topic was irrelevant: such as vaccination among adults, using a model to evaluate, or population does not be vaccinated; (2) study design: review, case series, case report, letter, conference abstract, or comment; (3) data were not sufficient for analysis, such as unable to extract or unable to pool effect values; and (4) duplicate articles.

The records downloaded from databases were managed using EndNote 20 (Thomson Research Soft, Stanford, CA, USA). First, we used EndNote to exclude duplicates. Then, two researchers independently screened the titles and abstracts of the records one by one. To obtain as much data as possible, only articles that clearly met the exclusion criteria were excluded when reading the title and abstract. The researchers read the full texts of the remaining records, and those who met the inclusion criteria were finally included. Disagreements between the two researchers in the above process were resolved through discussion or seeking the opinion of a third researcher.

Data extraction

The following data of included studies were extracted: (1) basic information: title, publication year, first author, and study design; (2) characteristics of population: age, nationality, sample size, and follow-up time; (3) information on COVID-19 vaccine: type and the number of vaccine doses; (4) information on immunogenicity: antibody detection methods and the number of seroconverted people; (5) information on effectiveness: the number of people infected with SARS-CoV-2, suffering from COVID-19, and hospitalized due to COVID-19, or any other data that can be used to determine vaccine effectiveness (VE); and (6) information on safety: the number of adverse events after each dose of vaccine. Data extraction was performed independently by two researchers. Disagreements were resolved through discussion or seeking the opinion of a third researcher.

Assessment of article quality

The following measurement tools were used for evaluation: (1) the revised Cochrane risk-of-bias tool [26] was used for randomized trials, and the results were divided into low risk of bias, some concerns, and high risk of bias; (2) the risk of bias in non-randomized studies of interventions assessment tool [27] was used for non-randomized studies, and the results were divided into low risk of bias, moderate risk of bias, serious risk of bias, critical risk of bias, and no information; (3) the Newcastle‒Ottawa scale [28] was used for cohort studies and case‒control studies, and the results were divided into low risk of bias (7–9 scores), moderate risk (5–6 scores), and high risk of bias (0–4 scores); and (4) the checklist recommended by the Agency for Healthcare Research and Quality [29] was used for cross-sectional studies, and the results were divided into low risk of bias (8–11 scores), moderate risk of bias (4–7 scores), and high risk of bias (0–3 scores). Assessment was performed independently by two researchers. Disagreements were resolved through discussion or seeking the opinion of a third researcher.

Outcomes and statistical analysis

For immunogenicity, the outcome was seroconversion rate. For effectiveness, the three outcomes we focused on were the VE against SARS-CoV-2 infection, COVID-19, and hospitalization. VE was defined as (1-RR) × 100% for clinical trials and cohort studies and (1-OR) × 100% for case‒control studies. RR was the risk of the three outcomes in the vaccinated group compared with the unvaccinated group. OR compared the odds of vaccination between cases and controls and can be used as an approximation of RR. VE indicates the reduction in risk of the three outcomes in the vaccinated group compared to the unvaccinated group and is expressed as a percentage (%). In the effectiveness analysis, vaccination status was divided into "fully vaccinated" and "partially vaccinated". "Fully vaccinated" was defined as being vaccinated with one dose of vaccines that only needed one dose (e.g., Ad26.COV2.S), or being vaccinated with two doses of vaccines that needed two doses (e.g., BNT162b2). “Partially vaccinated” was defined as being vaccinated with one dose of vaccine that needed two doses. For safety, the outcome was the incidence rate of adverse events after each dose of vaccines. Myocarditis, pericarditis, hypersensitivity, acute allergic reaction, Bell's palsy, convulsions, seizures, and thrombosis were called "special adverse events" in this study, occurring at a low rate with a denominator set to "per 100,000 people".

Effect values were pooled at the "cohort" level. Populations that differed in terms of age, vaccine type, the number of vaccine doses, or study time were considered different cohorts in our study. Heterogeneity was measured by the I2 statistic [30]. When I2 ≤ 50%, it can be considered that the heterogeneity between studies is low or moderate, and we use a fixed effect model to pool the effect value; when I2 > 50%, it can be considered that the heterogeneity between studies is high, and we use a random effects model to pool the effect value. In addition, we performed subgroup analyses of the above indicators with vaccine type and age. Data analysis was conducted by R (version 4.1.0).

Results

Characteristics of the included studies

The study selection process is shown in Fig. 1. We obtained 8721 records from MEDLINE (accessed through PubMed), Embase and Web of Science. In addition, 5892 records remained for screening after excluding duplicates by EndNote. After reading titles and abstracts, 501 records remained. After reading the full texts, 88 articles were eligible to be included. Of the 88 articles included, there were 12 RCTs, two non-randomized clinical trials, 40 cohort studies, 19 cross-sectional studies, and 15 case‒control studies. In the studies included, 16 articles were available for immunogenicity analysis (Supplementary Table 2) [14, 15, 18, 31,32,33,34,35,36,37,38,39,40,41,42,43]; 38 articles were available for effectiveness analysis (Supplementary Table 3) [14, 17, 19, 31, 44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]; and 49 articles were available for safety analysis (Supplementary Table 4) [14,15,16, 18, 20,21,22,23,24, 31, 34, 35, 37, 41, 43, 45, 47, 50, 55, 78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107]. Children and adolescents are involved in 27 countries, including the United States, China, Australia, Argentina, Italy, Israel, France, Denmark, and South Korea, which have larger cohorts (> 100,000 people). Vaccine types included mRNA vaccines (BNT162b2, mRNA-1273), inactivated vaccines (CoronaVac, BBIBP-CorV, BBV152, PastoCoVac), recombinant adenovirus-vectored vaccines (Ad5-nCoV-S, ChAdOx1-S/nCoV-19, Ad26.COV2.S), and DNA vaccine (ZyCoV-D). Among them, BNT162b2 was vaccinated most wildly among children and adolescents. The results of the article quality assessment showed that only six articles had a high risk of bias. Other articles had a low risk or moderate risk of bias. Overall, the quality of the included studies was good (Supplementary Tables 5, 6, 7).

Fig. 1
figure 1

Flowchart of study selection

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Immunogenicity

Antibodies were generally measured on day 28 post-vaccination for most studies. The immunogenicity results are shown in Table 1. The seroconversion rate increased sequentially after the first (86.10%), second (96.52%), and third (99.87%) doses of COVID-19 vaccines. Those who were vaccinated with mRNA vaccines had a higher seroconversion rate than those who were vaccinated with inactivated vaccines (98.78% vs. 92.77%). The seroconversion rate was higher in children aged 5–11 years than in children and adolescents aged 12–18 years (97.59% vs. 91.31%).

Table 1 Seroconversion rate after each dose
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Effectiveness

The effectiveness results are shown in Table 2. Compared with the partially vaccinated group, the fully vaccinated group showed higher effectiveness in the pooled VEs against SARS-CoV-2 infection (63.33% vs. 42.87%), COVID-19 (75.77% vs. 60.65%), and hospitalization due to COVID-19 (82.78% vs. 72.74%). In addition, in the fully vaccinated group, the pooled VE against hospitalization due to COVID-19 (82.78%) was higher than the VE against SARS-CoV-2 infection (63.33%) and the VE against COVID-19 (75.77%). All of the pooled VEs against SARS-CoV-2 infection (66.82% vs. 38.66%), COVID-19 (74.94% vs. 59.63%), and hospitalization due to COVID-19 (90.07% vs. 65.96%) in children and adolescents aged 12–18 were higher than those in children under 11 years. The pooled VEs against SARS-CoV-2 infection (33.41% vs. 63.00%), COVID-19 (55.98% vs. 79.81%), and hospitalization due to COVID-19 (72.10% vs. 91.47%) in the period of Omicron variant predominance were lower than those in the period of Delta variant predominance.

Table 2 Vaccine effectiveness of COVID-19 vaccines
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Safety

The occurrence of adverse events after each dose of vaccines is shown in Fig. 2, and the detailed data are shown in Supplementary Table 8. After the first dose of injection, the five adverse events with the highest incidence rates were tenderness (52.77%), injection site pain (50.98%), fatigue/asthenia/tiredness (24.04%), headache (20.30%), and myalgia/muscle pain (15.43%). However, the number of cohorts reporting tenderness was small (five cohorts). Considering the stability of the results, when the number of cohorts was limited to at least 10, the most common adverse events were injection site pain, fatigue/asthenia/tiredness, headache, myalgia/muscle pain, and chills (12.19%). Incidence rates of any adverse events (42.28%), any local adverse events (41.17%), and any systemic adverse events (32.57%) after the first dose were all over 30%.

Fig. 2
figure 2

Incidence rate of adverse events after each dose

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After the second dose of injection, when the number of cohorts was still limited to at least 10, the five most common adverse events were injection site pain (46.70%), fatigue/asthenia/tiredness (30.66%), headache (28.90%), myalgia/muscle pain (19.65%), and chills (16.58%). These five adverse reactions were consistent with those after the first dose. Except for injection site pain, the incidence rates of the other four adverse events after the second dose increased compared to those after the first dose. The incidence rates of any adverse events (38.04%), any local adverse events (38.49%), and any systemic adverse events (38.11%) were similar to those after the second dose. The incidence rates of adverse events after the third dose were very different from those after the first and second doses. However, the number of cohorts was less (all ≤ 6), and the stability was lower.

As shown in Table 3, the incidence of special adverse events was low. The most concerning adverse event was myocarditis or pericarditis, with an incidence rate of 2.42/100,000 people. The incidence rates of hypersensitivity/acute allergic reaction (3.86/100,000 people) and convulsions/seizures (2.15/100,000 people) were similar to those of myocarditis or pericarditis, but the number of cohorts was much smaller. The results of the subgroup analysis are shown in Table 4. We found that in age subgroups, the incidence rate of adverse events in children aged ≤ 5 years was lower than that in children aged 6–11 years and 12–18 years. In the vaccine type subgroup, the incidence rates of adverse events with mRNA vaccines, whether after the first, second, or third dose, were obviously higher than those with inactivated vaccines.

Table 3 Incidence rate of special adverse events
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Table 4 Results of subgroup analysis
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Discussion

This article is an update of a previous study we conducted, which was the first meta-analysis to evaluate the effectiveness and safety of COVID-19 vaccines among children and adolescents. In this study, a total of 88 relevant articles were included, of which 16 articles were used for immunogenicity analysis, 38 articles were used for effectiveness analysis, and 49 articles were used for safety analysis. The present study showed that the seroconversion rates after the first, second, and third doses of the vaccines were 86.10%, 96.52%, and 99.87%, respectively. VEs against SARS-CoV-2 infection in the partially vaccinated group and fully vaccinated group were 42.87% and 63.33%, respectively. VEs against COVID-19 in the partially vaccinated group and fully vaccinated group were 60.65% and 75.77%, respectively. VEs against hospitalization due to COVID-19 in the partially vaccinated group and fully vaccinated group were 72.74% and 82.78%, respectively. The incidence rates of any adverse events (42.28% vs. 38.04%) and local adverse events (41.17% vs. 38.49%) after the first dose were slightly higher than those after the second dose, while the incidence rate of systemic adverse events after the first dose (32.57% vs. 38.11%) was slightly lower than that after the second dose. Common adverse events included injection site pain, fatigue/asthenia/tiredness, headache, myalgia/muscle pain, and chills. The incidence of myocarditis or pericarditis was 2.42/100,000 people. In addition, the subgroup analysis showed that the incidence rates of adverse events of mRNA vaccines were higher than those of inactivated vaccines, whether after the first or second dose. The incidence rates of adverse events in children aged ≤ 5 years were the lowest, which may be related to the fact that they were all vaccinated with inactivated vaccines.

This study found that COVID-19 vaccines have good immunogenicity among children and adolescents. In particular, the seroconversion rate increased sequentially after the first (86.10%), second (96.52%), and third (99.87%) doses of COVID-19 vaccines. Du et al. [108] conducted a meta-analysis including three RCT studies by November 9, 2021 and found that the seroconversion rates of children and adolescents aged 3–17 after the first and second doses were 69.81%–94.63% and 98%–100%, respectively. They also found that the seroconversion rate in the vaccinated group was significantly higher than that in the unvaccinated group, especially after the second dose. Previous studies among healthy adults also suggested that two doses of vaccines can induce a stronger humoral immune response than a single dose [109, 110]. Therefore, there is a need for a two-dose vaccination strategy among children and adolescents. Furthermore, as a result of waning immunity and reduced protection after two doses of vaccines, offering third or booster doses was taken into consideration [111]. There is evidence that a third dose can boost antibody and neutralizing responses among adults [111, 112]. However, the WHO does not currently recommend that children and adolescents under 18 years receive a booster dose [13]. More studies are expected to explore the safety, immunogenicity, and effectiveness of booster vaccination among children and adolescents.

As a special population, children and adolescents present many influencing factors to consider when getting vaccinated. Vaccine safety and effectiveness are the most important considerations for children, adolescents, and their parents [113]. A meta-analysis including 44 articles by December 12, 2021, showed that the overall proportion of parents who intended to vaccinate their children against COVID-19 was 60.1%, and concerns about adverse events and effectiveness were important factors affecting parents’ willingness to vaccinate their children [114]. Vaccine hesitancy is also one of the main obstacles to the prevention and control of COVID-19 [115]. Previous studies showed that the major reasons for parents’ hesitancy to vaccinate their children included insufficient safety information and concerns about adverse effects and effectiveness [116, 117]. Our study suggested that COVID-19 vaccines have good safety and effectiveness among children and adolescents. This finding can help improve parents’ willingness to vaccinate their children, reduce vaccine hesitancy, and promote vaccination in children and adolescents.

For effectiveness, our results indicated that full vaccination with COVID-19 vaccines showed high VE against SARS-CoV-2 infection, COVID-19, and hospitalization due to COVID-19. However, the effectiveness was slightly lower than that in a previous meta-analysis without the Omicron variant [118]. Since the first report of the Omicron variant in South Africa on November 24, 2021, this variant has quickly become the predominant variant worldwide, and new and more contagious subtypes BA.4 and BA.5 have emerged [119]. The effectiveness of COVID-19 vaccines against the Omicron variant has become the focus. A meta-analysis involving 57 studies by March 4, 2022 showed that the VE against the Omicron variant (55.9%) was lower than that against the α variant (88.0%), β variant (73.0%), γ variant (63.0%), and Delta variant (77.8%) in the general population with complete vaccination, while the VE against the Omicron variant reached 80.8% after boost vaccination [120]. A prospective cohort study among 136,127 children aged 5–11 years found that the VE against symptomatic COVID-19 was 48% during the Omicron variant pandemic, lower than 90.7% during the Delta variant pandemic [17]. The lower VE might be related to the ability of Omicron variants to escape most neutralizing antibodies of SARS-CoV-2 [121, 122]. We also found that the VEs among children under 11 years were lower than those among adolescents aged 12–18 years. The potential reason is the later time of vaccination for children under 11 years. They were vaccinated when the Omicron variant was prevalent; therefore, the lower VEs among them might just reflect the lower VEs against this variant. In the future, more studies are needed to explore the effectiveness of COVID-19 vaccination and booster doses against Omicron variants among children and adolescents.

For safety, this study showed that the incidence rates of any adverse events, local adverse events, and systemic adverse events after the first and second doses of COVID-19 vaccines among children and adolescents were slightly higher than 30%, and the incidence rates of adverse events after vaccination with mRNA vaccines were higher than those after vaccination with inactivated vaccines. A meta-analysis involving 73,633 subjects in 14 RCT studies showed that the incidence rate of adverse events after COVID-19 vaccine vaccination was 36% [123]. A meta-analysis of six RCTs among participants aged 3–17 years found that the risk of total, local, and systemic adverse events in the mRNA vaccine group and adenovirus-vectored vaccine group significantly increased, while only the risk of local adverse events in the inactivated vaccine group was higher than that in the control group [108]. We also found that injection site pain, fatigue, and headache were the most common adverse events, similar to previous studies [118]. Additionally, myocarditis or pericarditis is a serious adverse event in children and adolescents, especially in male adolescents [124]. Between December 14, 2020, and July 16, 2021, 397 cases of myocarditis occurred among 8.9 million 12- to 17-year-old adolescents vaccinated with BNT162b2 in the United States [89]. Between December 2020 and August 2021, the incidence rates of myocarditis after the second dose of the BNT162b2 vaccine among adolescent males aged 12–15 and 16–17 years in the United States were 70.73/million doses and 105.86/million doses, respectively [124]. Currently, there is a lack of research on the long-term effects of COVID-19 vaccine-related myocarditis. In the future, more efforts are needed to strengthen the monitoring and follow-up of serious adverse events such as myocarditis or pericarditis and explore the treatment and management strategies of these adverse events.

However, there are some limitations in our study. First, heterogeneity between the included studies was somewhat high, making the results in need of future verification. Second, for immunogenicity, we only focused on the antibody seroconversion rate, not the antibody titer. Moreover, these studies did not use the same detection methods and reagents for SARS-CoV-2 antibodies, which may have an impact on the results. Third, for effectiveness, the vaccination status of most studies included in this meta-analysis was partially or fully vaccinated. More research is needed in the future to explore the effectiveness of booster doses of COVID-19 vaccines. Finally, for safety, the follow-up time of adverse events in most studies was within 30 days after vaccination, and there are only a few long-term follow-up studies.

In conclusion, as far as the current studies are concerned, COVID-19 vaccines have good immunogenicity, effectiveness, and safety among children and adolescents aged 2–18 years. COVID-19 vaccines can effectively prevent children and adolescents from being infected with SARS-CoV-2 and suffering from COVID-19. During the COVID-19 pandemic, we suggest that children and adolescents should be vaccinated as soon as possible to protect them and slow the spread of COVID-19. However, studies on the effectiveness of booster doses of COVID-19 vaccines among children and adolescents are currently insufficient. More basic research, clinical trials, and real-world studies are needed in the future to explore the immunogenicity, effectiveness, and safety of COVID-19 vaccines among children and adolescents.