key: cord-0254186-iurpluty authors: Lv, M.; Luo, X.; Shen, Q.; Lei, R.; Liu, X.; Liu, E.; Li, Q.; Chen, Y. title: Safety, Immunogenicity, and Efficacy of COVID-19 Vaccine in Children and Adolescents: A Systematic Review date: 2021-09-15 journal: nan DOI: 10.1101/2021.09.11.21262855 sha: 9c7d51f5cb303f75a6f748ed6a6718e7c5b03de4 doc_id: 254186 cord_uid: iurpluty Aim To identify the safety, immunogenicity, and protective efficacy of COVID-19 vaccine in children and adolescents. Methods We conducted a systematic review. Databases including PubMed, Web of Science, WHO COVID-19 database, and CNKI were searched on 23 July 2021. International Clinical Trials Registry Platform (ICTRP) was also searched to collect ongoing trials. We included published researches or ongoing clinical trials related to the safety, immunogenicity, and efficacy of COVID-19 vaccine in children or adolescents (aged [≤]18 years). Meta-analysis was performed if the consistency of the included studies was high. If not, descriptive analyses were performed. Results Eight published studies with 2851 children or adolescents and 28 ongoing clinical trials were included. Among eight published studies, two (25.0%) were RCTs, two (25.0%) case series, and four (50.0%) case reports. The results showed selected COVID-19 vaccines had a good safety profile in children and adolescents. Injection site pain, fatigue, headache, and chest pain were the most common adverse events. Some studies reported a few cases of myocarditis and pericarditis. Two RCTs showed that the immune response to BNT162b2 in adolescents aged 12-15 years was non-inferior to that in young people aged 16-25 years, while a stronger immune response was detected with 3g CoronaVac injection. Only one single RCT showed the efficacy of BNT162b2 was 100% (95% CI: 75.3 to 100). Of the 28 ongoing clinical trials, twenty-three are interventional studies. Fifteen countries are conducting interventional clinical trials of COVID-19 vaccines in children and adolescents. Among them, China (10, 43.5%) and United Stated (9, 39.1%) were the top two countries with the most trials. BNT162b2 was the most common vaccine, which is under testing. Conclusion Some of the COVID-19 vaccines have potential protective effects in children and adolescents, but awareness is needed to monitor possible adverse effects after injection. Clinical trials of the COVID-19 vaccine in children and adolescents with long follow-up, large sample size, and different vaccines are still urgently needed. Two reviewers (ML and XL) assessed the methodological quality of original studies to ensure the 1 reliability of the included studies to support our findings. We used the Risk of Bias tool 2 recommended by Cochrane Collaboration [15] to assess randomized trials with six domains of 3 bias (selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias). 4 We used the Newcastle-Ottawa Scale (NOS) to assess the quality of the included case-control and 5 cohort studies (selection, comparability, and exposure) [16] . We used the checklist proposed by 6 Murad et al [17] to assess case series and case reports (selection, ascertainment, causality and 7 reporting) and used the checklist proposed by the Joanna Briggs Institute (JBI) with eleven items 8 to assess cross-sectional study [18] . 9 2.6 Data analysis 1 0 For quantitative analysis, meta-analysis was planned if two or more separate studies were included, 1 1 and the heterogeneity was good. For dichotomous outcome data, the risk ratio (RR) or odds ratio 1 2 (OR) was used to calculate the effect measures. For continuous outcome data, the mean difference 1 3 (or difference in means) or standardized mean difference (SMD) was used. When the data are 1 4 conveniently available as summary statistics from each intervention group, the inverse-variance 1 5 method was implemented directly. Meanwhile, we planned to use both random-effects and 1 6 fixed-effects methods to perform the meta-analysis. Besides, a statistical test for heterogeneity 1 7 will be conducted and the Chi-squared (χ 2 ) test will be included in the forest plots. The preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 3 We assessed the methodological quality of included studies ( Table 2) . The overall quality of the 4 two RCTs was high and had low risk of bias. As for the rest case series and case reports, we didn't 5 assess items of "was there a challenge/rechallenge phenomenon" and "Was there a dose-response 6 effect?", because of not application. One study fulfilled five items, three fulfilled four items, and 7 one each fulfilled three and two items. The method of case selection for all case series and case 8 reports is unclear. Only one-third of the case reports and case series reported items "were other 9 alternative causes that may explain the observation ruled out?", and half study follow-up was not 1 0 long enough for outcomes to occur. 1 1 preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Marsha ll et al, All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 3 Results of two RCTs [20-21] showed that after COVID-19 vaccination in healthy children and 4 adolescents, the most common adverse event was injection site pain. Besides that, fever, headache, 5 and fatigue were also frequently reported. Most adverse events were not severe. No deaths case 6 was reported. With a similar result, a case series [22] included 13 patients with solid tumor 7 showed that injection site pain is also the most frequent adverse event (6 patients), which is 8 mild-to-moderate. Besides, a few diagnosed myocarditis and/or pericarditis cases related to COVID-19 vaccine were 1 1 reported in some studies. All cases occurred following the second dose of BNT162b mRNA 1 2 COVID-19 vaccination. We summarized the basic information of 28 cases from included studies 1 3 ( preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 3 Two RCTs indicated that COVID-19 vaccines (CoronaVac and BNT162b2) were immunogenic in 4 children and adolescents. Frenck et al. [20] reported that the immune response to BNT162b2 in 5 12-15 years old adolescents was noninferior to that in young adults (geometric mean ratio 6 (GMR)=1.75, 95%CI: 1.47~2.10), which even indicated a greater response in 12-15 years group. 7 Han et al. [19] found that in Phase 1, the seroconversion of neutralizing antibody after the second 8 dose was 100% both in 1.5μg group and 3.0μg group with GMT of 55·0 (95% CI 38.9-77.9) and 9 117·4 (87.8-157.0), respectively (P=0.0012). In Phase 2, the seroconversion was 96·8% (95%CI: 1 0 93·1-98·8) and 100% (95%CI: 98.0-100.0) in 1.5μg group and 3.0μg group (P=0.030). 1 1 preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.11.21262855 doi: medRxiv preprint inactivated (7 trials), protein subunit (4 trials), non replicating viral vector (4 trials), and 1 replicating viral vector (1 trial). Fifteen countries are conducting interventional clinical trials of COVID-19 vaccines in children 4 and adolescents. Among them, China (10, 43.5%) and United Stated (9, 39.1%) were the top two 5 countries with the most trials. BNT162b2 was the most common vaccine, which is under testing. 6 Figure 2 showed countries with ongoing clinical trials and vaccines used in trials. 7 8 Figure 2 ongoing COVID-19 vaccine trials in children and adolescents worldwide 9 (Notes: only interventional trials registered at ICTRP were shown in the figure. Color in the figure 1 0 indicated that the number of ongoing vaccine trials in children and adolescents per country.) 1 1 1 2 Similarly, when the COVID-19 outbreak emerged, researchers actively promoted the development 3 3 of a vaccine with the expectation that herd immunity could be reached after vaccination. Our 3 4 study showed that some vaccines have now been developed in pediatric populations with 3 5 associated RCTs and proven protective efficacy and safety, however, these two studies both have 3 6 limitations on small sample size and lack of long-term safety and immunogenicity data, for 3 7 example, myocarditis and pericarditis should be closely monitored. Most cases of myocarditis and 3 8 pericarditis associated with the COVID-19 vaccine were mild and mostly in males. According to 3 9 Washington State Department of Health data on immunization, Schauer et al. [26] estimated a 4 0 possible incidence of 0.008% in adolescents 16-17 years of age and 0.01% in those 12 through 15 4 1 years of age following the second dose. 4 2 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. vaccine did not increase the risk of KD following any of the above immunizations. Thus, children 2 0 and adolescents at high risk of severe COVID-19 or those with specific comorbidities should be 2 1 considered a priority of vaccination, and more research is needed to clarify whether the 2 2 COVID-19 vaccine can decrease the risks and bring benefits. according to an ongoing study [45] . At present, vaccines recommended in the guidelines are for 3 7 countries that have made vaccine progress among children or adolescents. We still need to wait for 3 8 more evidence from ongoing trials for some low-and middle-income countries with vaccine 3 9 shortages. With the conduction of more than twenty clinical trials, their findings may continue to 4 0 offer clues of better protecting younger generations away from COVID-19 . 4 1 4 2 However, public health authorities in countries that approved COVID-19 vaccine in children and 4 3 adolescents should also take more considerations into decision making. European Centre for 4 4 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.11.21262855 doi: medRxiv preprint Disease Prevention and Control proposed eight considerations on the overall potential public 1 health impact [46] . Opel et al. suggested nine criteria to consider when evaluating antigens for 2 inclusion in mandatory school immunization programs. Also, four additional criteria need to be 3 met for mandatory COVID-19 vaccination of children, but we currently know too little about the 4 performance of any COVID-19 vaccine or the epidemiology of SARS-CoV-2 in children to make 5 any definitive judgment about whether COVID-19 vaccine should be mandatory in children [11] . 6 Authorities could closely monitor and continually assess the benefits and potential risks of 7 vaccination in children and adolescents. In addition, the acceptability of the COVID-19 vaccine to 8 children, as well as to parents, is a major influencing factor on whether children can be vaccinated. 9 Studies have shown that approximately 80% of parents are reluctant to enroll their children in policies that actively encourage and support their children to be vaccinated against COVID-19. 3 0 This paper is, to the best of our knowledge, the first systematic review of the safety, 3 2 immunogenicity, and protective efficacy of COVID-19 vaccination in children and adolescents. 3 3 We systematically searched key databases as well as websites to conduct a comprehensive 3 4 evaluation and analysis of published studies and registry data records. However, this paper also 3 5 has some limitations. First, we didn't conduct a meta-analysis in this study, because of the great 3 6 heterogeneity among participants, outcomes, and study design. Second, this study only included 3 7 articles published in English. However, as the limited evidence published, it is reasonable to 3 8 expect that included studies up until this time covered most of the available knowledge. Finally, a 3 9 few studies that included children and adolescents didn't specify the age and outcome related to 4 0 children and adolescents. Given the limitation of time, we excluded these studies and didn't 4 1 contact authors to access original data. 4 2 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.11.21262855 doi: medRxiv preprint (Notes: only interventional trials registered at ICTRP were shown in the figure. Color in figure 6 indicated that the number of ongoing vaccine trials in children and adolescents per country) 7 8 9 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.11.21262855 doi: medRxiv preprint Full-text articles excluded (n =134) other study design (n =24) not children or adolescents (n = 36) study not related to COVID-19 vaccine (n = 73) study unavailable (n=1) Identification Screening Eligibility All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.11.21262855 doi: medRxiv preprint CDC. Vaccines: The Basics [2] The WORLD Bank.Population ages 0-14 (% of total population).